|
1
|
Fialková V, Ďúranová H, Borotová P, Klongová L, Grabacka M, Speváková I. Natural Stilbenes: Their Role in Colorectal Cancer Prevention, DNA Methylation, and Therapy. Nutr Cancer 2024; 76:760-788. [PMID: 38950568 DOI: 10.1080/01635581.2024.2364391] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2024] [Revised: 05/29/2024] [Accepted: 05/31/2024] [Indexed: 07/03/2024]
Abstract
The resistance of colorectal cancer (CRC) to conventional therapeutic modalities, such as radiation therapy and chemotherapy, along with the associated side effects, significantly limits effective anticancer strategies. Numerous epigenetic investigations have unveiled that naturally occurring stilbenes can modify or reverse abnormal epigenetic alterations, particularly aberrant DNA methylation status, offering potential avenues for preventing or treating CRC. By modulating the activity of the DNA methylation machinery components, phytochemicals may influence the various stages of CRC carcinogenesis through multiple molecular mechanisms. Several epigenetic studies, especially preclinical research, have highlighted the effective DNA methylation modulatory effects of stilbenes with minimal adverse effects on organisms, particularly in combination therapies for CRC. However, the available preclinical and clinical data regarding the effects of commonly encountered stilbenes against CRC are currently limited. Therefore, additional epigenetic research is warranted to explore the preventive potential of these phytochemicals in CRC development and to validate their therapeutic application in the prevention and treatment of CRC. This review aims to provide an overview of selected bioactive stilbenes as potential chemopreventive agents for CRC with a focus on their modulatory mechanisms of action, especially in targeting alterations in DNA methylation machinery in CRC.
Collapse
Affiliation(s)
- Veronika Fialková
- AgroBioTech Research Centre, Slovak University of Agriculture, Nitra, Slovakia
| | - Hana Ďúranová
- AgroBioTech Research Centre, Slovak University of Agriculture, Nitra, Slovakia
| | - Petra Borotová
- AgroBioTech Research Centre, Slovak University of Agriculture, Nitra, Slovakia
| | - Lucia Klongová
- AgroBioTech Research Centre, Slovak University of Agriculture, Nitra, Slovakia
| | - Maja Grabacka
- Department of Biotechnology and General Technology of Foods, Faculty of Food Technology, University of Agriculture, Cracow, Poland
| | - Ivana Speváková
- AgroBioTech Research Centre, Slovak University of Agriculture, Nitra, Slovakia
| |
Collapse
|
|
2
|
Lee S, Lee KY, Park JH, Kim DW, Oh HK, Oh ST, Jeon J, Lee D, Joe S, Chu HBK, Kang J, Lee JY, Cho S, Shim H, Kim SC, Lee HS, Kim YJ, Yang JO, Lee J, Kang SB. Exploring the DNA methylome of Korean patients with colorectal cancer consolidates the clinical implications of cancer-associated methylation markers. BMB Rep 2024; 57:161-166. [PMID: 37964634 PMCID: PMC10979344] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2023] [Revised: 07/26/2023] [Accepted: 11/13/2023] [Indexed: 11/16/2023] Open
Abstract
Aberrant DNA methylation plays a critical role in the development and progression of colorectal cancer (CRC), which has high incidence and mortality rates in Korea. Various CRC-associated methylation markers for cancer diagnosis and prognosis have been developed; however, they have not been validated for Korean patients owing to the lack of comprehensive clinical and methylome data. Here, we obtained reliable methylation profiles for 228 tumor, 103 adjacent normal, and two unmatched normal colon tissues from Korean patients with CRC using an Illumina Infinium EPIC array; the data were corrected for biological and experiment biases. A comparative methylome analysis confirmed the previous findings that hypermethylated positions in the tumor were highly enriched in CpG island and promoter, 5' untranslated, and first exon regions. However, hypomethylated positions were enriched in the open-sea regions considerably distant from CpG islands. After applying a CpG island methylator phenotype (CIMP) to the methylome data of tumor samples to stratify the CRC patients, we consolidated the previously established clinicopathological findings that the tumors with high CIMP signatures were significantly enriched in the right colon. The results showed a higher prevalence of microsatellite instability status and MLH1 methylation in tumors with high CMP signatures than in those with low or non-CIMP signatures. Therefore, our methylome analysis and dataset provide insights into applying CRC-associated methylation markers for Korean patients regarding cancer diagnosis and prognosis. [BMB Reports 2024; 57(3): 161-166].
Collapse
Affiliation(s)
- Sejoon Lee
- Precision Medicine Center, Seoul National University Bundang Hospital, Seongnam 13620, Korea
| | - Kil-yong Lee
- Department of Surgery, Uijeongbu St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Uijeongbu 11765, Korea
| | - Ji-Hwan Park
- Korea Bioinformation Center (KOBIC), Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Korea
- Department of Bioscience, University of Science and Technology (UST), Daejeon 34113, Korea
| | - Duck-Woo Kim
- Department of Surgery, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam 13620, Korea
| | - Heung-Kwon Oh
- Department of Surgery, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam 13620, Korea
| | - Seong-Taek Oh
- Department of Surgery, Uijeongbu St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Uijeongbu 11765, Korea
| | - Jongbum Jeon
- Korea Bioinformation Center (KOBIC), Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Korea
| | - Dongyoon Lee
- Korea Bioinformation Center (KOBIC), Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Korea
| | - Soobok Joe
- Korea Bioinformation Center (KOBIC), Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Korea
| | - Hoang Bao Khanh Chu
- Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Korea
| | - Jisun Kang
- Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Korea
| | - Jin-Young Lee
- Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Korea
| | - Sheehyun Cho
- Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Korea
| | - Hyeran Shim
- Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Korea
| | - Si-Cho Kim
- Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Korea
| | - Hong Seok Lee
- Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Korea
| | - Young-Joon Kim
- Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Korea
| | - Jin Ok Yang
- Korea Bioinformation Center (KOBIC), Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Korea
| | - Jaeim Lee
- Department of Surgery, Uijeongbu St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Uijeongbu 11765, Korea
| | - Sung-Bum Kang
- Department of Surgery, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam 13620, Korea
| |
Collapse
|
|
3
|
Lim SB, Joe S, Kim HJ, Lee JL, Park IJ, Yoon YS, Kim CW, Kim JH, Kim S, Lee JY, Shim H, Chu HBK, Cho S, Kang J, Kim SC, Lee HS, Kim YJ, Kim SY, Yu CS. Deciphering the DNA methylation landscape of colorectal cancer in a Korean cohort. BMB Rep 2023; 56:569-574. [PMID: 37605616 PMCID: PMC10618072 DOI: 10.5483/bmbrep.2023-0106] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Revised: 07/18/2023] [Accepted: 08/19/2023] [Indexed: 05/03/2025] Open
Abstract
Aberrant DNA methylation plays a pivotal role in the onset and progression of colorectal cancer (CRC), a disease with high incidence and mortality rates in Korea. Several CRC-associated diagnostic and prognostic methylation markers have been identified; however, due to a lack of comprehensive clinical and methylome data, these markers have not been validated in the Korean population. Therefore, in this study, we aimed to obtain the CRC methylation profile using 172 tumors and 128 adjacent normal colon tissues of Korean patients with CRC. Based on the comparative methylome analysis, we found that hypermethylated positions in the tumor were predominantly concentrated in CpG islands and promoter regions, whereas hypomethylated positions were largely found in the open-sea region, notably distant from the CpG islands. In addition, we stratified patients by applying the CpG island methylator phenotype (CIMP) to the tumor methylome data. This stratification validated previous clinicopathological implications, as tumors with high CIMP signatures were significantly correlated with the proximal colon, higher prevalence of microsatellite instability status, and MLH1 promoter methylation. In conclusion, our extensive methylome analysis and the accompanying dataset offers valuable insights into the utilization of CRC-associated methylation markers in Korean patients, potentially improving CRC diagnosis and prognosis. Furthermore, this study serves as a solid foundation for further investigations into personalized and ethnicity-specific CRC treatments. [BMB Reports 2023; 56(10): 569-574].
Collapse
Affiliation(s)
- Seok-Byung Lim
- Division of Colon and Rectal Surgery, Department of Surgery, Asan Medical Center, College of Medicine, Ulsan University, Seoul 05505, Korea
| | - Soobok Joe
- Korea Bioinformation Center (KOBIC), Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Korea
| | - Hyo-Ju Kim
- Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Korea
| | - Jong Lyul Lee
- Division of Colon and Rectal Surgery, Department of Surgery, Asan Medical Center, College of Medicine, Ulsan University, Seoul 05505, Korea
| | - In Ja Park
- Division of Colon and Rectal Surgery, Department of Surgery, Asan Medical Center, College of Medicine, Ulsan University, Seoul 05505, Korea
| | - Yong Sik Yoon
- Division of Colon and Rectal Surgery, Department of Surgery, Asan Medical Center, College of Medicine, Ulsan University, Seoul 05505, Korea
| | - Chan Wook Kim
- Division of Colon and Rectal Surgery, Department of Surgery, Asan Medical Center, College of Medicine, Ulsan University, Seoul 05505, Korea
| | - Jong-Hwan Kim
- Korea Bioinformation Center (KOBIC), Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Korea
| | - Sangok Kim
- Korea Bioinformation Center (KOBIC), Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Korea
| | - Jin-Young Lee
- Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Korea
| | - Hyeran Shim
- Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Korea
| | - Hoang Bao Khanh Chu
- Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Korea
| | - Sheehyun Cho
- Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Korea
| | - Jisun Kang
- Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Korea
| | - Si-Cho Kim
- Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Korea
| | - Hong Seok Lee
- Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Korea
| | - Young-Joon Kim
- Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Korea
- LepiDyne Co., Ltd., Seoul 04779, Korea
| | - Seon-Young Kim
- Korea Bioinformation Center (KOBIC), Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Korea
| | - Chang Sik Yu
- Division of Colon and Rectal Surgery, Department of Surgery, Asan Medical Center, College of Medicine, Ulsan University, Seoul 05505, Korea
| |
Collapse
|
|
4
|
Yu H, Wang X, Bai L, Tang G, Carter KT, Cui J, Huang P, Liang L, Ding Y, Cai M, Huang M, Liu H, Cao G, Gallinger S, Pai RK, Buchanan DD, Win AK, Newcomb PA, Wang J, Grady WM, Luo Y. DNA methylation profile in CpG-depleted regions uncovers a high-risk subtype of early-stage colorectal cancer. J Natl Cancer Inst 2023; 115:52-61. [PMID: 36171645 PMCID: PMC10089593 DOI: 10.1093/jnci/djac183] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Revised: 07/27/2022] [Accepted: 08/23/2022] [Indexed: 01/12/2023] Open
Abstract
BACKGROUND The current risk stratification system defined by clinicopathological features does not identify the risk of recurrence in early-stage (stage I-II) colorectal cancer (CRC) with sufficient accuracy. We aimed to investigate whether DNA methylation could serve as a novel biomarker for predicting prognosis in early-stage CRC patients. METHODS We analyzed the genome-wide methylation status of CpG loci using Infinium MethylationEPIC array run on primary tumor tissues and normal mucosa of early-stage CRC patients to identify potential methylation markers for prognosis. The machine-learning approach was applied to construct a DNA methylation-based prognostic classifier for early-stage CRC (MePEC) using the 4 gene methylation markers FAT3, KAZN, TLE4, and DUSP3. The prognostic value of the classifier was evaluated in 2 independent cohorts (n = 438 and 359, respectively). RESULTS The comprehensive analysis identified an epigenetic subtype with high risk of recurrence based on a group of CpG loci in the CpG-depleted region. In multivariable analysis, the MePEC classifier was independently and statistically significantly associated with time to recurrence in validation cohort 1 (hazard ratio = 2.35, 95% confidence interval = 1.47 to 3.76, P < .001) and cohort 2 (hazard ratio = 3.20, 95% confidence interval = 1.92 to 5.33, P < .001). All results were further confirmed after each cohort was stratified by clinicopathological variables and molecular subtypes. CONCLUSIONS We demonstrated the prognostic statistical significance of a DNA methylation profile in the CpG-depleted region, which may serve as a valuable source for tumor biomarkers. MePEC could identify an epigenetic subtype with high risk of recurrence and improve the prognostic accuracy of current clinical variables in early-stage CRC.
Collapse
Affiliation(s)
- Huichuan Yu
- Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
- Guangdong Institute of Gastroenterology, Guangzhou, Guangdong, China
| | - Xiaolin Wang
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
- Guangdong Institute of Gastroenterology, Guangzhou, Guangdong, China
| | - Liangliang Bai
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
- Guangdong Institute of Gastroenterology, Guangzhou, Guangdong, China
| | - Guannan Tang
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
- Guangdong Institute of Gastroenterology, Guangzhou, Guangdong, China
| | - Kelly T Carter
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
- Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA
| | - Ji Cui
- Departments of Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Pinzhu Huang
- Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Li Liang
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
- Guangdong Provincial Key Laboratory of Molecular Tumor Pathology, Guangzhou, Guangdong, China
| | - Yanqing Ding
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
- Guangdong Provincial Key Laboratory of Molecular Tumor Pathology, Guangzhou, Guangdong, China
| | - Muyan Cai
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
- Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Meijin Huang
- Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
- Guangdong Institute of Gastroenterology, Guangzhou, Guangdong, China
| | - Huanliang Liu
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
- Guangdong Institute of Gastroenterology, Guangzhou, Guangdong, China
| | - Guangwen Cao
- Department of Epidemiology, Second Military Medical University, Shanghai, China
| | - Steven Gallinger
- Wallace McCain Centre for Pancreatic Cancer, Department of Medical Oncology, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, ON, Canada
- PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, ON, Canada
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada
- Hepatobiliary/Pancreatic Surgical Oncology Program, University Health Network, Toronto, ON, Canada
| | - Rish K Pai
- Department of laboratory Medicine and Pathology, Mayo Clinic Arizona, Scottsdale, AZ, USA
| | - Daniel D Buchanan
- Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, Victoria, Australia
- University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Parkville, Victoria, Australia
- Genomic Medicine and Familial Cancer Centre, The Royal Melbourne Hospital, Parkville, Victoria, Australia
| | - Aung Ko Win
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Victoria, Australia
| | - Polly A Newcomb
- Department of Epidemiology, University of Washington School of Public Health, Seattle, WA, USA
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Jianping Wang
- Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
- Guangdong Institute of Gastroenterology, Guangzhou, Guangdong, China
| | - William M Grady
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
- Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA
| | - Yanxin Luo
- Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| |
Collapse
|
|
5
|
Angerilli V, Sabella G, Centonze G, Lonardi S, Bergamo F, Mangogna A, Pietrantonio F, Fassan M, Milione M. BRAF-mutated colorectal adenocarcinomas: Pathological heterogeneity and clinical implications. Crit Rev Oncol Hematol 2022; 172:103647. [PMID: 35248712 DOI: 10.1016/j.critrevonc.2022.103647] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Revised: 02/24/2022] [Accepted: 02/28/2022] [Indexed: 02/07/2023] Open
Abstract
Advances in molecular biology have markedly increased our understanding of the heterogeneous molecular landscape of colorectal cancer (CRC). Up to 15% of CRCs harbor the BRAF p.V600E somatic mutation (BRAFmt), a well-established negative prognostic marker in patients with metastatic CRC (mCRC). The BEACON CRC trial set a new standard of care in patients with progressive BRAFmt cancers, consisting of the combination of encorafenib and cetuximab. On these bases, BRAF mutational testing is now recommended in patients with mCRC. However, efforts are needed to further stratify patients carrying this mutation. Here, we discuss the heterogeneous pathologic and molecular landscape of BRAFmt CRCs, focusing on the promises and pitfalls of molecular diagnostics, on novel biomarkers to improve patients' stratification and on the current diagnostic scenario for CRC. We believe that a better stratification based on histopathological features and novel molecular biomarkers should be performed to optimize patient management and therapeutic decision-making.
Collapse
Affiliation(s)
| | - Giovanna Sabella
- Pathology Unit 1, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy
| | - Giovanni Centonze
- Pathology Unit 1, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy
| | - Sara Lonardi
- Oncology Unit 1, Department of Oncology, Veneto Institute of Oncology, IOV-IRCCS, Padua, Italy
| | - Francesca Bergamo
- Oncology Unit 1, Department of Oncology, Veneto Institute of Oncology, IOV-IRCCS, Padua, Italy
| | - Alessandro Mangogna
- Institute for Maternal and Child Health, IRCCS Burlo Garofalo, 34137 Trieste, Italy
| | | | - Matteo Fassan
- Department of Medicine, Surgical Pathology Unit, University of Padua, Italy; Veneto Institute of Oncology, IOV-IRCCS, Padua, Italy
| | - Massimo Milione
- Pathology Unit 1, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy.
| |
Collapse
|
|
6
|
Nakayama I, Hirota T, Shinozaki E. BRAF Mutation in Colorectal Cancers: From Prognostic Marker to Targetable Mutation. Cancers (Basel) 2020; 12:cancers12113236. [PMID: 33152998 PMCID: PMC7694028 DOI: 10.3390/cancers12113236] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Revised: 10/28/2020] [Accepted: 10/29/2020] [Indexed: 12/14/2022] Open
Abstract
Simple Summary Colorectal cancer with a mutation in an oncogene BRAF has paid much attention, as it comprises a population with dismal prognosis since two decades ago. A series of research since then has successfully changed this malignancy to be treatable with specific treatment. Here we thoroughly overviewed the basic, translational and clinical studies on colorectal cancer with BRAF mutation from a physician’s viewpoint. Accumulating lines of evidence suggest that intervention of the trunk cellular growth signal transduction pathway, namely EGFR-RAS-RAF-MEK-ERK pathway, is a clue to controlling this disease. However, it is not so straightforward. Recent studies unveil the diverse and plastic nature of this signal transduction pathway. We will introduce our endeavor to conquer this condition, based on newly arriving datasets, and discuss how we could open the door to future development of CRC treatment. Abstract The Raf murine sarcoma viral oncogene homolog B (BRAF) mutation is detected in 8–12% of metastatic colorectal cancers (mCRCs) and is strongly correlated with poor prognosis. The recent success of the BEACON CRC study and the development of targeted therapy have led to the determination of BRAF-mutated mCRCs as an independent category. For nearly two decades, a growing body of evidence has established the significance of the BRAF mutation in the development of CRC. Herein, we overview both basic and clinical data relevant to BRAF-mutated CRC, mainly focusing on the development of treatment strategies. This review is organized into eight sections, including clinicopathological features, molecular features, prognosis, the predictive value of anti-epidermal growth factor receptor (EGFR) therapy, resistant mechanisms for BRAF-targeting treatment, the heterogeneity of the BRAF mutation, future perspectives, and conclusions. A characterization of the canonical mitogen-activated protein kinase (MAPK) pathway is essential for controlling this malignancy, and the optimal combination of multiple interventions for treatments remains a point of debate.
