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Zhang T, Zou Y, Zhang SH, Wang YY, He S, Yuan W, Yang M, Liu T, Deng SH, Wu DM, Xu Y. Taletrectinib promotes pyroptosis in colorectal carcinoma via SRC/AKT/mTOR axis inhibition. Sci Rep 2025; 15:18049. [PMID: 40410374 PMCID: PMC12102285 DOI: 10.1038/s41598-025-02901-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2024] [Accepted: 05/16/2025] [Indexed: 05/25/2025] Open
Abstract
Drug resistance develops frequently after colorectal carcinoma (CRC) surgery, indicating the urgent need for new therapeutic strategies. Taletrectinib (DS-6051b/AB-106), a synthetic ROS1/NTRK inhibitor which has shown meaningful antitumor activity, is currently undergoing clinical trials aimed at addressing targeted resistance. However, the anti-cancer effect of taletrectinib on CRC remains unclear. In this study, our purpose was to evaluate taletrectinib-related cytotoxicity in vitro using two CRC cell lines, as well as in vivo in a mouse tumor model. The mechanism underlying the cytotoxicity of taletrectinib was evaluated using light microscopy, scanning electron microscopy, immunofluorescence assays, an annexin V-FITC/propidium iodide detection, lactate dehydrogenase (LDH) release assays, and western blotting. We found that the viability of CRC cells decreased with increasing concentrations of taletrectinib. In addition, transcriptome sequencing indicated that HCT116 and LOVO cell lines did not carry ROS1- or NTRK-related gene fusions and that the cytotoxic effect of taletrectinib was exerted via caspase-3/gasdermin E (GSDME)-dependent pyroptosis. Moreover, the effect of taletrectinib in promoting pyroptosis was reversed by treatment with the SRC agonist, tolimidone, both in vitro and in vivo. Overall, our findings suggest that taletrectinib suppresses tumor growth by inducing GSDME-mediated pyroptosis via the SRC/AKT/mTOR signaling pathway, indicating that taletrectinib shows potential as a promising therapeutic agent against CRC.
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Affiliation(s)
- Ting Zhang
- School of Clinical Medicine, The First Affiliated Hospital of Chengdu Medical College, Chengdu, 610500, China
| | - Ye Zou
- School of Clinical Medicine, Chengdu Medical College, Chengdu, Sichuan, China
| | - Sun-Han Zhang
- School of Clinical Medicine, Chengdu Medical College, Chengdu, Sichuan, China
| | - Yuan-Yi Wang
- School of Clinical Medicine, Chengdu Medical College, Chengdu, Sichuan, China
| | - Shuang He
- School of Clinical Medicine, Chengdu Medical College, Chengdu, Sichuan, China
| | - Wei Yuan
- School of Clinical Medicine, Chengdu Medical College, Chengdu, Sichuan, China
| | - Min Yang
- School of Clinical Medicine, The First Affiliated Hospital of Chengdu Medical College, Chengdu, 610500, China
| | - Teng Liu
- School of Clinical Medicine, The First Affiliated Hospital of Chengdu Medical College, Chengdu, 610500, China
| | - Shi-Hua Deng
- School of Clinical Medicine, The First Affiliated Hospital of Chengdu Medical College, Chengdu, 610500, China
| | - Dong-Ming Wu
- School of Clinical Medicine, The First Affiliated Hospital of Chengdu Medical College, Chengdu, 610500, China
| | - Ying Xu
- School of Clinical Medicine, The First Affiliated Hospital of Chengdu Medical College, Chengdu, 610500, China.