Collapse
Affiliation(s)
- Izuma Nakayama
- Department of Gastroenterological Chemotherapy, Cancer Institute Hospital of the Japanese Foundation for Cancer Research (JFCR), Tokyo 135-8550, Japan
- Correspondence: (I.N.); (E.S.); Tel.: +81-3-3520-0111
| | - Toru Hirota
- Department of Experimental Pathology, Cancer Institute of the Japanese Foundation for Cancer Research (JFCR), Tokyo 135-8550, Japan;
| | - Eiji Shinozaki
- Department of Gastroenterological Chemotherapy, Cancer Institute Hospital of the Japanese Foundation for Cancer Research (JFCR), Tokyo 135-8550, Japan
- Correspondence: (I.N.); (E.S.); Tel.: +81-3-3520-0111
| |
Collapse
|
|
7
|
Bruni D, Angell HK, Galon J. The immune contexture and Immunoscore in cancer prognosis and therapeutic efficacy. Nat Rev Cancer 2020; 20:662-680. [PMID: 32753728 DOI: 10.1038/s41568-020-0285-7] [Citation(s) in RCA: 1014] [Impact Index Per Article: 202.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/22/2020] [Indexed: 12/15/2022]
Abstract
The international American Joint Committee on Cancer/Union for International Cancer Control (AJCC/UICC) tumour-node-metastasis (TNM) staging system provides the current guidelines for the classification of cancer. However, among patients within the same stage, the clinical outcome can be very different. More recently, a novel definition of cancer has emerged, implicating at all stages a complex and dynamic interaction between tumour cells and the immune system. This has enabled the definition of the immune contexture, representing the pre-existing immune parameters associated with patient survival. Even so, the role of distinct immune cell types in modulating cancer progression is increasingly emerging. An immune-based assay named the 'Immunoscore' was defined to quantify the in situ T cell infiltrate and was demonstrated to be superior to the AJCC/UICC TNM classification for patients with colorectal cancer. This Review provides a broad overview of the main immune parameters positively or negatively shaping cancer development, including the Immunoscore, and their prognostic and predictive value. The importance of the immune system in cancer control is demonstrated by the requirement for a pre-existing intratumour adaptive immune response for effective immunotherapies, such as checkpoint inhibitors. Finally, we discuss how the combination of multiple immune parameters, rather than individual ones, might increase prognostic and/or predictive power.
Collapse
Affiliation(s)
- Daniela Bruni
- INSERM, Laboratory of Integrative Cancer Immunology; Équipe Labellisée Ligue Contre le Cancer; Sorbonne Université; Sorbonne Paris Cité; Université de Paris; Centre de Recherche des Cordeliers, Paris, France
| | - Helen K Angell
- Translational Medicine, Oncology R&D, AstraZeneca, Cambridge, UK
| | - Jérôme Galon
- INSERM, Laboratory of Integrative Cancer Immunology; Équipe Labellisée Ligue Contre le Cancer; Sorbonne Université; Sorbonne Paris Cité; Université de Paris; Centre de Recherche des Cordeliers, Paris, France.
| |
Collapse
|
|
8
|
Fanelli GN, Dal Pozzo CA, Depetris I, Schirripa M, Brignola S, Biason P, Balistreri M, Dal Santo L, Lonardi S, Munari G, Loupakis F, Fassan M. The heterogeneous clinical and pathological landscapes of metastatic Braf-mutated colorectal cancer. Cancer Cell Int 2020; 20:30. [PMID: 32015690 PMCID: PMC6990491 DOI: 10.1186/s12935-020-1117-2] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2019] [Accepted: 01/20/2020] [Indexed: 12/24/2022] Open
Abstract
Colorectal cancer (CRC) is a complex and molecularly heterogeneous disease representing one of the most frequent causes of cancer-related death worldwide. About 8-15% of CRCs harbor a mutation in BRAF gene, a proto-oncogene involved in cell proliferation, differentiation and survival through the MAPK signaling cascade. The acquisition of BRAF mutation is an early event in the "serrated" CRC carcinogenetic pathway and is associated with specific and aggressive clinico-pathological and molecular features. Despite that the presence of BRAF mutation is a well-recognized negative prognostic biomarker in metastatic CRC (mCRC), a great heterogeneity in survival outcome characterizes these patients, due to the complex, and still not completely fully elucidated, interactions between the clinical, genetic and epigenetic landscape of BRAF mutations. Because of the great aggressiveness of BRAF-mutated mCRCs, only 60% of patients can receive a second-line chemotherapy; so intensive combined and tailored first-line approach could be a potentially effective strategy, but to minimize the selective pressure of resistant clones and to reduce side effects, a better stratification of patients bearing BRAF mutations is needed.
Collapse
Affiliation(s)
- Giuseppe Nicolò Fanelli
- Surgical Pathology Unit, Department of Medicine (DIMED), University of Padua, via Gabelli 61, 35121 Padua, Italy
| | - Carlo Alberto Dal Pozzo
- Surgical Pathology Unit, Department of Medicine (DIMED), University of Padua, via Gabelli 61, 35121 Padua, Italy
| | - Ilaria Depetris
- Department of Oncology, Veneto Institute of Oncology IOV–IRCCS, Padua, Italy
| | - Marta Schirripa
- Department of Oncology, Veneto Institute of Oncology IOV–IRCCS, Padua, Italy
| | - Stefano Brignola
- Surgical Pathology Unit, Department of Medicine (DIMED), University of Padua, via Gabelli 61, 35121 Padua, Italy
| | - Paola Biason
- Department of Oncology, Veneto Institute of Oncology IOV–IRCCS, Padua, Italy
| | - Mariangela Balistreri
- Surgical Pathology Unit, Department of Medicine (DIMED), University of Padua, via Gabelli 61, 35121 Padua, Italy
| | - Luca Dal Santo
- Surgical Pathology Unit, Department of Medicine (DIMED), University of Padua, via Gabelli 61, 35121 Padua, Italy
| | - Sara Lonardi
- Department of Oncology, Veneto Institute of Oncology IOV–IRCCS, Padua, Italy
| | - Giada Munari
- Surgical Pathology Unit, Department of Medicine (DIMED), University of Padua, via Gabelli 61, 35121 Padua, Italy
- Department of Oncology, Veneto Institute of Oncology IOV–IRCCS, Padua, Italy
| | - Fotios Loupakis
- Department of Oncology, Veneto Institute of Oncology IOV–IRCCS, Padua, Italy
| | - Matteo Fassan
- Surgical Pathology Unit, Department of Medicine (DIMED), University of Padua, via Gabelli 61, 35121 Padua, Italy
| |
Collapse
|
|
9
|
Advani SM, Advani PS, Brown DW, DeSantis SM, Korphaisarn K, VonVille HM, Bressler J, Lopez DS, Davis JS, Daniel CR, Sarshekeh AM, Braithwaite D, Swartz MD, Kopetz S. Global differences in the prevalence of the CpG island methylator phenotype of colorectal cancer. BMC Cancer 2019; 19:964. [PMID: 31623592 PMCID: PMC6796359 DOI: 10.1186/s12885-019-6144-9] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2019] [Accepted: 09/10/2019] [Indexed: 02/07/2023] Open
Abstract
Background CpG Island Methylator Phenotype (CIMP) is an epigenetic phenotype in CRC characterized by hypermethylation of CpG islands in promoter regions of tumor suppressor genes, leading to their transcriptional silencing and loss of function. While the prevalence of CRC differs across geographical regions, no studies have compared prevalence of CIMP-High phenotype across regions. The purpose of this project was to compare the prevalence of CIMP across geographical regions after adjusting for variations in methodologies to measure CIMP in a meta-analysis. Methods We searched PubMed, Medline, and Embase for articles focusing on CIMP published from 2000 to 2018. Two reviewers independently identified 111 articles to be included in final meta-analysis. We classified methods used to quantify CIMP into 4 categories: a) Classical (MINT marker) Panel group b) Weisenberg-Ogino (W-O) group c) Human Methylation Arrays group and d) Miscellaneous group. We compared the prevalence of CIMP across geographical regions after correcting for methodological variations using meta-regression techniques. Results The pooled prevalence of CIMP-High across all studies was 22% (95% confidence interval:21–24%; I2 = 94.75%). Pooled prevalence of CIMP-H across Asia, Australia, Europe, North America and South America was 22, 21, 21, 27 and 25%, respectively. Meta-regression analysis identified no significant differences in the prevalence of CIMP-H across geographical regions after correction for methodological variations. In exploratory analysis, we observed variations in CIMP-H prevalence across countries. Conclusion Although no differences were found for CIMP-H prevalence across countries, further studies are needed to compare the influence of demographic, lifestyle and environmental factors in relation to the prevalence of CIMP across geographical regions.
Collapse
Affiliation(s)
- Shailesh Mahesh Advani
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 0426, Houston, TX, 77030, USA. .,Cancer Prevention and Control Program, Lombardi Comprehensive Cancer Center, Georgetown University, Washington DC, 20007, USA. .,Social Behavioral Research Branch, National Human Genome Research Institute, National Institute of Health, Bethesda, MD, 20892, USA.
| | - Pragati Shailesh Advani
- Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Institutes of Health, National Cancer Institute, Rockville, MD, 20850, USA
| | - Derek W Brown
- Department of Biostatistics and Data Science, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA
| | - Stacia M DeSantis
- Department of Biostatistics and Data Science, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA
| | - Krittiya Korphaisarn
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 0426, Houston, TX, 77030, USA
| | - Helena M VonVille
- Library, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA
| | - Jan Bressler
- Department of Epidemiology, Human Genetics and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA
| | - David S Lopez
- Division of Urology- UTHealth McGovern Medical School, Houston, TX, 77030, USA.,Department of Preventive Medicine and Community Health, UTMB Health-School of Medicine, Galveston, TX, 77555-1153, USA
| | - Jennifer S Davis
- Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Carrie R Daniel
- Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Amir Mehrvarz Sarshekeh
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 0426, Houston, TX, 77030, USA
| | - Dejana Braithwaite
- Cancer Prevention and Control Program, Lombardi Comprehensive Cancer Center, Georgetown University, Washington DC, 20007, USA
| | - Michael D Swartz
- Department of Biostatistics and Data Science, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA
| | - Scott Kopetz
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 0426, Houston, TX, 77030, USA.
| |
Collapse
|
|
10
|
Loupakis F, Biason P, Prete AA, Cremolini C, Pietrantonio F, Pella N, Dell'Aquila E, Sperti E, Zichi C, Intini R, Dadduzio V, Schirripa M, Bergamo F, Antoniotti C, Morano F, Cortiula F, De Maglio G, Rimassa L, Smiroldo V, Calvetti L, Aprile G, Salvatore L, Santini D, Munari G, Salmaso R, Guzzardo V, Mescoli C, Lonardi S, Rugge M, Zagonel V, Di Maio M, Fassan M. CK7 and consensus molecular subtypes as major prognosticators in V600EBRAF mutated metastatic colorectal cancer. Br J Cancer 2019; 121:593-599. [PMID: 31474758 PMCID: PMC6889398 DOI: 10.1038/s41416-019-0560-0] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2019] [Accepted: 08/09/2019] [Indexed: 11/09/2022] Open
Abstract
BACKGROUND V600EBRAF mutated metastatic colorectal cancer (mCRC) is a subtype (10%) with overall poor prognosis, but the clinical experience suggests a great heterogeneity in survival. It is still unexplored the real distribution of traditional and innovative biomarkers among V600EBRAF mutated mCRC and which is their role in the improvement of clinical prediction of survival outcomes. METHODS Data and tissue specimens from 155 V600EBRAF mutated mCRC patients treated at eight Italian Units of Oncology were collected. Specimens were analysed by means of immunohistochemistry profiling performed on tissue microarrays. Primary endpoint was overall survival (OS). RESULTS CDX2 loss conferred worse OS (HR = 1.72, 95%CI 1.03-2.86, p = 0.036), as well as high CK7 expression (HR = 2.17, 95%CI 1.10-4.29, p = 0.026). According to Consensus Molecular Subtypes (CMS), CMS1 patients had better OS compared to CMS2-3/CMS4 (HR = 0.37, 95%CI 0.19-0.71, p = 0.003). Samples showing less TILs had worse OS (HR = 1.72, 95%CI 1.16-2.56, p = 0.007). Progression-free survival analyses led to similar results. At multivariate analysis, CK7 and CMS subgrouping retained their significant correlation with OS. CONCLUSION The present study provides new evidence on how several well-established biomarkers perform in a homogenousV600EBRAF mutated mCRC population, with important and independent information added to standard clinical prognosticators. These data could be useful to inform further translational research, for patients' stratification in clinical trials and in routine clinical practice to better estimate patients' prognosis.
Collapse
Affiliation(s)
- Fotios Loupakis
- Department of Oncology, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy.
| | - Paola Biason
- Department of Oncology, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy
| | | | - Chiara Cremolini
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
| | - Filippo Pietrantonio
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
- Department of Oncology and Hemato-oncology, University of Milan, Milan, Italy
| | - Nicoletta Pella
- Department of Oncology, University and General Hospital, Udine, Italy
| | - Emanuela Dell'Aquila
- Department of Medical Oncology, Campus Bio-Medico University of Rome, Rome, Italy
| | - Elisa Sperti
- Department of Oncology, University of Turin at Umberto I "Ordine Mauriziano" Hospital, Turin, Italy
| | - Clizia Zichi
- Department of Oncology, University of Turin at Umberto I "Ordine Mauriziano" Hospital, Turin, Italy
| | - Rossana Intini
- Department of Oncology, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy
| | - Vincenzo Dadduzio
- Department of Oncology, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy
| | - Marta Schirripa
- Department of Oncology, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy
| | - Francesca Bergamo
- Department of Oncology, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy
| | - Carlotta Antoniotti
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
| | - Federica Morano
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Francesco Cortiula
- Department of Oncology, University and General Hospital, Udine, Italy
- Department of Medicine (DAME), University of Udine, Udine, Italy
| | | | - Lorenza Rimassa
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, Humanitas Clinical and Research Center-IRCCS Rozzano, Milan, Italy
| | - Valeria Smiroldo
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, Humanitas Clinical and Research Center-IRCCS Rozzano, Milan, Italy
| | - Lorenzo Calvetti
- Department of Oncology, General Hospital San Bortolo, Unità Locale Socio-Sanitaria 8 Berica, Vicenza, Italy
| | - Giuseppe Aprile
- Department of Oncology, General Hospital San Bortolo, Unità Locale Socio-Sanitaria 8 Berica, Vicenza, Italy
| | - Lisa Salvatore
- Unit of Oncology, Polyclinic GB Rossi, AOUI, Verona, Italy
- U.O.C Oncologia, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Roma, Italy
| | - Daniele Santini
- Department of Medical Oncology, Campus Bio-Medico University of Rome, Rome, Italy
| | - Giada Munari
- Department of Oncology, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy
- Surgical Pathology & Cytopathology Unit, Department of Medicine (DIMED), University of Padua, Padua, Italy
| | - Roberta Salmaso
- Surgical Pathology & Cytopathology Unit, Department of Medicine (DIMED), University of Padua, Padua, Italy
| | - Vincenza Guzzardo
- Surgical Pathology & Cytopathology Unit, Department of Medicine (DIMED), University of Padua, Padua, Italy
| | - Claudia Mescoli
- Surgical Pathology & Cytopathology Unit, Department of Medicine (DIMED), University of Padua, Padua, Italy
| | - Sara Lonardi
- Department of Oncology, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy
| | - Massimo Rugge
- Surgical Pathology & Cytopathology Unit, Department of Medicine (DIMED), University of Padua, Padua, Italy
| | - Vittorina Zagonel
- Department of Oncology, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy
| | - Massimo Di Maio
- Department of Oncology, University of Turin at Umberto I "Ordine Mauriziano" Hospital, Turin, Italy
| | - Matteo Fassan
- Surgical Pathology & Cytopathology Unit, Department of Medicine (DIMED), University of Padua, Padua, Italy.
| |
Collapse
|
|
11
|
Loss of SATB2 Expression in Colorectal Carcinoma Is Associated With DNA Mismatch Repair Protein Deficiency and BRAF Mutation. Am J Surg Pathol 2019; 42:1409-1417. [PMID: 30001238 DOI: 10.1097/pas.0000000000001116] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The special AT-rich sequence binding protein (SATB2) has been reported to be a specific immunohistochemical marker for colorectal carcinoma; however, correlation of SATB2 expression with molecular alterations commonly assessed in colorectal carcinoma has not been performed. We examined the immunohistochemical expression of SATB2 in 586 adenocarcinomas of the gastrointestinal (GI) tract and pancreas to assess its utility in diagnosis and analyze the clinicopathologic and molecular characteristics of colorectal carcinoma stratified by SATB2 expression. SATB2 and CDX2 expression were evaluated in 266 adenocarcinomas of lower GI tract origin (246 colorectal and 20 appendiceal mucinous), 208 adenocarcinomas of upper GI tract and small intestinal origin (74 esophagus/esophagogastric junction, 103 stomach, 20 duodenal, and 11 jejunoileal), and 112 pancreatic ductal adenocarcinomas. SATB2 expression was more frequently identified in adenocarcinomas of lower GI tract origin (222/266, 83%) compared with upper GI tract, small intestinal, or pancreatic origin (26/320, 8%) (P<0.001). Compared with CDX2 alone, dual positive expression for SATB2 and CDX2 (SATB2/CDX2) has a significantly higher specificity for adenocarcinoma of lower GI tract origin (94% vs. 57%, P<0.001). In colorectal carcinoma, loss of SATB2 expression was more frequently observed in DNA mismatch repair (MMR) protein deficient tumors (31%) compared with MMR protein proficient tumors (13%) (P<0.01). A BRAF V600E mutation was more frequently identified in colorectal carcinomas with loss of SATB2 expression compared with those with positive SATB2 expression (29% vs. 3%) (P<0.001). In summary, SATB2 expression is a relatively specific marker of lower GI tract origin; however, loss of SATB2 expression is more commonly seen in colorectal carcinoma with MMR protein deficiency and BRAF mutation.
Collapse
|
|
12
|
Ma C, Olevian D, Miller C, Herbst C, Jayachandran P, Kozak MM, Chang DT, Pai RK. SATB2 and CDX2 are prognostic biomarkers in DNA mismatch repair protein deficient colon cancer. Mod Pathol 2019; 32:1217-1231. [PMID: 30962505 DOI: 10.1038/s41379-019-0265-1] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2018] [Revised: 02/14/2019] [Accepted: 02/14/2019] [Indexed: 12/23/2022]
Abstract
DNA mismatch repair protein deficient colon cancer frequently displays reduced CDX2 expression, and recent literature has suggested that negative CDX2 expression is a poor prognostic biomarker in colon cancer. We have recently demonstrated that SATB2 is an immunohistochemical marker that is complementary to CDX2. Using a tissue microarray approach, we evaluated SATB2 and CDX2 immunohistochemical expression in 514 patients with colonic adenocarcinoma including 146 with mismatch repair protein deficient tumors and correlated expression with histopathologic variables, molecular alterations, and survival. Overall, SATB2-negative and/or CDX2-negative expression was identified in 33% of mismatch repair protein deficient tumors compared with only 15% of mismatch repair protein proficient tumors (p < 0.001) and in 36% of BRAF V600E mutated compared with only 13% of BRAF wild-type tumors (p < 0.001). Both SATB2-negative and CDX2-negative colonic adenocarcinomas more often displayed lymphatic invasion, venous invasion, and perineural invasion (all with p < 0.05). SATB2-negative expression was also more frequently identified in tumors with mucinous or signet ring cell differentiation (p < 0.01 for both). In a multivariable analysis of survival in patients with mismatch repair protein deficient tumors (n = 131), only tumor stage (p = 0.01) and SATB2-negative and/or CDX2-negative expression (p = 0.009) independently predicted disease-specific survival. Of the 99 patients with stage II or III mismatch repair protein deficient tumors, death from disease only occurred in patients with either SATB2-negative or CDX2-negative tumors, and no patients with SATB2-positive/CDX2-positive tumors developed recurrence or died of disease. SATB2 and CDX2 expression had no effect on patient survival in mismatch repair protein proficient, BRAF-mutated, or KRAS-mutated tumors. In summary, our results suggest that SATB2 and CDX2 are prognostic biomarkers in patients with mismatch repair protein deficient colon cancer and that inclusion of SATB2 and CDX2 immunohistochemistry may be helpful as part of a comprehensive pathologic risk assessment in mismatch repair protein deficient colon cancer.
Collapse
Affiliation(s)
- Changqing Ma
- Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Dane Olevian
- Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Caitlyn Miller
- Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Cameron Herbst
- Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Priya Jayachandran
- Department of Radiation Oncology, Stanford University, Stanford, CA, USA
| | - Margaret M Kozak
- Department of Radiation Oncology, Stanford University, Stanford, CA, USA
| | - Daniel T Chang
- Department of Radiation Oncology, Stanford University, Stanford, CA, USA
| | - Reetesh K Pai
- Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
| |
Collapse
|
|
13
|
CDX2 and Muc2 immunohistochemistry as prognostic markers in stage II colon cancer. Hum Pathol 2019; 90:70-79. [PMID: 31121192 DOI: 10.1016/j.humpath.2019.05.005] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2019] [Revised: 05/09/2019] [Accepted: 05/14/2019] [Indexed: 12/31/2022]
Abstract
The treatment for colorectal cancer is largely surgical followed by adjuvant chemotherapy in high-risk cases. In patients with stage II cancer, there is no clear benefit for chemotherapy, and the current tools for assessment of risk are inadequate. A recent study identified that colorectal cancer with a gene signature similar to undifferentiated colonic stem cells was associated with a worse outcome. It was later shown that loss of CDX2 detected by immunohistochemistry (IHC) alone resulted in a worse prognosis and that this could be used to predict patients who would benefit from chemotherapy. Having observed that CDX2 expression can be patchy, we elected to validate these prior results for clinical practice using whole-slide IHC. The pathology of all cases was reviewed, and 3 blocks were selected for CDX2 IHC. We also expanded the panel beyond CDX2 to assess whether other markers in the gene signature including CDX1, Muc2, GPX2, and villin could better predict outcome. Among 210 cases, CDX2 expression was diffusely lost in 11% and focally lost in 23% of cases. There was no difference in survival based on CDX2 expression, but Muc2 loss was associated with reduced survival (hazard ratio, 3.32; 95% confidence interval, 1.20 to 9.20). No significant differences in outcome were identified based on CDX1, GPX2, or villin expression. In keeping with this, assessment of The Cancer Genome Atlas gene expression data demonstrated that decreased Muc2 expression was associated with reduced overall survival. Our results with whole-slide IHC are different from the previous studies and caution against the use of CDX2 in isolation as a prognostic marker in clinical practice. We have identified that loss of Muc2 is associated with reduced survival. This supports the use of the colonic differentiation gene expression signature to identify high-risk patients but cautions against the use of any one IHC-based marker in isolation.
Collapse
|
|
14
|
Xu W, Zhu Y, Shen W, Ding W, Wu T, Guo Y, Chen X, Zhou M, Chen Y, Cui L, Du P. Combination of CDX2 expression and T stage improves prognostic prediction of colorectal cancer. J Int Med Res 2019; 47:1829-1842. [PMID: 30616445 PMCID: PMC6567745 DOI: 10.1177/0300060518819620] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2018] [Accepted: 11/22/2018] [Indexed: 12/25/2022] Open
Abstract
OBJECTIVE Prognostic prediction of colorectal cancer (CRC) remains challenging because of its heterogeneity. Aberrant expression of caudal-type homeobox transcription factor 2 (CDX2) is strongly correlated with the prognosis of CRC. METHODS Tissue samples of patients with CRC who underwent surgery in Xinhua Hospital (Shanghai, China) from January 2010 to January 2013 were collected. CDX2 expression was semiquantitatively evaluated via immunohistochemistry. RESULTS In total, 138 patients were enrolled in this study from a prospectively maintained institutional cancer database. The median follow-up duration was 57.5 months (interquartile range, 17.0-71.0 months). In the Cox proportional hazards model, low CDX2 expression combined with stage T4 CRC was significantly the worst prognostic factor for disease-free survival (hazard ratio = 7.020, 95% confidence interval = 3.922-12.564) and overall survival (hazard ratio = 5.176, 95% CI = 3.237-10.091). In the Kaplan-Meier survival analysis, patients with low CDX2 expression and stage T4 CRC showed significantly worse disease-free survival and overall survival than those with low CDX2 expression alone. CONCLUSION CDX2 expression combined with the T stage was more accurate for predicting the prognosis of CRC. Determining the prognosis of CRC using more than one variable is valuable in developing appropriate treatment and follow-up strategies.
Collapse
Affiliation(s)
- Weimin Xu
- Department of Colorectal Surgery, Xin-Hua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Yilian Zhu
- Department of Colorectal Surgery, Xin-Hua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Wei Shen
- Department of Colorectal Surgery, Xin-Hua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Wenjun Ding
- Department of Colorectal Surgery, Xin-Hua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Tingyu Wu
- Department of Colorectal Surgery, Xin-Hua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Yuegui Guo
- Department of Colorectal Surgery, Xin-Hua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Xiaobing Chen
- Department of Oncology, Henan Cancer Hospital, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, China
| | - Mingxia Zhou
- Department of Gastroenterology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yingwei Chen
- Department of Gastroenterology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Long Cui
- Department of Colorectal Surgery, Xin-Hua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Peng Du
- Department of Colorectal Surgery, Xin-Hua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| |
Collapse
|
|
15
|
Khan M, Loree JM, Advani SM, Ning J, Li W, Pereira AAL, Lam M, Raghav K, Morris VK, Broaddus R, Maru D, Overman MJ, Kopetz S. Prognostic Implications of Mucinous Differentiation in Metastatic Colorectal Carcinoma Can Be Explained by Distinct Molecular and Clinicopathologic Characteristics. Clin Colorectal Cancer 2018; 17:e699-e709. [PMID: 30205948 PMCID: PMC6588353 DOI: 10.1016/j.clcc.2018.07.005] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2018] [Revised: 07/09/2018] [Accepted: 07/11/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND The mucinous histologic subtype accounts for 5% to 20% of colorectal cancer (CRC) cases but remains poorly characterized. The present study characterized the baseline characteristics, mutational profile, and clinical outcomes of patients diagnosed with mucinous CRC. MATERIALS AND METHODS We identified 1877 patients with metastatic CRC with available histologic findings and molecular profiling and summarized the baseline clinical and pathologic characteristics and overall survival (OS) stratified by the histologic type. The data from separate cohorts with consensus molecular subtype (CMS) and CpG island methylator information were also summarized. RESULTS The mucinous histologic type was found in 277 of the 1877 patients (14.8%) and was associated with an increased prevalence of microsatellite instability (P < .001) and a right-sided primary (P < .001). An increased frequency of CMS1 (microsatellite instability immune) and lower rates of CMS2 (canonical) were identified, with mucinous compared with nonmucinous adenocarcinoma (P < .0001). Mutations in SMAD4 (P < .001), GNAS (P < .001), ERBB2 (P = .02), BRAF (P < .001), and KRAS (P < .001) occurred at greater frequencies in the mucinous CRC cases, and TP53 (P < .001), APC (P < .001), and NRAS mutations (P = .03) were less common. Univariate (hazard ratio [HR], 1.38; 95% confidence interval [CI], 1.17-1.63; P < .001) and multivariate analysis (HR, 1.36; 95% CI, 1.12-1.64; P = .002) demonstrated that the mucinous histologic type is associated with worse OS. The features associated with the mucinous histologic subtype were independent predictors for shorter OS, including BRAF (HR, 1.74; 95% CI, 1.35-2.25; P < .001) and KRAS (HR, 1.42; 95% CI, 1.22-1.65; P < .001) mutations, right-sided location (HR, 1.20; 95% CI, 1.04-1.39; P = .01), and synchronous metastases (HR, 2.92; 95% CI, 2.49-3.42; P < .001). CONCLUSION Compared with nonmucinous adenocarcinoma, the mucinous histologic type is associated with a worse prognosis, even when controlling for known prognostic features. This unique biologic behavior should be considered in the treatment and prognostic assessment of patients with CRC.
Collapse
Affiliation(s)
- Maliha Khan
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Jonathan M Loree
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Shailesh M Advani
- Department of Oncology, Georgetown Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC
| | - Jing Ning
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Wen Li
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Allan A L Pereira
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Michael Lam
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Kanwal Raghav
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Van K Morris
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Russell Broaddus
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Dipen Maru
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Michael J Overman
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Scott Kopetz
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX.
| |
Collapse
|
|
16
|
How the BRAF V600E Mutation Defines a Distinct Subgroup of Colorectal Cancer: Molecular and Clinical Implications. Gastroenterol Res Pract 2018; 2018:9250757. [PMID: 30598662 PMCID: PMC6287148 DOI: 10.1155/2018/9250757] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2018] [Accepted: 10/18/2018] [Indexed: 12/13/2022] Open
Abstract
The BRAF oncogene is an integral component of the MAP kinase pathway, and an activating V600E mutation occurs in 15% of sporadic colorectal cancer. This is an early event in serrated pathway tumourigenesis, and the BRAF V600E has been commonly associated with the CpG island methylator phenotype, microsatellite instability (MSI), and a consistent clinical presentation including a proximal location and predilection for elderly females. A proportion of the BRAF mutant lesions remain as microsatellite stable (MSS), and in contrast to the MSI cancers, they have an aggressive phenotype and correlate with poor patient outcomes. Recent studies have found that they have clinical and molecular features of both the BRAF mutant/MSI and the conventional BRAF wild-type cancers and comprise a distinct colorectal cancer subgroup. This review highlights the importance of the BRAF mutation occurring in colorectal cancer stratified for molecular background and discusses its prognostic and clinical significance.
Collapse
|
|
17
|
Graule J, Uth K, Fischer E, Centeno I, Galván JA, Eichmann M, Rau TT, Langer R, Dawson H, Nitsche U, Traeger P, Berger MD, Schnüriger B, Hädrich M, Studer P, Inderbitzin D, Lugli A, Tschan MP, Zlobec I. CDX2 in colorectal cancer is an independent prognostic factor and regulated by promoter methylation and histone deacetylation in tumors of the serrated pathway. Clin Epigenetics 2018; 10:120. [PMID: 30257705 PMCID: PMC6158822 DOI: 10.1186/s13148-018-0548-2] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2018] [Accepted: 08/27/2018] [Indexed: 01/01/2023] Open
Abstract
Background In colorectal cancer, CDX2 expression is lost in approximately 20% of cases and associated with poor outcome. Here, we aim to validate the clinical impact of CDX2 and investigate the role of promoter methylation and histone deacetylation in CDX2 repression and restoration. Methods CDX2 immunohistochemistry was performed on multi-punch tissue microarrays (n = 637 patients). Promoter methylation and protein expression investigated on 11 colorectal cancer cell lines identified two CDX2 low expressors (SW620, COLO205) for treatment with decitabine (DNA methyltransferase inhibitor), trichostatin A (TSA) (general HDAC inhibitor), and LMK-235 (specific HDAC4 and HDAC5 inhibitor). RNA and protein levels were assessed. HDAC5 recruitment to the CDX2 gene promoter region was tested by chromatin immunoprecipitation. Results Sixty percent of tumors showed focal CDX2 loss; 5% were negative. Reduced CDX2 was associated with lymph node metastasis (p = 0.0167), distant metastasis (p = 0.0123), and unfavorable survival (multivariate analysis: p = 0.0008; HR (95%CI) 0.922 (0.988–0.997)) as well as BRAFV600E, mismatch repair deficiency, and CpG island methylator phenotype. Decitabine treatment alone induced CDX2 RNA and protein with values from 2- to 25-fold. TSA treatment ± decitabine also led to successful restoration of RNA and/or protein. Treatment with LMK-235 alone had marked effects on RNA and protein levels, mainly in COLO205 cells that responded less to decitabine. Lastly, decitabine co-treatment was more effective than LMK-235 alone at restoring CDX2. Conclusion CDX2 loss is an adverse prognostic factor and linked to molecular features of the serrated pathway. RNA/protein expression is restored in CDX2 low-expressing CRC cell lines by demethylation and HDAC inhibition. Importantly, our data underline HDAC4 and HDAC5 as new epigenetic CDX2 regulators that warrant further investigation. Electronic supplementary material The online version of this article (10.1186/s13148-018-0548-2) contains supplementary material, which is available to authorized users.