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Wala J, de Bruijn I, Coy S, Gagné A, Chan S, Chen YA, Hoffer J, Muhlich J, Schultz N, Santagata S, Sorger PK. Integrating spatial profiles and cancer genomics to identify immune-infiltrated mismatch repair proficient colorectal cancers. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.09.24.614701. [PMID: 39386479 PMCID: PMC11463659 DOI: 10.1101/2024.09.24.614701] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/12/2024]
Abstract
Predicting the progression of solid cancers based solely on genetics is challenging due to the influence of the tumor microenvironment (TME). For colorectal cancer (CRC), tumors deficient in mismatch repair (dMMR) are more immune infiltrated than mismatch repair proficient (pMMR) tumors and have better prognosis following resection. Here we quantify features of the CRC TME by combining spatial profiling with genetic analysis and release our findings via a spatially enhanced version of cBioPortal that facilitates multi-modal data exploration and analysis. We find that ∼20% of pMMR tumors exhibit similar levels of T cell infiltration as dMMR tumors and that this is associated with better survival but not any specific somatic mutation. These T cell-infiltrated pMMR (tipMMR) tumors contain abundant cells expressing PD1 and PDL1 as well as T regulatory cells, consistent with a suppressed immune response. Thus, like dMMR CRC, tipMMR CRC may benefit from immune checkpoint inhibitor therapy. SIGNIFICANCE pMMR tumors with high T cell infiltration and active immunosuppression are identifiable with a mid-plex imaging assay whose clinical deployment might double the number of treatment-naïve CRCs eligible for ICIs. Moreover, the low tumor mutational burden in tipMMR CRC shows that MMR status is not the only factor promoting immune infiltration.
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Ogata Y, Sadahiro S, Sakamoto K, Tsuchiya T, Takahashi T, Ohge H, Sato T, Kondo K, Baba H, Itabashi M, Ikeda M, Hamada M, Maeda K, Masuko H, Takahashi K, Kusano M, Hyodo I, Sakamoto J, Taguri M, Morita S. Final analyses of the prospective controlled trial on the efficacy of uracil and tegafur/leucovorin as an adjuvant treatment for stage II colon cancer with risk factors for recurrence using propensity score-based methods (JFMC46-1201). Int J Clin Oncol 2024; 29:1284-1292. [PMID: 38833114 PMCID: PMC11347494 DOI: 10.1007/s10147-024-02565-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2024] [Accepted: 05/28/2024] [Indexed: 06/06/2024]
Abstract
BACKGROUND The efficacy of adjuvant chemotherapy for high-risk stage II colon cancer (CC) has not been well established. Using propensity score matching, we previously reported that the 3-year disease-free survival (DFS) rate was significantly higher in patients treated with uracil and tegafur plus leucovorin (UFT/LV) against surgery alone. We report the final results, including updated 5-year overall survival (OS) rates and risk factor analysis outcomes. METHODS In total, 1902 high-risk stage II CC patients with T4, perforation/penetration, poorly differentiated adenocarcinoma/mucinous carcinoma, and/or < 12 dissected lymph nodes were enrolled in this prospective, non-randomized controlled study based on their self-selected treatment. Oral UFT/LV therapy was administered for six months after surgery. RESULTS Of the 1880 eligible patients, 402 in Group A (surgery alone) and 804 in Group B (UFT/LV) were propensity score-matched. The 5-year DFS rate was significantly higher in Group B than in Group A (P = 0.0008). The 5-year OS rates were not significantly different between groups. The inverse probability of treatment weighting revealed significantly higher 5-year DFS (P = 0.0006) and 5-year OS (P = 0.0122) rates in group B than in group A. Multivariate analyses revealed that male sex, age ≥ 70 years, T4, < 12 dissected lymph nodes, and no adjuvant chemotherapy were significant risk factors for DFS and/or OS. CONCLUSION The follow-up data from our prospective non-randomized controlled study revealed a considerable survival advantage in DFS offered by adjuvant chemotherapy with UFT/LV administered for six months over surgery alone in individuals with high-risk stage II CC. TRIAL REGISTRATION Japan Registry of Clinical Trials: jRCTs031180155 (date of registration: 25/02/2019), UMIN Clinical Trials Registry: UMIN000007783 (date of registration: 18/04/2012).