Collapse
Affiliation(s)
- Janina Graule
- Institute of Pathology, University of Bern, Murtenstrasse 31, Room L310, 3008, Bern, Switzerland
| | - Kristin Uth
- Institute of Pathology, University of Bern, Murtenstrasse 31, Room L310, 3008, Bern, Switzerland.,Graduate School for Cellular and Biomedical Sciences, University of Bern, Freiestrasse 1, 3012, Bern, Switzerland
| | - Elia Fischer
- Institute of Pathology, University of Bern, Murtenstrasse 31, Room L310, 3008, Bern, Switzerland
| | - Irene Centeno
- Institute of Pathology, University of Bern, Murtenstrasse 31, Room L310, 3008, Bern, Switzerland
| | - José A Galván
- Institute of Pathology, University of Bern, Murtenstrasse 31, Room L310, 3008, Bern, Switzerland
| | - Micha Eichmann
- Institute of Pathology, University of Bern, Murtenstrasse 31, Room L310, 3008, Bern, Switzerland
| | - Tilman T Rau
- Institute of Pathology, University of Bern, Murtenstrasse 31, Room L310, 3008, Bern, Switzerland
| | - Rupert Langer
- Institute of Pathology, University of Bern, Murtenstrasse 31, Room L310, 3008, Bern, Switzerland
| | - Heather Dawson
- Institute of Pathology, University of Bern, Murtenstrasse 31, Room L310, 3008, Bern, Switzerland
| | - Ulrich Nitsche
- Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Ismaninger Strasse 22, Munich, 81675, Germany
| | - Peter Traeger
- Careanesth AG, Nelkenstrasse 15, Zürich, 8006, Switzerland
| | - Martin D Berger
- Department of Medical Oncology, University Hospital of Bern, 3010, Bern, Switzerland.,Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, 90033, CA, USA
| | - Beat Schnüriger
- Department of Visceral and Internal Medicine, University Hospital of Bern, 3008, Bern, Switzerland
| | - Marion Hädrich
- Department of Visceral and Internal Medicine, University Hospital of Bern, 3008, Bern, Switzerland
| | - Peter Studer
- Department of Visceral and Internal Medicine, University Hospital of Bern, 3008, Bern, Switzerland
| | - Daniel Inderbitzin
- University of Bern and Bürgerspital Solothurn, Schöngrünstrasse 42, 4500, Solothurn, Switzerland
| | - Alessandro Lugli
- Institute of Pathology, University of Bern, Murtenstrasse 31, Room L310, 3008, Bern, Switzerland
| | - Mario P Tschan
- Institute of Pathology, University of Bern, Murtenstrasse 31, Room L310, 3008, Bern, Switzerland.,Graduate School for Cellular and Biomedical Sciences, University of Bern, Freiestrasse 1, 3012, Bern, Switzerland
| | - Inti Zlobec
- Institute of Pathology, University of Bern, Murtenstrasse 31, Room L310, 3008, Bern, Switzerland.
| |
Collapse
|
|
18
|
Clinical, Pathological, and Molecular Characteristics of CpG Island Methylator Phenotype in Colorectal Cancer: A Systematic Review and Meta-analysis. Transl Oncol 2018; 11:1188-1201. [PMID: 30071442 PMCID: PMC6080640 DOI: 10.1016/j.tranon.2018.07.008] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2018] [Revised: 07/10/2018] [Accepted: 07/10/2018] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND: CpG island methylator phenotype (CIMP) tumors, comprising 20% of colorectal cancers, are associated with female sex, age, right-sided location, and BRAF mutations. However, other factors potentially associated with CIMP have not been robustly examined. This meta-analysis provides a comprehensive assessment of the clinical, pathologic, and molecular characteristics that define CIMP tumors. METHODS: We conducted a comprehensive search of the literature from January 1999 through April 2018 and identified 122 articles, on which comprehensive data abstraction was performed on the clinical, pathologic, molecular, and mutational characteristics of CIMP subgroups, classified based on the extent of DNA methylation of tumor suppressor genes assessed using a variety of laboratory methods. Associations of CIMP with outcome parameters were estimated using pooled odds ratio or standardized mean differences using random-effects model. RESULTS: We confirmed prior associations including female sex, older age, right-sided tumor location, poor differentiation, and microsatellite instability. In addition to the recognized association with BRAF mutations, CIMP was also associated with PIK3CA mutations and lack of mutations in KRAS and TP53. Evidence of an activated immune response was seen with high rates of tumor-infiltrating lymphocytes (but not peritumoral lymphocytes), Crohn-like infiltrates, and infiltration with Fusobacterium nucleatum bacteria. Additionally, CIMP tumors were associated with advance T-stage and presence of perineural and lymphovascular invasion. CONCLUSION: The meta-analysis highlights key features distinguishing CIMP in colorectal cancer, including molecular characteristics of an active immune response. Improved understanding of this unique molecular subtype of colorectal cancer may provide insights into prevention and treatment.
Collapse
|
|
19
|
Poh A, Chang HSY, Tan KY, Sam XX, Khoo A, Choo SN, Nga ME, Wan WK. Extent of field change in colorectal cancers with BRAF mutation. Singapore Med J 2018; 59:139-143. [PMID: 28210747 PMCID: PMC5861336 DOI: 10.11622/smedj.2017012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
INTRODUCTION Sporadic colorectal cancers with BRAF mutations constitute two distinct subgroups of colorectal cancers. Recent studies have linked the presence of the BRAF mutation to a familial inheritance pattern. This was a proof-of-concept study that aimed to examine: (a) the extent of field change in sporadic colorectal cancers with BRAF mutation; and (b) the extent of resection margins required and the pattern of DNA mismatch repair protein loss in these tumours. METHODS Eight microsatellite instability-high tumours with positive BRAF mutation from an existing histopathological database were selected for BRAF mutation and mismatch repair protein analysis. RESULTS All the resection margins were negative for BRAF mutation. Three tumours had loss of MLH1 and PMS2 expressions, and five tumours had no protein loss. Six peritumoral tissues were negative and one was positive for BRAF mutation. CONCLUSION The results suggest that any early field change effect is restricted to the immediate vicinity of the tumour and is not a pan-colonic phenomenon. Current guidelines on resection margins are adequate for BRAF mutation-positive colorectal cancers. Any suggestion of a hereditary link to these tumours is likely not related to germline BRAF gene mutations. The pattern of protein loss reinforces previous findings for the two subgroups of BRAF mutation-positive colorectal cancers.
Collapse
Affiliation(s)
- Aaron Poh
- Department of General Surgery, Khoo Teck Puat Hospital, Singapore
| | | | - Kok Yang Tan
- Department of General Surgery, Khoo Teck Puat Hospital, Singapore
| | - Xin Xiu Sam
- Histopathology Translational Research Group, Department of Pathology, Singapore General Hospital, Singapore
| | - Avery Khoo
- Histopathology Translational Research Group, Department of Pathology, Singapore General Hospital, Singapore
| | - Shoa Nian Choo
- Department of Pathology, National University Hospital, Singapore
| | - Min En Nga
- Department of Pathology, National University Hospital, Singapore
| | - Wei Keat Wan
- Department of Pathology, Singapore General Hospital, Singapore
| |
Collapse
|
|
20
|
Tóth C, Sükösd F, Valicsek E, Herpel E, Schirmacher P, Tiszlavicz L. Loss of CDX2 gene expression is associated with DNA repair proteins and is a crucial member of the Wnt signaling pathway in liver metastasis of colorectal cancer. Oncol Lett 2018; 15:3586-3593. [PMID: 29467879 PMCID: PMC5796384 DOI: 10.3892/ol.2018.7756] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2017] [Accepted: 12/13/2017] [Indexed: 12/23/2022] Open
Abstract
Caudal type homeobox 2 (CDX2) has been well-established as a diagnostic marker for colorectal cancer (CRC); however, less is known about its regulation, particularly its potential interactions with the DNA repair proteins, adenomatous polyposis coli (APC) and β-catenin, in a non-transcriptional manner. In the present study, the protein expression of CDX2 was analyzed, depending on the expression of the DNA repair proteins, mismatch repair (MMR), O6-methylguanine DNA methyltransferase (MGMT) and excision repair cross-complementing 1 (ERCC1), and its importance in Wnt signaling was also determined. A total of 101 liver metastases were punched into tissue microarray (TMA) blocks and serial sections were cut for immunohistochemistry. For each protein, an immunoreactive score was generated according to literature data and the scores were fitted to TMA. Subsequently, statistical analysis was performed to compare the levels of expression with each other and with clinical data. CDX2 loss of expression was observed in 38.5% of the CRC liver metastasis cases. A statistically significant association between CDX2 and each of the investigated MMRs was observed: MutL Homolog 1 (P<0.01), MutS protein Homolog (MSH) 2 (P<0.01), MSH6 (P<0.01), and postmeiotic segregation increased 2 (P=0.040). Furthermore, loss of MGMT and ERCC1 was also associated with CDX2 loss (P=0.039 and P<0.01, respectively). In addition, CDX2 and ERCC1 were inversely associated with metastatic tumor size (P=0.038 and P=0.027, respectively). Sustained CDX2 expression was associated with a higher expression of cytoplasmic/membranous β-catenin and with nuclear APC expression (P=0.042 and P<0.01, respectively). In conclusion, CDX2 loss of expression was not a rare event in liver metastasis of CRC and the results suggested that CDX2 may be involved in mechanisms resulting in the loss of DNA repair protein expression, and in turn methylation; however, its exact function in this context remains to be elucidated.
Collapse
Affiliation(s)
- Csaba Tóth
- Institute of Pathology, University Hospital Heidelberg, D-69120 Heidelberg, Germany
| | - Farkas Sükösd
- Department of Pathology, University of Szeged, 6725 Szeged, Hungary
| | - Erzsébet Valicsek
- Department of Oncotherapy, University of Szeged, 6725 Szeged, Hungary
| | - Esther Herpel
- Institute of Pathology, University Hospital Heidelberg, D-69120 Heidelberg, Germany.,Tissue Bank of The National Center for Tumor Diseases (NCT), D-69120 Heidelberg, Germany
| | - Peter Schirmacher
- Institute of Pathology, University Hospital Heidelberg, D-69120 Heidelberg, Germany
| | | |
Collapse
|
|
21
|
Reggiani Bonetti L, Lionti S, Vitarelli E, Barresi V. Prognostic significance of CDX2 immunoexpression in poorly differentiated clusters of colorectal carcinoma. Virchows Arch 2017; 471:731-741. [PMID: 28819729 DOI: 10.1007/s00428-017-2219-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2017] [Revised: 08/01/2017] [Accepted: 08/09/2017] [Indexed: 12/26/2022]
Abstract
CDX2 is a transcription factor that acts as a tumor suppressor in colorectal cancer (CRC). Its loss triggers metastatic process and tumor progression; however, its prognostic role in patients with CRC is still controversial. Poorly differentiated clusters (PDCs) are aggregates of neoplastic cells which likely have high metastatic potential in CRC. In this study, we analyzed and compared CDX2 expression in PDC (CDX2-PDC) and corresponding main tumor (CDX2 main tumor) in 42 CRCs showing at least 10 PDC (PDC G3). Five of 42 CRCs (12%) were classified as CDX2 main tumor negative (4/5 were also PDC-CDX2 negative); all had tumor recurrence and died of CRC. Twenty nine of 42 cases were CDX2-PDC negative. Among CRC CDX2 main tumor positive, 15 had recurrences and 13 died from CRC; 13 and 11 of them, respectively, were CDX2-PDC negative. By assigning one point to CDX2 main tumor or CDX2-PDC positivity, we assessed CDX2-staining score for each case. Twelve cases had CDX2-staining score 2 (CDX2 positive in main tumor and PDC); 26 had score 1 (CDX2 positive in main tumor or PDC), and 4 had CDX2 score 0 (CDX2 negative in main tumor and PDC). In our patients, CDX2-staining score had higher prognostic value compared to CDX2 main tumor or CDX2-PDC alone. In addition, it represented a significant and independent prognostic variable for disease-free survival (DFS) and cancer-specific survival (CSS). Our findings suggest that, although loss of CDX2 in the main tumor identifies high-risk patients with high specificity, CDX2-PDC should also be considered in CDX2 main tumor positive cases to predict prognosis.
Collapse
Affiliation(s)
- Luca Reggiani Bonetti
- Department of Laboratory Integrated Activities, Anatomic Pathology and Legal Medicine, University of Modena and Reggio Emilia, Modena, Italy
| | - Simona Lionti
- Department of Pathology in Evolutive Age and Adulthood "Gaetano Barresi", University of Messina, Polyclinic G. Martino, Pad D, Via Consolare Valeria, 98125, Messina, Italy
| | - Enrica Vitarelli
- Department of Pathology in Evolutive Age and Adulthood "Gaetano Barresi", University of Messina, Polyclinic G. Martino, Pad D, Via Consolare Valeria, 98125, Messina, Italy
| | - Valeria Barresi
- Department of Pathology in Evolutive Age and Adulthood "Gaetano Barresi", University of Messina, Polyclinic G. Martino, Pad D, Via Consolare Valeria, 98125, Messina, Italy.
| |
Collapse
|
|
22
|
Geißler AL, Geißler M, Kottmann D, Lutz L, Fichter CD, Fritsch R, Weddeling B, Makowiec F, Werner M, Lassmann S. ATM mutations and E-cadherin expression define sensitivity to EGFR-targeted therapy in colorectal cancer. Oncotarget 2017; 8:17164-17190. [PMID: 28199979 PMCID: PMC5370031 DOI: 10.18632/oncotarget.15211] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2016] [Accepted: 01/16/2017] [Indexed: 12/23/2022] Open
Abstract
EGFR-targeted therapy is a key treatment approach in patients with RAS wildtype metastatic colorectal cancers (CRC). Still, also RAS wildtype CRC may be resistant to EGFR-targeted therapy, with few predictive markers available for improved stratification of patients. Here, we investigated response of 7 CRC cell lines (Caco-2, DLD1, HCT116, HT29, LS174T, RKO, SW480) to Cetuximab and correlated this to NGS-based mutation profiles, EGFR promoter methylation and EGFR expression status as well as to E-cadherin expression. Moreover, tissue specimens of primary and/or recurrent tumors as well as liver and/or lung metastases of 25 CRC patients having received Cetuximab and/or Panitumumab were examined for the same molecular markers. In vitro and in situ analyses showed that EGFR promoter methylation and EGFR expression as well as the MSI and or CIMP-type status did not guide treatment responses. In fact, EGFR-targeted treatment responses were also observed in RAS exon 2 p.G13 mutated CRC cell lines or CRC cases and were further linked to PIK3CA exon 9 mutations. In contrast, non-response to EGFR-targeted treatment was associated with ATM mutations and low E-cadherin expression. Moreover, down-regulation of E-cadherin by siRNA in otherwise Cetuximab responding E-cadherin positive cells abrogated their response. Hence, we here identify ATM and E-cadherin expression as potential novel supportive predictive markers for EGFR-targeted therapy.
Collapse
Affiliation(s)
- Anna-Lena Geißler
- Institute of Surgical Pathology, University of Freiburg, Freiburg im Breisgau, Germany.,Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, Germany.,Faculty of Biology, University of Freiburg, Freiburg im Breisgau, Germany.,German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Miriam Geißler
- Institute of Surgical Pathology, University of Freiburg, Freiburg im Breisgau, Germany.,Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, Germany.,Faculty of Biology, University of Freiburg, Freiburg im Breisgau, Germany
| | - Daniel Kottmann
- Institute of Surgical Pathology, University of Freiburg, Freiburg im Breisgau, Germany.,Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, Germany.,Faculty of Biology, University of Freiburg, Freiburg im Breisgau, Germany
| | - Lisa Lutz
- Institute of Surgical Pathology, University of Freiburg, Freiburg im Breisgau, Germany.,Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, Germany
| | - Christiane D Fichter
- Institute of Surgical Pathology, University of Freiburg, Freiburg im Breisgau, Germany.,Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, Germany.,Faculty of Biology, University of Freiburg, Freiburg im Breisgau, Germany
| | - Ralph Fritsch
- Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, Germany.,Department of Internal Medicine, University of Freiburg, Freiburg im Breisgau, Germany.,Comprehensive Cancer Center Freiburg, All Medical Center - University of Freiburg, Freiburg im Breisgau, Germany
| | - Britta Weddeling
- Institute of Surgical Pathology, University of Freiburg, Freiburg im Breisgau, Germany.,Comprehensive Cancer Center Freiburg, All Medical Center - University of Freiburg, Freiburg im Breisgau, Germany
| | - Frank Makowiec
- Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, Germany.,Department of Surgery, University of Freiburg, Freiburg im Breisgau, Germany.,Comprehensive Cancer Center Freiburg, All Medical Center - University of Freiburg, Freiburg im Breisgau, Germany
| | - Martin Werner
- Institute of Surgical Pathology, University of Freiburg, Freiburg im Breisgau, Germany.,Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, Germany.,German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany.,Comprehensive Cancer Center Freiburg, All Medical Center - University of Freiburg, Freiburg im Breisgau, Germany
| | - Silke Lassmann
- Institute of Surgical Pathology, University of Freiburg, Freiburg im Breisgau, Germany.,Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, Germany.,German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany.,Comprehensive Cancer Center Freiburg, All Medical Center - University of Freiburg, Freiburg im Breisgau, Germany.,BIOSS Centre for Biological Signaling Studies, University of Freiburg, Freiburg im Breisgau, Germany
| |
Collapse
|
|
23
|
Nishihara R, Glass K, Mima K, Hamada T, Nowak JA, Qian ZR, Kraft P, Giovannucci EL, Fuchs CS, Chan AT, Quackenbush J, Ogino S, Onnela JP. Biomarker correlation network in colorectal carcinoma by tumor anatomic location. BMC Bioinformatics 2017. [PMID: 28623901 PMCID: PMC5474023 DOI: 10.1186/s12859-017-1718-5] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Background Colorectal carcinoma evolves through a multitude of molecular events including somatic mutations, epigenetic alterations, and aberrant protein expression, influenced by host immune reactions. One way to interrogate the complex carcinogenic process and interactions between aberrant events is to model a biomarker correlation network. Such a network analysis integrates multidimensional tumor biomarker data to identify key molecular events and pathways that are central to an underlying biological process. Due to embryological, physiological, and microbial differences, proximal and distal colorectal cancers have distinct sets of molecular pathological signatures. Given these differences, we hypothesized that a biomarker correlation network might vary by tumor location. Results We performed network analyses of 54 biomarkers, including major mutational events, microsatellite instability (MSI), epigenetic features, protein expression status, and immune reactions using data from 1380 colorectal cancer cases: 690 cases with proximal colon cancer and 690 cases with distal colorectal cancer matched by age and sex. Edges were defined by statistically significant correlations between biomarkers using Spearman correlation analyses. We found that the proximal colon cancer network formed a denser network (total number of edges, n = 173) than the distal colorectal cancer network (n = 95) (P < 0.0001 in permutation tests). The value of the average clustering coefficient was 0.50 in the proximal colon cancer network and 0.30 in the distal colorectal cancer network, indicating the greater clustering tendency of the proximal colon cancer network. In particular, MSI was a key hub, highly connected with other biomarkers in proximal colon cancer, but not in distal colorectal cancer. Among patients with non-MSI-high cancer, BRAF mutation status emerged as a distinct marker with higher connectivity in the network of proximal colon cancer, but not in distal colorectal cancer. Conclusion In proximal colon cancer, tumor biomarkers tended to be correlated with each other, and MSI and BRAF mutation functioned as key molecular characteristics during the carcinogenesis. Our findings highlight the importance of considering multiple correlated pathways for therapeutic targets especially in proximal colon cancer. Electronic supplementary material The online version of this article (doi:10.1186/s12859-017-1718-5) contains supplementary material, which is available to authorized users.
Collapse
Affiliation(s)
- Reiko Nishihara
- Program of MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. .,Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA. .,Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA. .,Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
| | - Kimberly Glass
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Kosuke Mima
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA
| | - Tsuyoshi Hamada
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA
| | - Jonathan A Nowak
- Program of MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Zhi Rong Qian
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA
| | - Peter Kraft
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Edward L Giovannucci
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.,Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Charles S Fuchs
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.,Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.,Yale Cancer Center, New Haven, CT, USA.,Department of Medicine, Yale School of Medicine, New Haven, CT, USA.,Smilow Cancer Hospital, New Haven, CT, USA
| | - Andrew T Chan
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.,Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - John Quackenbush
- Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.,Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA
| | - Shuji Ogino
- Program of MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. .,Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA. .,Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA. .,Department of Oncologic Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
| | - Jukka-Pekka Onnela
- Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
| |
Collapse
|
|
24
|
Shvartsur A, Givechian KB, Garban H, Bonavida B. Overexpression of RKIP and its cross-talk with several regulatory gene products in multiple myeloma. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2017; 36:62. [PMID: 28476134 PMCID: PMC5420138 DOI: 10.1186/s13046-017-0535-z] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/22/2016] [Accepted: 04/26/2017] [Indexed: 12/27/2022]
Abstract
Multiple myeloma (MM) is a clonal plasma-cell neoplastic disorder arising from an indolent premalignant disease known as monoclonal gammopathy of undetermined significance (MGUS). MM is a biologically complex heterogeneous disease reflected by its variable clinical responses of patients receiving the same treatment. Therefore, a molecular identification of stage-specific biomarkers will support a more individualized precise diagnostic/prognostic approach, an effective therapeutic regime, and will assist in the identification of novel therapeutic molecular targets. The metastatic suppressor/anti-resistance factor Raf-1 kinase inhibitor protein (RKIP) is poorly expressed in the majority of cancers and is often almost absent in metastatic tumors. RKIP inhibits the Raf/MEK/ERK1/2 and the NF-κB pathways. Whereby all tumors examined exhibited low levels of RKIP, in contrast, our recent findings demonstrated that RKIP is overexpressed primarily in its inactive phosphorylated form in MM cell lines and patient-derived tumor tissues. The underlying mechanism of RKIP overexpression in MM, in contrast to other tumors, is not known. We examined transcriptomic datasets on Oncomine platform (Life Technologies) for the co-expression of RKIP and other gene products in both pre-MM and MM. The transcription of several gene products was found to be either commonly overexpressed (i.e., RKIP, Bcl-2, and DR5) or underexpressed (i.e., Bcl-6 and TNFR2) in both pre-MM and MM. Noteworthy, a significant inverse correlation of differentially expressed pro-apoptotic genes was observed in pre-MM: overexpression of Fas and TNF-α and underexpression of YY1 versus expression of anti-apoptotic genes in MM: overexpression of YY1 and underexpression of Fas and TNF-α. Based on the analysis on mRNA levels and reported studies on protein levels of the above various genes, we have constructed various schemes that illustrate the possible cross-talks between RKIP (active/inactive) and the identified gene products that underlie the mechanism of RKIP overexpression in MM. Clearly, such cross-talks would need to be experimentally validated in both MM cell lines and patient-derived tumor tissues. If validated, the differential molecular signatures between pre-MM and MM might lead to a more precise diagnosis/prognosis of the disease and disease stages and will also identify novel molecular therapeutic targets for pre-MM and MM.
Collapse
Affiliation(s)
- Anna Shvartsur
- Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, 90095, USA
| | - Kevin B Givechian
- Department of Biological Sciences, USC Dana and David Dornsife College of Letters, Arts and Sciences at the University of Southern California, Los Angeles, CA, 90089, USA
| | - Hermes Garban
- California NanoSystems Institute (CnSI), University of California Los Angeles, Los Angeles, CA, 90095, USA
| | - Benjamin Bonavida
- Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, 90095, USA.
| |
Collapse
|
|
25
|
Lee S, Wottrich S, Bonavida B. Crosstalks between Raf-kinase inhibitor protein and cancer stem cell transcription factors (Oct4, KLF4, Sox2, Nanog). Tumour Biol 2017; 39:1010428317692253. [PMID: 28378634 DOI: 10.1177/1010428317692253] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
Raf-kinase inhibitor protein has been reported to inhibit both the Raf/mitogen extracellular signal-regulated kinase/extracellular signal-regulated kinase and nuclear factor kappa-light-chain of activated B cells pathways. It has also been reported in cancers that Raf-kinase inhibitor protein behaves as a metastatic suppressor as well as a chemo-immunosensitizing factor to drug/immune-mediated apoptosis. The majority of cancers exhibit low or no levels of Raf-kinase inhibitor protein. Hence, the activities of Raf-kinase inhibitor protein contrast, in part, to those mediated by several cancer stem cell transcription factors for their roles in resistance and metastasis. In this review, the existence of crosstalks in the signaling pathways between Raf-kinase inhibitor protein and several cancer stem cell transcription factors (Oct4, KLF4, Sox2 and Nanog) was assembled. Oct4 is induced by Lin28, and Raf-kinase inhibitor protein inhibits the microRNA binding protein Lin28. The expression of Raf-kinase inhibitor protein inversely correlates with the expression of Oct4. KLF4 does not interact directly with Raf-kinase inhibitor protein, but rather interacts indirectly via Raf-kinase inhibitor protein's regulation of the Oct4/Sox2/KLF4 complex through the mitogen-activated protein kinase pathway. The mechanism by which Raf-kinase inhibitor protein inhibits Sox2 is via the inhibition of the mitogen-activated protein kinase pathway by Raf-kinase inhibitor protein. Thus, Raf-kinase inhibitor protein's relationship with Sox2 is via its regulation of Oct4. Inhibition of extracellular signal-regulated kinase by Raf-kinase inhibitor protein results in the upregulation of Nanog. The inhibition of Oct4 by Raf-kinase inhibitor protein results in the failure of the heterodimer formation of Oct4 and Sox2 that is necessary to bind to the Nanog promoter for the transcription of Nanog. The findings revealed that there exists a direct correlation between the expression of Raf-kinase inhibitor protein and the expression of each of the above transcription factors. Based on these analyses, we suggest that the expression level of Raf-kinase inhibitor protein may be involved in the regulation of the cancer stem cell phenotype.
Collapse
Affiliation(s)
- SoHyun Lee
- Department of Microbiology, Immunology & Molecular Genetics, David Geffen School of Medicine, Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA, USA
| | - Stephanie Wottrich
- Department of Microbiology, Immunology & Molecular Genetics, David Geffen School of Medicine, Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA, USA
| | - Benjamin Bonavida
- Department of Microbiology, Immunology & Molecular Genetics, David Geffen School of Medicine, Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA, USA
| |
Collapse
|
|
26
|
|
|
27
|
Kovaleva V, Geissler AL, Lutz L, Fritsch R, Makowiec F, Wiesemann S, Hopt UT, Passlick B, Werner M, Lassmann S. Spatio-temporal mutation profiles of case-matched colorectal carcinomas and their metastases reveal unique de novo mutations in metachronous lung metastases by targeted next generation sequencing. Mol Cancer 2016; 15:63. [PMID: 27756406 PMCID: PMC5069823 DOI: 10.1186/s12943-016-0549-8] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2016] [Accepted: 10/06/2016] [Indexed: 12/13/2022] Open
Abstract
Background Targeted next generation sequencing (tNGS) has become part of molecular pathology diagnostics for determining RAS mutation status in colorectal cancer (CRC) patients as predictive tool for decision on EGFR-targeted therapy. Here, we investigated mutation profiles of case-matched tissue specimens throughout the disease course of CRC, to further specify RAS-status dynamics and to identify de novo mutations associated with distant metastases. Methods Case-matched formalin-fixed and paraffin-embedded (FFPE) resection specimens (n = 70; primary tumours, synchronous and/or metachronous liver and/or lung metastases) of 14 CRC cases were subjected to microdissection of normal colonic epithelial, primary and metastatic tumour cells, their DNA extraction and an adapted library protocol for limited DNA using the 48 gene TruSeq Amplicon Cancer PanelTM, MiSeq sequencing and data analyses (Illumina). Results By tNGS primary tumours were RAS wildtype in 5/14 and mutated in 9/14 (8/9 KRAS exon 2; 1/9 NRAS Exon 3) of cases. RAS mutation status was maintained in case-matched metastases throughout the disease course, albeit with altered allele frequencies. Case-matched analyses further identified a maximum of three sequence variants (mainly in APC, KRAS, NRAS, TP53) shared by all tumour specimens throughout the disease course per individual case. In addition, further case-matched de novo mutations were detected in synchronous and/or metachronous liver and/or lung metastases (e.g. in APC, ATM, FBXW7, FGFR3, GNAQ, KIT, PIK3CA, PTEN, SMAD4, SMO, STK11, TP53, VHL). Moreover, several de novo mutations were more frequent in synchronous (e.g. ATM, KIT, PIK3CA, SMAD4) or metachronous (e.g. FBXW7, SMO, STK11) lung metastases. Finally, some de novo mutations occurred only in metachronous lung metastases (CDKN2A, FGFR2, GNAS, JAK3, SRC). Conclusion Together, this study employs an adapted FFPE-based tNGS approach to confirm conservation of RAS mutation status in primary and metastatic tissue specimens of CRC patients. Moreover, it identifies genes preferentially mutated de novo in late disease stages of metachronous CRC lung metastases, several of which might be actionable by targeted therapies. Electronic supplementary material The online version of this article (doi:10.1186/s12943-016-0549-8) contains supplementary material, which is available to authorized users.
Collapse
Affiliation(s)
- Valentina Kovaleva
- Institute for Surgical Pathology, Medical Center-Faculty of Medicine, University of Freiburg, Breisacherstr. 115A, 79106, Freiburg, Germany.,German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Anna-Lena Geissler
- Institute for Surgical Pathology, Medical Center-Faculty of Medicine, University of Freiburg, Breisacherstr. 115A, 79106, Freiburg, Germany.,German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany.,Faculty of Biology, University of Freiburg, Freiburg, Germany
| | - Lisa Lutz
- Institute for Surgical Pathology, Medical Center-Faculty of Medicine, University of Freiburg, Breisacherstr. 115A, 79106, Freiburg, Germany
| | - Ralph Fritsch
- Department of Medicine I, Medical Center-Faculty of Medicine, University of Freiburg, Freiburg, Germany.,Comprehensive Cancer Center Freiburg, Medical Center-Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Frank Makowiec
- Comprehensive Cancer Center Freiburg, Medical Center-Faculty of Medicine, University of Freiburg, Freiburg, Germany.,Department of General and Visceral Surgery, Medical Center- Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Sebastian Wiesemann
- Comprehensive Cancer Center Freiburg, Medical Center-Faculty of Medicine, University of Freiburg, Freiburg, Germany.,Department of Thoracic Surgery, Medical Center-Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Ulrich T Hopt
- Comprehensive Cancer Center Freiburg, Medical Center-Faculty of Medicine, University of Freiburg, Freiburg, Germany.,Department of General and Visceral Surgery, Medical Center- Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Bernward Passlick
- Comprehensive Cancer Center Freiburg, Medical Center-Faculty of Medicine, University of Freiburg, Freiburg, Germany.,Department of Thoracic Surgery, Medical Center-Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Martin Werner
- Institute for Surgical Pathology, Medical Center-Faculty of Medicine, University of Freiburg, Breisacherstr. 115A, 79106, Freiburg, Germany.,German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany.,Comprehensive Cancer Center Freiburg, Medical Center-Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Silke Lassmann
- Institute for Surgical Pathology, Medical Center-Faculty of Medicine, University of Freiburg, Breisacherstr. 115A, 79106, Freiburg, Germany. .,German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany. .,Comprehensive Cancer Center Freiburg, Medical Center-Faculty of Medicine, University of Freiburg, Freiburg, Germany. .,BIOSS Centre for Biological Signaling Studies, University of Freiburg, Freiburg, Germany.
| |
Collapse
|
|
28
|
Zhuo C, Li Q, Wu Y, Li Y, Nie J, Li D, Peng J, Lian P, Li B, Cai G, Li X, Cai S. LINE-1 hypomethylation in normal colon mucosa is associated with poor survival in Chinese patients with sporadic colon cancer. Oncotarget 2016; 6:23820-36. [PMID: 26172297 PMCID: PMC4695154 DOI: 10.18632/oncotarget.4450] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2015] [Accepted: 06/19/2015] [Indexed: 12/20/2022] Open
Abstract
Genetic and epigenetic pathways are not independent in colorectal cancer (CRC) carcinogenesis. We aimed to determine the influence of various molecular features on Chinese patients' colon cancer-specific survival (CCSS). Various genetic and epigenetic modifications were detected in paired tumor and normal mucosa tissue samples. The prognostic variables regarding patient CCSS were determined. Overall, 127 patients, including 83 males and 44 females, completed a median follow-up of 65 (3–85) months. A mean LINE-1 methylation rate of 64.62% (range, 9.45–86.93) was observed. Hypermethylation at the hMLH1 gene promoter was detected in 26 (20.47%) patients. KRAS was mutated in 52 (40.94%) patients. Sixteen (12.60%) patients were confirmed as microsatellite instability (MSI)-High, and 76 (59.84%) were found to have loss of heterozygosity at 18q. The LINE-1 methylation level, MSI status, perineural invasion and distant metastases were confirmed as independent prognostic factors for patient CCSS. A stratified survival analysis further revealed that certain subgroups of patients with LINE-1 hypomethylation had significantly worse survival (all p < 0.05). Our data revealed that both genetic and epigenetic abnormalities can concurrently exist during colonic tumorigenesis. As a global epigenetic change, LINE-1 hypomethylation in normal colon mucosa might be associated with a worse outcome in certain Chinese patients with colon cancer.
Collapse
Affiliation(s)
- Changhua Zhuo
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, People's Republic of China.,Department of Surgical Oncology, Fujian Provincial Cancer Hospital, Teaching Hospital of Fujian Medical University, Fuzhou 350014, People's Republic of China
| | - Qingguo Li
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, People's Republic of China
| | - Yuchen Wu
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, People's Republic of China
| | - Yiwei Li
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, People's Republic of China
| | - Jia Nie
- Key Laboratory of Molecular Virology & Immunology, Unit of Molecular Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, People's Republic of China
| | - Dawei Li
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, People's Republic of China
| | - Junjie Peng
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, People's Republic of China
| | - Peng Lian
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, People's Republic of China
| | - Bin Li
- Key Laboratory of Molecular Virology & Immunology, Unit of Molecular Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, People's Republic of China
| | - Guoxiang Cai
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, People's Republic of China
| | - Xinxiang Li
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, People's Republic of China
| | - Sanjun Cai
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, People's Republic of China
| |
Collapse
|
|
29
|
Immunohistochemical staining for p16 and BRAFV600E is useful to distinguish between sporadic and hereditary (Lynch syndrome-related) microsatellite instable colorectal carcinomas. Virchows Arch 2016; 469:135-44. [PMID: 27220764 DOI: 10.1007/s00428-016-1958-1] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2015] [Revised: 05/09/2016] [Accepted: 05/11/2016] [Indexed: 12/14/2022]
Abstract
DNA mismatch repair (MMR) protein analysis by immunohistochemistry (IHC) can identify colorectal cancer (CRC) with microsatellite instability (MSI). As MLH1-deficient CRC can be hereditary or sporadic, markers to distinguish between them are needed. MLH1 promoter methylation assay is the reference method; however, sometimes, it is challenging on formalin-fixed paraffin-embedded tissue samples. We assessed by IHC the expression of BRAFV600E, p16, MGMT, and CDX2 in 55 MLH1-deficient MSI CRC samples (of which 8 had a germline MLH1 mutation) to determine whether this panel differentiates between sporadic and hereditary CRCs. We also analyzed MLH1 promoter methylation by methylation-specific PCR and pyrosequencing and BRAF status by genotyping. None of the hereditary CRCs showed MLH1 methylation, BRAF mutation, BRAFV600E-positive immunostaining, or loss of p16 expression. We detected MLH1 promoter methylation in 67 % and a BRAF mutation in 42 % of CRC, all showing MLH1 promoter methylation. BRAFV600E IHC and BRAF genotyping gave concordant results in all but two samples. Loss of expression of p16 was found in 30 % of CRC with methylation of the MLH1 promoter, but its expression was retained in all non-methylated and part of MLH1-methylated tumors (100 % specificity, 30 % sensitivity). CDX2 and MGMT expression was not associated with MLH1 status. Thus, BRAFV600E and p16 IHC may help in differentiating sporadic from hereditary MLH1-deficient CRC with MSI. Specifically, p16 IHC might be used as a surrogate marker for MLH1 promoter methylation, because all p16-negative CRCs displayed MLH1 methylation, whereas hereditary CRCs were all p16-positive.