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Affiliation(s)
- Yutaka Ogata
- Department of Surgery, Kurume University School of Medicine, 67 Asahi-Machi, Kurume, Fukuoka, 830-0011, Japan.
| | - Sotaro Sadahiro
- Department of Surgery, Tokai University, 143 Shimokasuya, Isehara, Kanagawa, 259-1193, Japan
| | - Kazuhiro Sakamoto
- Department of Coloproctological Surgery, Juntendo University, 2-1-1 Hongo, Bunkyo-Ku, Tokyo, 113-8421, Japan
| | - Takashi Tsuchiya
- Department of Surgery, Sendai City Medical Center, 5-22-1 Tsurugaya, Miyagino-Ku, Sendai, Miyagi, 983-0824, Japan
| | - Takao Takahashi
- Department of Digestive Surgery, Gifu University Hospital, 1-1 Yanagido, Gifu, 501-1194, Japan
- Department of Surgery, Seino Kosei Hospital, 293-1 Shimoiso Ono-Cho, Ibi-Gun, Gifu, 501-0532, Japan
| | - Hiroki Ohge
- Department of Infectious Diseases, Hiroshima University Hospital, 1-2-3 Kasumi, Minami-Ku, Hiroshima, 734-8551, Japan
| | - Toshihiko Sato
- Department of Surgery, Yamagata Prefectural Central Hospital, 1800 Aoyagi, Yamagata, 990-2292, Japan
| | - Ken Kondo
- Department of Surgery, Nagoya Medical Center, 4-1-1 Sannomaru, Naka-Ku, Nagoya, Aichi, 460-0001, Japan
| | - Hideo Baba
- Department of Gastroen- Terological Surgery, Kumamoto University, 1-1-1 Honjo, Chuo-Ku, Kumamoto, 860-8556, Japan
| | - Michio Itabashi
- Department of Surgery, Division of Inflammatory Bowel Disease Surgery, Tokyo Women's Medical University, 8-1 Kawada-Cho, Shinjuku-Ku, Tokyo, 162-8666, Japan
| | - Masataka Ikeda
- Department of Gastroenterological Surgery, Division of Lower GI, Hyogo Medical University, 1-1 Mukogawa-Cho, Nishinomiya, Hyogo, 663-8501, Japan
| | - Madoka Hamada
- Department of Gastrointestinal Surgery, Kansai Medical University Hospital, 2-3-1 Shinmachi Hirakata, Osaka, 573-1191, Japan
| | - Kiyoshi Maeda
- Department of Gastroenterological Surgery, Osaka Metropolitan University, 1-4-3 Asahimachi, Abeno-Ku, Osaka, 545-8585, Japan
| | - Hiroyuki Masuko
- Department of Surgery, Nikko Memorial Hospital, 1-5-13 Shintomi-Cho, Muroran, Hokkaido, 051-8501, Japan
| | - Keiichi Takahashi
- Tokyo Metropolitan Health and Hospitals Corporation Ohkubo Hospital, 2-44-1 Kabuki-Cho, Shinjuku-Ku, Tokyo, 160-8488, Japan
| | - Mitsuo Kusano
- Department of Physical Medicine, Yoichi Hospital, 19-1-1 Kurokawa-Cho Yoichi, Hokkaido, 046-0003, Japan
| | - Ichinosuke Hyodo
- Department of Gastrointestinal Medical Oncology, National Hospital Organization Shikoku Cancer Center, 160 Kou, Minamiumemoto, Matsuyama, Ehime, 791-0280, Japan
| | - Junichi Sakamoto
- Tokai Central Hospital, 4-6-2 Sohara Higashijima-Cho, Kakamigahara, Gifu, 504-8601, Japan
| | - Masataka Taguri
- Department of Health Data Science, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-Ku, Tokyo, 160-8402, Japan
| | - Satoshi Morita
- Department of Biomedical Statistics and Bioinformatics, Kyoto University, 54 Kawahara-Cho, Shogoin, Sakyo-Ku, Kyoto, 606-8507, Japan
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Dourado J, Rogers P, Emile S, Wignakumar A, Weiss B, Horesh N, Garoufalia Z, Aeschbacher P, Wexner S. Predictors of nodal positivity in clinically under-staged patients with colon cancer: A National Cancer Database study and proposal of a predictive scoring system. Am J Surg 2024; 235:115777. [PMID: 38834421 DOI: 10.1016/j.amjsurg.2024.115777] [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: 03/25/2024] [Revised: 05/16/2024] [Accepted: 05/23/2024] [Indexed: 06/06/2024]
Abstract
BACKGROUND Colon cancer pathological and clinical staging may be disoncordant. This study assessed patients with colon cancer in whom the nodal status was clinically understaged. METHODS Patients with stage I-III clinical node-negative colon cancer from the National Cancer Database were included. Regression analyses were conducted to elucidate risk factors for clinical nodal understaging and a scoring system was developed to identify high-risk patients. RESULTS The study included 94,945 patients with 78.4 % of patients correctly staged and 21.6 % clinically understaged. The predictors of nodal positivity in clinically understaged patients were age <65 (OR 1.43), left-sided tumors (OR 1.41), elevated CEA (OR 2.03), moderately (OR 1.81) or poorly/undifferentiated tumors (OR 3.76), T1 tumors (OR 1.29), signet-ring cell histology (OR 2.26), and microsatellite-stable tumors (OR 1.4). CONCLUSION Patients with colon cancer and the above factors are more likely to have their nodal status clinically understaged. A scoring system has been developed to identify high-risk patients.