Collapse
|
|
30
|
Zong L, Abe M, Ji J, Zhu WG, Yu D. Tracking the Correlation Between CpG Island Methylator Phenotype and Other Molecular Features and Clinicopathological Features in Human Colorectal Cancers: A Systematic Review and Meta-Analysis. Clin Transl Gastroenterol 2016; 7:e151. [PMID: 26963001 PMCID: PMC4822093 DOI: 10.1038/ctg.2016.14] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2015] [Accepted: 01/21/2016] [Indexed: 01/08/2023] Open
Abstract
OBJECTIVES The controversy of CpG island methylator phenotype (CIMP) in colorectal cancers (CRCs) persists, despite many studies that have been conducted on its correlation with molecular and clinicopathological features. To drive a more precise estimate of the strength of this postulated relationship, a meta-analysis was performed. METHODS A comprehensive search for studies reporting molecular and clinicopathological features of CRCs stratified by CIMP was performed within the PubMed, EMBASE, and Cochrane Library. CIMP was defined by either one of the three panels of gene-specific CIMP markers (Weisenberger panel, classic panel, or a mixture panel of the previous two) or the genome-wide DNA methylation profile. The associations of CIMP with outcome parameters were estimated using odds ratio (OR) or weighted mean difference (WMD) or hazard ratios (HRs) with 95% confidence interval (CI) for each study using a fixed effects or random effects model. RESULTS A total of 29 studies involving 9,393 CRC patients were included for analysis. We observed more BRAF mutations (OR 34.87; 95% CI, 22.49-54.06) and microsatellite instability (MSI) (OR 12.85 95% CI, 8.84-18.68) in CIMP-positive vs. -negative CRCs, whereas KRAS mutations were less frequent (OR 0.47; 95% CI, 0.30-0.75). Subgroup analysis showed that only the genome-wide methylation profile-defined CIMP subset encompassed all BRAF-mutated CRCs. As expected, CIMP-positive CRCs displayed significant associations with female (OR 0.64; 95% CI, 0.56-0.72), older age at diagnosis (WMD 2.77; 95% CI, 1.15-4.38), proximal location (OR 6.91; 95% CI, 5.17-9.23), mucinous histology (OR 3.81; 95% CI, 2.93-4.95), and poor differentiation (OR 4.22; 95% CI, 2.52-7.08). Although CIMP did not show a correlation with tumor stage (OR 1.10; 95% CI, 0.82-1.46), it was associated with shorter overall survival (HR 1.73; 95% CI, 1.27-2.37). CONCLUSIONS The meta-analysis highlights that CIMP-positive CRCs take their own molecular feature, especially overlapping with BRAF mutations, and clinicopathological features and worse prognosis from CIMP-negative CRCs, suggesting CIMP could be used as an independent prognostic marker for CRCs.
Collapse
Affiliation(s)
- Liang Zong
- Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan
- Department of Gastrointestinal Surgery, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
- Department of Gastrointestinal Surgery, Su Bei People's Hospital of Jiangsu Province, Yangzhou University, Yangzhou, China
| | - Masanobu Abe
- Division for Health Service Promotion, University of Tokyo Hospital, Tokyo, Japan
| | - Jiafu Ji
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Surgery, Peking University Cancer Hospital and Institute, Beijing, China
| | - Wei-Guo Zhu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing, China
- Peking-Tsinghua University Center for Life Sciences, Peking University, Beijing, China
| | - Duonan Yu
- Non-coding RNA Center, Yangzhou University, Yangzhou, China
- Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Senile Disease, Yangzhou, China
- Institute of Comparative Medicine, Yangzhou University, Yangzhou, China
- Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Disease and Zoonosis, Yangzhou, China
| |
Collapse
|
|
31
|
Rau TT, Atreya R, Aust D, Baretton G, Eck M, Erlenbach-Wünsch K, Hartmann A, Lugli A, Stöhr R, Vieth M, Wirsing AM, Zlobec I, Katzenberger T. Inflammatory response in serrated precursor lesions of the colon classified according to WHO entities, clinical parameters and phenotype-genotype correlation. JOURNAL OF PATHOLOGY CLINICAL RESEARCH 2016; 2:113-24. [PMID: 27499921 PMCID: PMC4907061 DOI: 10.1002/cjp2.41] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/17/2015] [Accepted: 01/23/2016] [Indexed: 12/14/2022]
Abstract
Studies on traditional serrated adenoma (TSA) and sessile serrated adenoma with dysplasia (SSA‐D) are rare due to the low frequency of these lesions, which are well defined by the latest WHO classification. However, introducing new morphological criteria such as intra‐epithelial lymphocytes (IELs) might facilitate colorectal polyp diagnoses. Additionally, the phenotype–genotype correlation needs to be updated as the terminology has repeatedly changed. This study analysed 516 polyps, consisting of 118 classical adenomas (CAD), 116 hyperplastic polyps (HPP), 179 SSAs, 41 SSA‐Ds, and 62 TSAs. The lesions were analysed in relation to the patients’ clinical parameters including gender, age, localisation, and size. The inflammatory background of the polyps was quantified and BRAF and KRAS mutations as well as MLH1 and CDKN2A promoter methylation were assessed. In multivariate analyses, an increase in IELs was an independent and robust new criterion for the diagnosis of SSA‐D (p < 0.001). Superficial erosions and acute neutrophil granulocytes led to reactive changes potentially resembling dysplasia. KRAS and BRAF mutations were associated with CAD/TSA and HPP/SSA, respectively. However, almost half of TSAs had a BRAF mutation and were KRAS wild type. CDKN2A seems to precede MLH1 hyper‐methylation within the serrated carcinogenesis model. The genotyping of WHO‐based entities – and especially SSA – has sharpened in comparison to previously published data. TSAs can be sub‐grouped according to their mutation status. Of note, the higher number of IELs in SSA‐D reflects their close relationship to colorectal cancers with micro‐satellite instability. Therefore, IELs might represent a new diagnostic tool for SSA‐D.
Collapse
Affiliation(s)
- Tilman T Rau
- Institute of Pathology, University Bern, BernSwitzerland; Institute of Pathology, Friedrich-Alexander University Erlangen-NurembergErlangenGermany
| | - Raja Atreya
- Medical Clinic 1, Friedrich-Alexander University Erlangen-Nuremberg Erlangen Germany
| | - Daniela Aust
- Institute of Pathology, University Hospital Dresden Carl Gustav Carus Dresden Germany
| | - Gustavo Baretton
- Institute of Pathology, University Hospital Dresden Carl Gustav Carus Dresden Germany
| | - Matthias Eck
- Institute of Pathology, Hospital Aschaffenburg Aschaffenburg Germany
| | | | - Arndt Hartmann
- Institute of Pathology, Friedrich-Alexander University Erlangen-Nuremberg Erlangen Germany
| | | | - Robert Stöhr
- Institute of Pathology, Friedrich-Alexander University Erlangen-Nuremberg Erlangen Germany
| | - Michael Vieth
- Institute of Pathology, Hospital Bayreuth Bayreuth Germany
| | - Anna M Wirsing
- Institute of Pathology, Friedrich-Alexander University Erlangen-NurembergErlangenGermany; Department of Medical Biology, Faculty of Health SciencesUniversity of TromsøTromsøNorway
| | - Inti Zlobec
- Institute of Pathology, University Bern, Bern Switzerland
| | | |
Collapse
|
|
32
|
LEF-1 is frequently expressed in colorectal carcinoma and not in other gastrointestinal tract adenocarcinomas: an immunohistochemical survey of 602 gastrointestinal tract neoplasms. Appl Immunohistochem Mol Morphol 2015; 22:728-34. [PMID: 25394300 DOI: 10.1097/pai.0000000000000109] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
LEF-1 is a DNA-binding protein that interacts with β-catenin and activates Wnt-responsive target genes. We analyzed the immunohistochemical expression of LEF-1 in 602 gastrointestinal and pancreatobiliary neoplasms in an attempt to (1) investigate the utility of LEF-1 immunohistochemistry as an ancillary marker in gastrointestinal/pancreatobiliary neoplasia, and (2) to perform a clinicopathologic and survival analysis of colorectal carcinoma stratified by LEF-1 expression. LEF-1 nuclear positivity was frequently identified in colorectal carcinoma (89/241, 37%) and only infrequently identified in other neoplasms: 11% esophagus/esophagogastric adenocarcinomas, 7% gastric adenocarcinomas, 1% pancreatic ductal adenocarcinomas, 4% pancreatic intraductal papillary mucinous neoplasms, and in no cases of appendiceal mucinous neoplasms or pancreatic mucinous cystic neoplasms. LEF-1 expression was identified in 35% of colorectal carcinomas that lacked CK20 and CDX2 expression. In colorectal carcinomas, LEF-1-positive tumors more frequently harbored KRAS mutations compared with LEF-1-negative tumors (39% vs. 16%, P=0.005). Patients with moderate/strong LEF-1-positive colorectal carcinoma had a trend of worse overall survival compared with patients with colorectal carcinomas with weak/negative LEF-1 expression (5 y overall survival, 31% vs. 47%, P=0.15). In conclusion, LEF-1 is most commonly expressed in colorectal carcinoma and infrequently observed in the upper gastrointestinal tract and pancreatic adenocarcinoma. LEF-1 Immunohistochemistry may be especially useful as an ancillary diagnostic marker in colorectal carcinomas, which lack the expression of both CK20 and CDX2. LEF-1 expression is associated with the presence of KRAS mutations and may have prognostic value as a trend of worse overall survival is seen in patients with LEF-1-positive colorectal carcinoma.
Collapse
|
|
33
|
Bae JM, Lee TH, Cho NY, Kim TY, Kang GH. Loss of CDX2 expression is associated with poor prognosis in colorectal cancer patients. World J Gastroenterol 2015; 21:1457-1467. [PMID: 25663765 PMCID: PMC4316088 DOI: 10.3748/wjg.v21.i5.1457] [Citation(s) in RCA: 99] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2014] [Revised: 10/04/2014] [Accepted: 11/19/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the clinicopathologic characteristics and prognostic implications associated with loss of CDX2 expression in colorectal cancers (CRCs).
METHODS: We immunohistochemically evaluated CDX2 expression in 713 CRCs and paired our findings to clinicopathologic and molecular characteristics of each individual. Endpoints included cytokeratin 7 and CK20 expression, microsatellite instability, CpG island methylator phenotype, and KRAS and BRAF mutation statuses. Univariate and multivariate survival analysis was performed to reveal the prognostic value of CDX2 downregulation.
RESULTS: CDX2 expression was lost in 42 (5.9%) patients. Moreover, loss of CDX2 expression was associated with proximal location, infiltrative growth, advanced T, N, M and overall stage. On microscopic examination, loss of CDX2 expression was associated with poor differentiation, increased number of tumor-infiltrating lymphocytes, luminal serration and mucin production. Loss of CDX2 expression was also associated with increased CK7 expression, decreased CK20 expression, CpG island methylator phenotype, microsatellite instability and BRAF mutation. In a univariate survival analysis, patients with loss of CDX2 expression showed worse overall survival (P < 0.001) and progression-free survival (P < 0.001). In a multivariate survival analysis, loss of CDX2 expression was an independent poor prognostic factor of overall survival [hazard ratio (HR) = 1.72, 95%CI: 1.04-2.85, P = 0.034] and progression-free survival (HR = 1.94, 95%CI: 1.22-3.07, P = 0.005).
CONCLUSION: Loss of CDX2 expression is associated with aggressive clinical behavior and can be used as a prognostic marker in CRCs.
Collapse
|
|
34
|
Lochhead P, Chan AT, Nishihara R, Fuchs CS, Beck AH, Giovannucci E, Ogino S. Etiologic field effect: reappraisal of the field effect concept in cancer predisposition and progression. Mod Pathol 2015; 28:14-29. [PMID: 24925058 PMCID: PMC4265316 DOI: 10.1038/modpathol.2014.81] [Citation(s) in RCA: 159] [Impact Index Per Article: 15.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2013] [Revised: 02/12/2014] [Accepted: 04/02/2014] [Indexed: 02/07/2023]
Abstract
The term 'field effect' (also known as field defect, field cancerization, or field carcinogenesis) has been used to describe a field of cellular and molecular alteration, which predisposes to the development of neoplasms within that territory. We explore an expanded, integrative concept, 'etiologic field effect', which asserts that various etiologic factors (the exposome including dietary, lifestyle, environmental, microbial, hormonal, and genetic factors) and their interactions (the interactome) contribute to a tissue microenvironmental milieu that constitutes a 'field of susceptibility' to neoplasia initiation, evolution, and progression. Importantly, etiological fields predate the acquisition of molecular aberrations commonly considered to indicate presence of filed effect. Inspired by molecular pathological epidemiology (MPE) research, which examines the influence of etiologic factors on cellular and molecular alterations during disease course, an etiologically focused approach to field effect can: (1) broaden the horizons of our inquiry into cancer susceptibility and progression at molecular, cellular, and environmental levels, during all stages of tumor evolution; (2) embrace host-environment-tumor interactions (including gene-environment interactions) occurring in the tumor microenvironment; and, (3) help explain intriguing observations, such as shared molecular features between bilateral primary breast carcinomas, and between synchronous colorectal cancers, where similar molecular changes are absent from intervening normal colon. MPE research has identified a number of endogenous and environmental exposures which can influence not only molecular signatures in the genome, epigenome, transcriptome, proteome, metabolome and interactome, but also host immunity and tumor behavior. We anticipate that future technological advances will allow the development of in vivo biosensors capable of detecting and quantifying 'etiologic field effect' as abnormal network pathology patterns of cellular and microenvironmental responses to endogenous and exogenous exposures. Through an 'etiologic field effect' paradigm, and holistic systems pathology (systems biology) approaches to cancer biology, we can improve personalized prevention and treatment strategies for precision medicine.
Collapse
Affiliation(s)
- Paul Lochhead
- Gastrointestinal Research Group, Institute of Medical Sciences, University of Aberdeen, Aberdeen, UK
| | - Andrew T Chan
- 1] Division of Gastroenterology, Massachusetts General Hospital, Boston, MA, USA [2] Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Reiko Nishihara
- 1] Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA [2] Department of Nutrition, Harvard School of Public Health, Boston, MA, USA
| | - Charles S Fuchs
- 1] Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA [2] Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Andrew H Beck
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Edward Giovannucci
- 1] Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA [2] Department of Nutrition, Harvard School of Public Health, Boston, MA, USA [3] Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA
| | - Shuji Ogino
- 1] Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA [2] Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA [3] Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| |
Collapse
|
|
35
|
Li T, Liao X, Lochhead P, Morikawa T, Yamauchi M, Nishihara R, Inamura K, Kim SA, Mima K, Sukawa Y, Kuchiba A, Imamura Y, Baba Y, Shima K, Meyerhardt JA, Chan AT, Fuchs CS, Ogino S, Qian ZR. SMO expression in colorectal cancer: associations with clinical, pathological, and molecular features. Ann Surg Oncol 2014; 21:4164-73. [PMID: 25023548 PMCID: PMC4221469 DOI: 10.1245/s10434-014-3888-y] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2013] [Indexed: 12/15/2022]
Abstract
BACKGROUND Smoothened, frizzled family receptor (SMO) is an important component of the hedgehog signaling pathway, which has been implicated in various human carcinomas. However, clinical, molecular, and prognostic associations of SMO expression in colorectal cancer remain unclear. METHODS Using a database of 735 colon and rectal cancers in the Nurse's Health Study and the Health Professionals Follow-up Study, we examined the relationship of tumor SMO expression (assessed by immunohistochemistry) to prognosis, and to clinical, pathological, and tumor molecular features, including mutations of KRAS, BRAF, and PIK3CA, microsatellite instability, CpG island methylator phenotype (CIMP), LINE-1 methylation, and expression of phosphorylated AKT and CTNNB1. RESULTS SMO expression was detected in 370 tumors (50 %). In multivariate logistic regression analysis, SMO expression was independently inversely associated with phosphorylated AKT expression [odds ratio (OR) 0.48; 95 % confidence interval (CI) 0.34-0.67] and CTNNB1 nuclear localization (OR 0.48; 95 % CI 0.35-0.67). SMO expression was not significantly associated with colorectal cancer-specific or overall survival. However, in CIMP-high tumors, but not CIMP-low/0 tumors, SMO expression was significantly associated with better colorectal cancer-specific survival (log-rank P = 0.012; multivariate hazard ratio, 0.36; 95 % CI 0.13-0.95; P interaction = 0.035, for SMO and CIMP status). CONCLUSIONS Our data reveal novel potential associations between the hedgehog, the WNT/CTNNB1, and the PI3K (phosphatidylinositol-4,5-bisphosphonate 3-kinase)/AKT pathways, supporting pivotal roles of SMO and hedgehog signaling in pathway networking. SMO expression in colorectal cancer may interact with tumor CIMP status to affect patient prognosis, although confirmation by future studies is needed.
Collapse
Affiliation(s)
- Tingting Li
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
36
|
Lochhead P, Chan AT, Giovannucci E, Fuchs CS, Wu K, Nishihara R, O'Brien M, Ogino S. Progress and opportunities in molecular pathological epidemiology of colorectal premalignant lesions. Am J Gastroenterol 2014; 109:1205-14. [PMID: 24935274 PMCID: PMC4125459 DOI: 10.1038/ajg.2014.153] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2013] [Accepted: 04/18/2014] [Indexed: 02/06/2023]
Abstract
Molecular pathological epidemiology (MPE) is an integrative molecular and population health science that addresses the molecular pathogenesis and heterogeneity of disease processes. The MPE of colonic and rectal premalignant lesions (including hyperplastic polyps, tubular adenomas, tubulovillous adenomas, villous adenomas, traditional serrated adenomas, sessile serrated adenomas/sessile serrated polyps, and hamartomatous polyps) can provide unique opportunities for examining the influence of diet, lifestyle, and environmental exposures on specific pathways of carcinogenesis. Colorectal neoplasia can provide a practical model by which both malignant epithelial tumor (carcinoma) and its precursor are subjected to molecular pathological analyses. KRAS, BRAF, and PIK3CA oncogene mutations, microsatellite instability, CpG island methylator phenotype, and LINE-1 methylation are commonly examined tumor biomarkers. Future opportunities include interrogation of comprehensive genomic, epigenomic, or panomic datasets, and the adoption of in vivo pathology techniques. Considering the colorectal continuum hypothesis and emerging roles of gut microbiota and host immunity in tumorigenesis, detailed information on tumor location is important. There are unique strengths and caveats, especially with regard to case ascertainment by colonoscopy. The MPE of colorectal premalignant lesions can identify etiologic exposures associated with neoplastic initiation and progression, help us better understand colorectal carcinogenesis, and facilitate personalized prevention, screening, and therapy.
Collapse
Affiliation(s)
- Paul Lochhead
- 1] Institute of Medical Sciences, University of Aberdeen, Aberdeen, UK [2] The first two authors contributed equally to this work
| | - Andrew T Chan
- 1] Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts, USA [2] Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts, USA [3] The first two authors contributed equally to this work
| | - Edward Giovannucci
- 1] Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts, USA [2] Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA [3] Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, USA
| | - Charles S Fuchs
- 1] Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts, USA [2] Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA
| | - Kana Wu
- Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, USA
| | - Reiko Nishihara
- 1] Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, USA [2] Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA
| | - Michael O'Brien
- Department of Pathology, Boston University Medical Center, Boston, Massachusetts, USA
| | - Shuji Ogino
- 1] Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA [2] Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA [3] Department of Pathology, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts, USA
| |
Collapse
|
|
37
|
Intermediate serrated polyp as an intermediate lesion of hyperplastic polyp and sessile serrated polyp/adenoma in terms of morphological and molecular features. Hum Pathol 2014; 45:1759-65. [DOI: 10.1016/j.humpath.2014.04.014] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2013] [Revised: 04/17/2014] [Accepted: 04/18/2014] [Indexed: 01/13/2023]
|
|
38
|
Olsen J, Espersen MLM, Jess P, Kirkeby LT, Troelsen JT. The clinical perspectives of CDX2 expression in colorectal cancer: a qualitative systematic review. Surg Oncol 2014; 23:167-76. [PMID: 25126956 DOI: 10.1016/j.suronc.2014.07.003] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2014] [Accepted: 07/05/2014] [Indexed: 12/22/2022]
Abstract
INTRODUCTION Homeobox genes are often deregulated in cancer. They can have both oncogenic and tumor-suppressing potential. The Caudal-related homeobox transcription factor 2 (CDX2) is an intestine-specific transcription factor. It is implicated in differentiation, proliferation, cell-adhesion, and migration. CDX2 has been proposed as a tumor suppressor in colorectal cancer but its role is still controversial. This systematic review were undertaken in order to clarify CDX2s role in colorectal cancer. METHODS A literature search was performed in the MEDLINE database from 1966 to February 2014. Only studies in which all or a part of the experimental design were performed on human colorectal cancer tissue were included. Thus, studies solely performed in cell-lines or animal models were excluded. RESULTS Fifty-two articles of relevance were identified. CDX2 expression was rarely lost in colorectal cancers, however the expression pattern may often be heterogeneous within the tumor and can be selectively down regulated at the invasive front and in tumor buddings. Loss of CDX2 expression is probably correlated to tumor grade, stage, right-sided tumor location, MMR-deficiency, CIMP, and BRAF mutations. The CDX2 gene is rarely mutated but the locus harboring the gene is often amplified and may suggest CDX2 as a linage-survival oncogene. CDX2 might be implicated in cell proliferation and migration through cross-talk with the Wnt-signaling pathway, tumor-stroma proteins, and inflammatory cytokines. CONCLUSION A clear role for CDX2 expression in colorectal cancer remains to be elucidated, and it might differ in relation to the underlying molecular pathways leading to the cancer formation.
Collapse
Affiliation(s)
- J Olsen
- Department of Science, Systems and Models, Roskilde University, Universitetsvej 1, DK-4000 Roskilde, Denmark; Department of Surgery, Roskilde University Hospital, Roskilde Sygehus, Køgevej 7-13, DK-4000 Roskilde, Denmark.
| | - M L M Espersen
- Department of Science, Systems and Models, Roskilde University, Universitetsvej 1, DK-4000 Roskilde, Denmark; The Molecular Unit, Department of Pathology, Herlev University Hospital, DK-2730 Herlev, Denmark.
| | - P Jess
- Department of Surgery, Roskilde University Hospital, Roskilde Sygehus, Køgevej 7-13, DK-4000 Roskilde, Denmark.
| | - L T Kirkeby
- Department of Surgery, Roskilde University Hospital, Roskilde Sygehus, Køgevej 7-13, DK-4000 Roskilde, Denmark.
| | - J T Troelsen
- Department of Science, Systems and Models, Roskilde University, Universitetsvej 1, DK-4000 Roskilde, Denmark.
| |
Collapse
|
|
39
|
Ogino S, Lochhead P, Giovannucci E, Meyerhardt JA, Fuchs CS, Chan AT. Discovery of colorectal cancer PIK3CA mutation as potential predictive biomarker: power and promise of molecular pathological epidemiology. Oncogene 2014; 33:2949-55. [PMID: 23792451 PMCID: PMC3818472 DOI: 10.1038/onc.2013.244] [Citation(s) in RCA: 104] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2013] [Revised: 04/26/2013] [Accepted: 04/27/2013] [Indexed: 12/18/2022]
Abstract
Regular use of aspirin reduces incidence and mortality of various cancers, including colorectal cancer. Anticancer effect of aspirin represents one of the 'Provocative Questions' in cancer research. Experimental and clinical studies support a carcinogenic role for PTGS2 (cyclooxygenase-2), which is an important enzymatic mediator of inflammation, and a target of aspirin. Recent 'molecular pathological epidemiology' (MPE) research has shown that aspirin use is associated with better prognosis and clinical outcome in PIK3CA-mutated colorectal carcinoma, suggesting somatic PIK3CA mutation as a molecular biomarker that predicts response to aspirin therapy. The PI3K (phosphatidylinositol-4,5-bisphosphonate 3-kinase) enzyme has a pivotal role in the PI3K-AKT signaling pathway. Activating PIK3CA oncogene mutations are observed in various malignancies including breast cancer, ovarian cancer, brain tumor, hepatocellular carcinoma, lung cancer and colon cancer. The prevalence of PIK3CA mutations increases continuously from rectal to cecal cancers, supporting the 'colorectal continuum' paradigm, and an important interplay of gut microbiota and host immune/inflammatory reaction. MPE represents an interdisciplinary integrative science, conceptually defined as 'epidemiology of molecular heterogeneity of disease'. As exposome and interactome vary from person to person and influence disease process, each disease process is unique (the unique disease principle). Therefore, MPE concept and paradigm can extend to non-neoplastic diseases including diabetes mellitus, cardiovascular diseases, metabolic diseases, and so on. MPE research opportunities are currently limited by paucity of tumor molecular data in the existing large-scale population-based studies. However, genomic, epigenomic and molecular pathology testings (for example, analyses for microsatellite instability, MLH1 promoter CpG island methylation, and KRAS and BRAF mutations in colorectal tumors) are becoming routine clinical practices. In order for integrative molecular and population science to be routine practice, we must first reform education curricula by integrating both population and molecular biological sciences. As consequences, next-generation hybrid molecular biological and population scientists can advance science, moving closer to personalized precision medicine and health care.
Collapse
Affiliation(s)
- S Ogino
- 1] Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA [2] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA [3] Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA
| | - P Lochhead
- Institute of Medical Sciences, University of Aberdeen, Aberdeen, UK
| | - E Giovannucci
- 1] Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA [2] Department of Nutrition, Harvard School of Public Health, Boston, MA, USA [3] Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - J A Meyerhardt
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - C S Fuchs
- 1] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA [2] Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - A T Chan
- 1] Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA [2] Division of Gastroenterology, Massachusetts General Hospital, Boston, MA, USA
| |
Collapse
|
|
40
|
Environmental Exposures, Tumor Heterogeneity, and Colorectal Cancer Outcomes. CURRENT COLORECTAL CANCER REPORTS 2014. [DOI: 10.1007/s11888-014-0221-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
|
|
41
|
Landau MS, Kuan SF, Chiosea S, Pai RK. BRAF-mutated microsatellite stable colorectal carcinoma: an aggressive adenocarcinoma with reduced CDX2 and increased cytokeratin 7 immunohistochemical expression. Hum Pathol 2014; 45:1704-12. [PMID: 24908142 DOI: 10.1016/j.humpath.2014.04.008] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2014] [Revised: 04/07/2014] [Accepted: 04/09/2014] [Indexed: 12/23/2022]
Abstract
Reduced CDX2 and cytokeratin 20 (CK20) expression in colorectal carcinoma with BRAF mutation and high-level microsatellite instability (MSI-H) has been well documented. The immunophenotype of BRAF-mutated microsatellite stable (MSS) colorectal carcinoma has not been reported. We analyzed 205 colorectal carcinomas including 28 BRAF-mutated MSS, 53 BRAF-mutated MSI-H, and 124 BRAF wild-type MSS tumors for CDX2, cytokeratin 7 (CK7), and CK20 immunohistochemical expression. CDX2 was scored semiquantitatively for both staining intensity and percent of tumor cells staining and a modified CDX2 H-score was calculated. Patients with BRAF-mutated MSS colorectal carcinomas were more frequently stage IV at presentation compared to patients with BRAF-mutated MSI-H colorectal carcinomas and BRAF wild-type MSS colorectal carcinomas (32% versus 8% versus 15%, P < .001). BRAF-mutated MSS colorectal carcinoma displayed reduced CDX2 expression compared to BRAF wild-type MSS colorectal carcinoma (75% versus 94%; mean CDX2 H-score 98 versus 150, P < .001). CK7 expression was more often identified in BRAF-mutated MSS colorectal carcinoma compared to both BRAF-mutated MSI-H colorectal carcinoma and BRAF wild-type MSS colorectal carcinoma (39% versus 6% versus 6%, P = .0001). BRAF-mutated MSI-H colorectal carcinomas were less often CK20 positive compared to BRAF-mutated MSS and BRAF wild-type MSS tumors (70% versus 93% versus 90%, P = 0.001). In summary, BRAF-mutated MSS colorectal carcinoma often displays reduced CDX2 and increased CK7 expression. Knowledge of this altered immunophenotype is important as patients with BRAF-mutated MSS colorectal carcinoma often present with metastatic disease and the altered tumor immunophenotype may lead to the erroneous assumption that origin from the colon/rectum is unlikely.
Collapse
Affiliation(s)
- Michael S Landau
- Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA
| | - Shih-Fan Kuan
- Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA
| | - Simon Chiosea
- Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA
| | - Reetesh K Pai
- Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA.
| |
Collapse
|
|
42
|
Kim JH, Kang GH. Molecular and prognostic heterogeneity of microsatellite-unstable colorectal cancer. World J Gastroenterol 2014; 20:4230-4243. [PMID: 24764661 PMCID: PMC3989959 DOI: 10.3748/wjg.v20.i15.4230] [Citation(s) in RCA: 75] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2013] [Revised: 01/30/2014] [Accepted: 02/20/2014] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancers (CRCs) with a high level of microsatellite instability (MSI-H) are clinicopathologically distinct tumors characterized by predominance in females, proximal colonic localization, poor differentiation, mucinous histology, tumor-infiltrating lymphocytes, a Crohn's-like lymphoid reaction and a favorable prognosis. In terms of their molecular features, MSI-H CRCs are heterogeneous tumors associated with various genetic and epigenetic alterations, including DNA mismatch repair deficiency, target microsatellite mutations, BRAF mutations, a CpG island methylator phenotype-high (CIMP-H) status, and a low level of genomic hypomethylation. The molecular heterogeneity of MSI-H CRCs also depends on ethnic differences; for example, in Eastern Asian countries, relatively low frequencies of CIMP-H and BRAF mutations have been observed in MSI-H CRCs compared to Western countries. Although the prognostic features of MSI-H CRCs include a favorable survival of patients and low benefit of adjuvant chemotherapy, there may be prognostic differences based on the molecular heterogeneity of MSI-H CRCs. Here, we have reviewed and discussed the molecular and prognostic features of MSI-H CRCs, as well as several putative prognostic or predictive molecular markers, including HSP110 expression, beta2-microglobulin mutations, myosin 1a expression, CDX2/CK20 expression, SMAD4 expression, CIMP status and LINE-1 methylation levels.
Collapse
|
|
43
|
Galon J, Mlecnik B, Bindea G, Angell HK, Berger A, Lagorce C, Lugli A, Zlobec I, Hartmann A, Bifulco C, Nagtegaal ID, Palmqvist R, Masucci GV, Botti G, Tatangelo F, Delrio P, Maio M, Laghi L, Grizzi F, Asslaber M, D'Arrigo C, Vidal-Vanaclocha F, Zavadova E, Chouchane L, Ohashi PS, Hafezi-Bakhtiari S, Wouters BG, Roehrl M, Nguyen L, Kawakami Y, Hazama S, Okuno K, Ogino S, Gibbs P, Waring P, Sato N, Torigoe T, Itoh K, Patel PS, Shukla SN, Wang Y, Kopetz S, Sinicrope FA, Scripcariu V, Ascierto PA, Marincola FM, Fox BA, Pagès F. Towards the introduction of the 'Immunoscore' in the classification of malignant tumours. J Pathol 2014; 232:199-209. [PMID: 24122236 PMCID: PMC4255306 DOI: 10.1002/path.4287] [Citation(s) in RCA: 1061] [Impact Index Per Article: 96.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2013] [Revised: 09/25/2013] [Accepted: 09/26/2013] [Indexed: 02/06/2023]
Abstract
The American Joint Committee on Cancer/Union Internationale Contre le Cancer (AJCC/UICC) TNM staging system provides the most reliable guidelines for the routine prognostication and treatment of colorectal carcinoma. This traditional tumour staging summarizes data on tumour burden (T), the presence of cancer cells in draining and regional lymph nodes (N) and evidence for distant metastases (M). However, it is now recognized that the clinical outcome can vary significantly among patients within the same stage. The current classification provides limited prognostic information and does not predict response to therapy. Multiple ways to classify cancer and to distinguish different subtypes of colorectal cancer have been proposed, including morphology, cell origin, molecular pathways, mutation status and gene expression-based stratification. These parameters rely on tumour-cell characteristics. Extensive literature has investigated the host immune response against cancer and demonstrated the prognostic impact of the in situ immune cell infiltrate in tumours. A methodology named 'Immunoscore' has been defined to quantify the in situ immune infiltrate. In colorectal cancer, the Immunoscore may add to the significance of the current AJCC/UICC TNM classification, since it has been demonstrated to be a prognostic factor superior to the AJCC/UICC TNM classification. An international consortium has been initiated to validate and promote the Immunoscore in routine clinical settings. The results of this international consortium may result in the implementation of the Immunoscore as a new component for the classification of cancer, designated TNM-I (TNM-Immune).