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Affiliation(s)
- Justin Dourado
- Ellen Leifer Shulman and Steven Shulman Digestive Disease Center, Cleveland Clinic Florida, Weston, FL, USA
| | - Peter Rogers
- Ellen Leifer Shulman and Steven Shulman Digestive Disease Center, Cleveland Clinic Florida, Weston, FL, USA
| | - Sameh Emile
- Ellen Leifer Shulman and Steven Shulman Digestive Disease Center, Cleveland Clinic Florida, Weston, FL, USA; Colorectal Surgery Unit, General Surgery Department, Mansoura University Hospitals, Mansoura, Egypt
| | - Anjelli Wignakumar
- Ellen Leifer Shulman and Steven Shulman Digestive Disease Center, Cleveland Clinic Florida, Weston, FL, USA
| | - Brett Weiss
- Ellen Leifer Shulman and Steven Shulman Digestive Disease Center, Cleveland Clinic Florida, Weston, FL, USA
| | - Nir Horesh
- Ellen Leifer Shulman and Steven Shulman Digestive Disease Center, Cleveland Clinic Florida, Weston, FL, USA; Department of Surgery and Transplantation, Sheba Medical Center, Ramat-Gan, Israel
| | - Zoe Garoufalia
- Ellen Leifer Shulman and Steven Shulman Digestive Disease Center, Cleveland Clinic Florida, Weston, FL, USA
| | - Pauline Aeschbacher
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Switzerland
| | - Steven Wexner
- Ellen Leifer Shulman and Steven Shulman Digestive Disease Center, Cleveland Clinic Florida, Weston, FL, USA.
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Xiang X, Ma X, Ying L, Zou H. Enhanced Commendable Sensitivity and Specificity for MSI in Colorectal Cancer by a New PCR-HRM Based 8-Loci MSI Assay. J Clin Lab Anal 2024; 38:e25085. [PMID: 39132875 PMCID: PMC11492358 DOI: 10.1002/jcla.25085] [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: 10/07/2023] [Revised: 04/13/2024] [Accepted: 06/10/2024] [Indexed: 08/13/2024] Open
Abstract
BACKGROUND This study evaluated the performance of the PCR-HRM assay by comparing it with immunohistochemistry (IHC) for mismatch repair (MMR) proteins and the PCR capillary electrophoresis (PCR-CE) methods. RESULTS A total of 224 patients with colorectal cancer participated in the study, with nearly half having mismatch repair deficiency (dMMR) tissues and the remainder possessing pMMR tissues. There was a 97.77% concordance between the PCR-HRM assay and IHC, and a 97.56% concordance between PCR-HRM and the PCR-CE assay. In comparison with IHC for dMMR proteins, the PCR-HRM demonstrated a sensitivity of 96.36% and a specificity of 99.12%. When juxtaposed with the PCR-CE assay, its sensitivity was 98.96% and specificity stood at 96.33%. The mutations observed in the microsatellite loci were uniformly distributed across all eight loci. Discrepant outcomes were more frequent in instances of MLH1 and PMS2 deficiency. Furthermore, the germline mutation status of MLH1, MSH2, PMS2, and MSH6 in 62 patients was ascertained using next-generation sequencing. All patients displaying MMR gene pathogenic mutations (N = 14) were identified as MSI-H by PCR-HRM, whereas those with MSS tissues (N = 43) did not exhibit MMR gene pathogenic mutations. Thus, the PCR-HRM method proficiently pinpoints tumors with verified germline MMR mutations, indicative of Lynch syndrome. CONCLUSION Conclusively, the PCR-HRM assay emerges as a swift and congruent diagnostic tool for microsatellite instability, boasting commendable sensitivity and specificity in colorectal cancer.