Collapse
Affiliation(s)
- Jérôme Galon
- INSERM, U872, Laboratory of Integrative Cancer ImmunologyParis, France
- Université Paris DescartesParis, France
- Centre de Recherche des CordeliersUniversité Pierre et Marie Curie Paris 6, France
| | - Bernhard Mlecnik
- INSERM, U872, Laboratory of Integrative Cancer ImmunologyParis, France
- Université Paris DescartesParis, France
- Centre de Recherche des CordeliersUniversité Pierre et Marie Curie Paris 6, France
| | - Gabriela Bindea
- INSERM, U872, Laboratory of Integrative Cancer ImmunologyParis, France
- Université Paris DescartesParis, France
- Centre de Recherche des CordeliersUniversité Pierre et Marie Curie Paris 6, France
| | - Helen K Angell
- INSERM, U872, Laboratory of Integrative Cancer ImmunologyParis, France
- Université Paris DescartesParis, France
- Centre de Recherche des CordeliersUniversité Pierre et Marie Curie Paris 6, France
| | - Anne Berger
- Digestive Surgery Department, Georges Pompidou European HospitalParis, France
| | | | | | - Inti Zlobec
- Institute of Pathology, University of BernSwitzerland
| | | | - Carlo Bifulco
- Department of Pathology, Providence Portland Medical CenterPortland, OR, USA
| | - Iris D Nagtegaal
- Pathology Department, Radboud University Nijmegen Medical CentreThe Netherlands
| | | | | | - Gerardo Botti
- Department of Pathology, Istituto Nazionale per lo Studio e la Cura dei Tumouri, ‘Fondazione G Pascale’Naples, Italy
| | - Fabiana Tatangelo
- Department of Pathology, Istituto Nazionale per lo Studio e la Cura dei Tumouri, ‘Fondazione G Pascale’Naples, Italy
| | - Paolo Delrio
- Colorectal Surgery Department, Istituto Nazionale per lo Studio e la Cura dei Tumouri, ‘Fondazione G Pascale’Naples, Italy
| | - Michele Maio
- Division of Medical Oncology and Immunotherapy, University Hospital of Siena, Istituto Toscano TumouriSiena, Italy
| | - Luigi Laghi
- Molecular Gastroenterology and Department of Gastroenterology, Humanitas Clinical and Research CentreRozzano, Milan, Italy
| | - Fabio Grizzi
- Molecular Gastroenterology and Department of Gastroenterology, Humanitas Clinical and Research CentreRozzano, Milan, Italy
| | | | - Corrado D'Arrigo
- Department of Histopathology, Dorset County HospitalDorchester, UK
| | - Fernando Vidal-Vanaclocha
- CEU-San Pablo University School of Medicine and HM Hospital of Madrid Scientific Foundation, Institute of Applied Molecular Medicine (IMMA)Madrid, Spain
| | - Eva Zavadova
- Department of Oncology, Charles University in Prague, First Faculty of Medicine, Department of Oncology of the First Faculty of Medicine and General HospitalPrague, Czech Republic
| | | | - Pamela S Ohashi
- Ontario Cancer Institute and Campbell Family Institute for Cancer Research, Princess Margaret Hospital, University Health NetworkToronto, ON, Canada
| | - Sara Hafezi-Bakhtiari
- Department of Pathology and Laboratory Medicine, University Health NetworkToronto, ON, Canada
| | - Bradly G Wouters
- Department of Pathology and Laboratory Medicine, University Health NetworkToronto, ON, Canada
| | - Michael Roehrl
- UHN Program in BioSpecimen Sciences, University Health NetworkToronto, ON, Canada
| | - Linh Nguyen
- Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, University Health NetworkToronto, ON, Canada
| | - Yutaka Kawakami
- Division of Cellular Signalling, Institute for Advanced Medical Research, Keio University School of MedicineTokyo, Japan
| | - Shoichi Hazama
- Department of Digestive Surgery and Surgical Oncology, Yamaguchi University Graduate School of MedicineJapan
| | - Kiyotaka Okuno
- Department of Surgery, Kinki University School of MedicineOsaka-sayama, Japan
| | - Shuji Ogino
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School and Department of Medical Oncology, Dana-Farber Cancer InstituteBoston, MA, USA
| | - Peter Gibbs
- Department of Medical Oncology, Royal Melbourne HospitalAustralia
| | - Paul Waring
- Department of Pathology, University of MelbourneAustralia
| | - Noriyuki Sato
- Department of Pathology, Sapporo Medical University School of MedicineJapan
| | - Toshihiko Torigoe
- Department of Pathology, Sapporo Medical University School of MedicineJapan
| | - Kyogo Itoh
- Department of Immunology and Immunotherapy, Kurume University School of MedicineJapan
| | - Prabhu S Patel
- The Gujarat Cancer and Research InstituteAsarwa, Ahmedabad, India
| | - Shilin N Shukla
- The Gujarat Cancer and Research InstituteAsarwa, Ahmedabad, India
| | - Yili Wang
- Institute for Cancer Research, Centre of Translational Medicine, Xi'an Jiaotong UniversityXian, People's Republic of China
| | | | | | - Viorel Scripcariu
- Department of Surgery, University of Medicine and Pharmacy ‘Gr T Popa’, Department of Surgical Oncology, Regional Institute of OncologyIaşi, Romania
| | - Paolo A Ascierto
- Medical Oncology and Innovative Therapies Unit, Istituto Nazionale per lo Studio e la Cura dei Tumouri, Fondazione ‘G Pascale’Napoli, Italy
| | | | - Bernard A Fox
- Laboratory of Molecular and Tumour Immunology, Earle A. Chiles Research Institute, Robert W. Franz Cancer Center, Providence Portland Medical CenterPortland, OR, USA
- Department of Molecular Microbiology and Immunology, Oregon Health and Science UniversityPortland, OR, USA
| | - Franck Pagès
- INSERM, U872, Laboratory of Integrative Cancer ImmunologyParis, France
- Université Paris DescartesParis, France
- Centre de Recherche des CordeliersUniversité Pierre et Marie Curie Paris 6, France
- Immunomonitoring Platform, Laboratory of Immunology, Georges Pompidou European HospitalParis, France
| |
Collapse
|
|
44
|
Chang YS, Chang SJ, Yeh KT, Lin TH, Chang JG. RAS, BRAF, and TP53 gene mutations in Taiwanese colorectal cancer patients. ACTA ACUST UNITED AC 2013; 36:719-24. [PMID: 24356563 DOI: 10.1159/000356814] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
BACKGROUND Colorectal cancer (CRC) plays an important role in cancer mortality and morbidity. This study examined colorectal tissues for RAS, BRAF, and TP53 gene mutations to assess their value as indicators of outcomes of CRC therapy. MATERIAL AND METHODS DNA was extracted from tissues taken from 165 patients with CRC. RAS gene mutations (exons 2 and 3) were detected by primer extension analysis. BRAF gene mutations (V600E) were detected by high resolution melting (HRM) analysis. TP53 gene mutations (exons 5-8) were detected by direct sequencing. RESULTS RAS, BRAF, and TP53 mutations occurred in 36.97% (61/165), 4.24% (7/165), and 37.58% (62/165), respectively. The KRAS mutation is a predictor for poor 5-year survival (p = 0.05), and the co-presence of KRAS and TP53 mutations correlates with lymph node involvement (p = 0.029), tumor stage (p = 0.029), and poor survival (p = 0.021). Multivariate analysis adjusted for tumor size, histologic grade, lymph node metastasis, sex, and age also indicated that KRAS mutations correlate significantly with overall survival (p = 0.036). CONCLUSION The KRAS mutation is not present in about one-third of CRC patients, and therefore other gene mutations need to be investigated to better understand the molecular mechanisms of CRC and its treatment.
Collapse
Affiliation(s)
- Ya-Sian Chang
- Epigenome Research Center, China Medical University Hospital, Taichung, Taiwan
| | | | | | | | | |
Collapse
|
|
45
|
Kim HS. [Site-specific colorectal cancer; how is it different?]. THE KOREAN JOURNAL OF GASTROENTEROLOGY 2013; 61:63-70. [PMID: 23458982 DOI: 10.4166/kjg.2013.61.2.63] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
One of the most critical characteristics of colorectal cancer (CRC) is the difference between proximal (right-sided colon cancer, RCC) and distal (left-sided colon cancer, LCC) disease. The recent CRC studies showed the unique characteristics of RCC; RCCs were more prevalent in women than men and old patients, and the age difference between RCC and LCC was more apparent in women. Moreover, relatively poor protection against RCC by colonoscopy is a clearly hot issue for alarm. Thus, the left and right colon have been considered as dichotomous or even different organs in the view of molecular, histopathological, epidemiologic and clinical bases for over three decades. However, the evolutionary data suggesting linearity from the rectum to ascending colon beyond the simple right-left dichotomization in the views of cancer molecular features and site-specific clinicopathological differences, support the need for a paradigm shift to the colorectal continuum model rather than the traditional two-colon concept. This new multi-segmental or colorectal continuum hypothesis would provide both the better understanding of the complex etiology of colorectal carcinogenesis and the tailored preventive and therapeutic strategies for CRC including individualized CRC screening programs.
Collapse
Affiliation(s)
- Hyun-Soo Kim
- Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea.
| |
Collapse
|
|
46
|
Dawson H, Galván JA, Helbling M, Muller DE, Karamitopoulou E, Koelzer VH, Economou M, Hammer C, Lugli A, Zlobec I. Possible role of Cdx2 in the serrated pathway of colorectal cancer characterized by BRAF mutation, high-level CpG Island methylator phenotype and mismatch repair-deficiency. Int J Cancer 2013; 134:2342-51. [PMID: 24166180 DOI: 10.1002/ijc.28564] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2013] [Revised: 09/27/2013] [Accepted: 10/10/2013] [Indexed: 12/17/2022]
Abstract
Colorectal cancer is a heterogeneous disease at the histomorphological, clinical and molecular level. Approximately 20% of cases may progress through the "serrated" pathway characterized by BRAF mutation and high-level CpG Island Methylator Phenotype (CIMP). A large subgroup are additionally microsatellite instable (MSI) and demonstrate significant loss of tumor suppressor Cdx2. The aim of this study is to determine the specificity of Cdx2 protein expression and CpG promoter hypermethylation for BRAF(V600E) and high-level CIMP in colorectal cancer. Cdx2, Mlh1, Msh2, Msh6, and Pms2 were analyzed by immunohistochemistry using a multi-punch tissue microarray (TMA; n = 220 patients). KRAS and BRAF(V600E) mutation analysis, CDX2 methylation and CIMP were investigated. Loss of Cdx2 was correlated with larger tumor size (P = 0.0154), right-sided location (P = 0.0014), higher tumor grade (P < 0.0001), more advanced pT (P = 0.0234) and lymphatic invasion (P = 0.0351). Specificity was 100% for mismatch repair (MMR)-deficiency (P < 0.0001), 92.2% (P < 0.0001) for BRAF(V600E) and 91.8% for CIMP-high. Combined analysis of BRAF(V600E)/CIMP identified Cdx2 loss as sensitive (80%) and specific (91.5%) for mutation/high status. These results were validated on eight well-established colorectal cancer cell lines. CDX2 methylation correlated with BRAF(V600E) (P = 0.0184) and with Cdx2 protein loss (P = 0.0028). These results seem to indicate that Cdx2 may play a role in the serrated pathway to colorectal cancer as underlined by strong relationships with BRAF(V600E), CIMP-high and MMR-deficiency. Whether this protein can only be used as a "surrogate" marker, or is functionally involved in the progression of these tumors remains to be elucidated.
Collapse
Affiliation(s)
- Heather Dawson
- Department of Clinical Pathology, Institute of Pathology, University of Bern, Bern, Switzerland; Translational Research Unit, Institute of Pathology, University of Bern, Bern, Switzerland
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
47
|
Dawson H, Koelzer VH, Lukesch AC, Mallaev M, Inderbitzin D, Lugli A, Zlobec I. Loss of Cdx2 Expression in Primary Tumors and Lymph Node Metastases is Specific for Mismatch Repair-Deficiency in Colorectal Cancer. Front Oncol 2013; 3:265. [PMID: 24130965 PMCID: PMC3795344 DOI: 10.3389/fonc.2013.00265] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2013] [Accepted: 09/26/2013] [Indexed: 12/19/2022] Open
Abstract
Background: Approximately 20% of all colorectal cancers are hypothesized to arise from the “serrated pathway” characterized by mutation in BRAF, high-level CpG Island Methylator Phenotype, and microsatellite instability/mismatch repair (MMR)-deficiency. MMR-deficient cancers show frequent losses of Cdx2, a homeodomain transcription factor. Here, we determine the predictive value of Cdx2 expression for MMR-deficiency and investigate changes in expression between primary cancers and matched lymph node metastases. Methods: Immunohistochemistry for Cdx2, Mlh1, Msh2, Msh6, and Pms2 was performed on whole tissue sections from 201 patients with primary colorectal cancer and 59 cases of matched lymph node metastases. Receiver operating characteristic curve analysis and Area under the Curve (AUC) were investigated; association of Cdx2 with clinicopathological features and patient survival was carried out. Results: Loss of Cdx2 expression was associated with higher tumor grade (p = 0.0002), advanced pT (p = 0.0166), and perineural invasion (p = 0.0228). Cdx2 loss was an unfavorable prognostic factor in univariate (p = 0.0145) and multivariate [p = 0.0427; HR (95% CI): 0.58 (0.34–0.98)] analysis. The accuracy (AUC) for discriminating MMR-proficient and – deficient cancers was 87% [OR (95% CI): 0.96 (0.95–0.98); p < 0.0001]. Specificity and negative predictive value for MMR-deficiency was 99.1 and 96.3%. One hundred and seventy-four patients had MMR-proficient cancers, of which 60 (34.5%) showed Cdx2 loss. Cdx2 loss in metastases was related to MMR-deficiency (p < 0.0001). There was no difference in expression between primary tumors and matched metastases. Conclusion: Loss of Cdx2 is a sensitive and specific predictor of MMR-deficiency, but is not limited to these tumors, suggesting that events “upstream” of the development of microsatellite instability may impact Cdx2 expression.
Collapse
Affiliation(s)
- Heather Dawson
- Department of Clinical Pathology, Institute of Pathology, University of Bern , Bern , Switzerland ; Translational Research Unit, Institute of Pathology, University of Bern , Bern , Switzerland
| | | | | | | | | | | | | |
Collapse
|
|
48
|
Lochhead P, Kuchiba A, Imamura Y, Liao X, Yamauchi M, Nishihara R, Qian ZR, Morikawa T, Shen J, Meyerhardt JA, Fuchs CS, Ogino S. Microsatellite instability and BRAF mutation testing in colorectal cancer prognostication. J Natl Cancer Inst 2013; 105:1151-6. [PMID: 23878352 PMCID: PMC3735463 DOI: 10.1093/jnci/djt173] [Citation(s) in RCA: 344] [Impact Index Per Article: 28.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2012] [Revised: 03/09/2013] [Accepted: 05/30/2013] [Indexed: 02/07/2023] Open
Abstract
BRAF mutation in colorectal cancer is associated with microsatellite instability (MSI) through its relationship with high-level CpG island methylator phenotype (CIMP) and MLH1 promoter methylation. MSI and BRAF mutation analyses are routinely used for familial cancer risk assessment. To clarify clinical outcome associations of combined MSI/BRAF subgroups, we investigated survival in 1253 rectal and colon cancer patients within the Nurses' Health Study and Health Professionals Follow-up Study with available data on clinical and other molecular features, including CIMP, LINE-1 hypomethylation, and KRAS and PIK3CA mutations. Compared with the majority subtype of microsatellite stable (MSS)/BRAF-wild-type, MSS/BRAF-mutant, MSI-high/BRAF-mutant, and MSI-high/BRAF-wild-type subtypes showed multivariable colorectal cancer-specific mortality hazard ratios of 1.60 (95% confidence interval [CI] =1.12 to 2.28; P = .009), 0.48 (95% CI = 0.27 to 0.87; P = .02), and 0.25 (95% CI = 0.12 to 0.52; P < .001), respectively. No evidence existed for a differential prognostic role of BRAF mutation by MSI status (P(interaction) > .50). Combined BRAF/MSI status in colorectal cancer is a tumor molecular biomarker for prognosic risk stratification.
Collapse
Affiliation(s)
- Paul Lochhead
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA
| | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
49
|
|
|
50
|
Nishihara R, Lochhead P, Kuchiba A, Jung S, Yamauchi M, Liao X, Imamura Y, Qian ZR, Morikawa T, Wang M, Spiegelman D, Cho E, Giovannucci E, Fuchs CS, Chan AT, Ogino S. Aspirin use and risk of colorectal cancer according to BRAF mutation status. JAMA 2013. [PMID: 23800934 DOI: 10.1001/jama.2013.65] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
IMPORTANCE Aspirin use reduces the risk of colorectal carcinoma. Experimental evidence implicates a role of RAF kinases in up-regulation of prostaglandin-endoperoxide synthase 2 (PTGS2, cyclooxygenase 2), suggesting that BRAF-mutant colonic cells might be less sensitive to the antitumor effects of aspirin than BRAF-wild-type neoplastic cells. OBJECTIVE To examine whether the association of aspirin intake with colorectal cancer risk differs according to status of tumor BRAF oncogene mutation. DESIGN AND SETTING We collected biennial questionnaire data on aspirin use and followed up participants in the Nurses' Health Study (from 1980) and the Health Professionals Follow-up Study (from 1986) until July 1, 2006, for cancer incidence and until January 1, 2012, for cancer mortality. Duplication-method Cox proportional cause-specific hazards regression for competing risks data was used to compute hazard ratios (HRs) for colorectal carcinoma incidence according to BRAF mutation status. MAIN OUTCOMES AND MEASURES Incidence of colorectal cancer cases according to tumor BRAF mutation status. RESULTS Among 127,865 individuals, with 3,165,985 person-years of follow-up, we identified 1226 incident rectal and colon cancers with available molecular data. Compared with nonuse, regular aspirin use was associated with lower BRAF-wild-type cancer risk (multivariable HR, 0.73; 95% CI, 0.64 to 0.83; age-adjusted incidence rate difference [RD], -9.7; 95% CI, -12.6 to -6.7 per 100,000 person-years). This association was observed irrespective of status of tumor PTGS2 expression or PIK3CA or KRAS mutation. In contrast, regular aspirin use was not associated with a lower risk of BRAF-mutated cancer (multivariable HR, 1.03; 95% CI, 0.76 to 1.38; age-adjusted, incidence RD, 0.7; 95% CI, -0.3 to 1.7 per 100,000 person-years: P for heterogeneity = .037, between BRAF-wild-type vs BRAF-mutated cancer risks). Compared with no aspirin use, aspirin use of more than 14 tablets per week was associated with a lower risk of BRAF-wild-type cancer (multivariable HR, 0.43; 95% CI, 0.25 to 0.75; age-adjusted incidence RD, -19.8; 95% CI, -26.3 to -13.3 per 100,000 person-years). The relationship between the number of aspirin tablets per week and colorectal cancer risk differed significantly by BRAF mutation status (P for heterogeneity = .005). CONCLUSIONS AND RELEVANCE Regular aspirin use was associated with lower risk of BRAF-wild-type colorectal cancer but not with BRAF-mutated cancer risk. These findings suggest that BRAF-mutant colon tumor cells may be less sensitive to the effect of aspirin. Given the modest absolute risk difference, further investigations are necessary to determine clinical implications of our findings.
Collapse
Affiliation(s)
- Reiko Nishihara
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|