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Affiliation(s)
- Xueping Xiang
- Department of Pathology, The Second Affiliated Hospital, School of MedicineZhejiang UniversityHangzhouZhejiangChina
| | - Xiaojing Ma
- Department of Pathology, The Second Affiliated Hospital, School of MedicineZhejiang UniversityHangzhouZhejiangChina
| | - Linlin Ying
- Department of Pathology, The Second Affiliated Hospital, School of MedicineZhejiang UniversityHangzhouZhejiangChina
| | - Hong Zou
- Department of Pathology, The Second Affiliated Hospital, School of MedicineZhejiang UniversityHangzhouZhejiangChina
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Wang Y, Liu K, He W, Dan J, Zhu M, Chen L, Zhou W, Li M, Li J. Precision prognosis of colorectal cancer: a multi-tiered model integrating microsatellite instability genes and clinical parameters. Front Oncol 2024; 14:1396726. [PMID: 39055563 PMCID: PMC11269184 DOI: 10.3389/fonc.2024.1396726] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Accepted: 06/24/2024] [Indexed: 07/27/2024] Open
Abstract
Background Prognostic assessment for colorectal cancer (CRC) displays substantial heterogeneity, as reliance solely on traditional TNM staging falls short of achieving precise individualized predictions. The integration of diverse biological information sources holds the potential to enhance prognostic accuracy. Objective To establish a comprehensive multi-tiered precision prognostic evaluation system for CRC by amalgamating gene expression profiles, clinical characteristics, and tumor microsatellite instability (MSI) status in CRC patients. Methods We integrated genomic data, clinical information, and survival follow-up data from 483 CRC patients obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. MSI-related gene modules were identified using differential expression analysis and Weighted Gene Co-expression Network Analysis (WGCNA). Three prognostic models were constructed: MSI-Related Gene Prognostic Model (Model I), Clinical Prognostic Model (Model II), and Integrated Multi-Layered Prognostic Model (Model III) by combining clinical features. Model performance was assessed and compared using Receiver Operating Characteristic (ROC) curves, Kaplan-Meier analysis, and other methods. Results Six MSI-related genes were selected for constructing Model I (AUC = 0.724); Model II used two clinical features (AUC = 0.684). Compared to individual models, the integrated Model III exhibited superior performance (AUC = 0.825) and demonstrated good stability in an independent dataset (AUC = 0.767). Conclusion This study successfully developed and validated a comprehensive multi-tiered precision prognostic assessment model for CRC, providing an effective tool for personalized medical management of CRC.
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Affiliation(s)
- Yonghong Wang
- Department of Gastrointestinal Surgery, The People's Hospital of Leshan, Leshan, China
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Okamoto K, Nozawa H, Emoto S, Murono K, Sasaki K, Ishihara S. Adjuvant chemotherapy for elderly patients with colorectal cancer: a single-centre observational study in Japan. J Chemother 2024; 36:319-328. [PMID: 37881011 DOI: 10.1080/1120009x.2023.2273096] [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: 05/08/2023] [Accepted: 10/16/2023] [Indexed: 10/27/2023]
Abstract
Adjuvant chemotherapy improves the prognosis of patients with colorectal cancer (CRC) following radical resection. The aim of the present study is to review appropriate chemotherapeutic regimens for elderly patients. We examined 1138 Japanese patients who were operated for high-risk stage II or stage III CRC between July 2010 and June 2021 at our hospital. Patients were divided according to an age of 70 years. The efficacy of adjuvant therapy was analyzed in association with age and adjuvant chemotherapeutic regimens. A total of 507 patients (45%) were ≥70 years old. They were less likely to receive adjuvant chemotherapy (p < 0.001) or palliative chemotherapy after recurrence (p < 0.001) than patients aged <70 years. Cancer-specific survival (CSS) in stage III CRC patients was longer in the <70 years group than in the ≥70 years group (p = 0.006); however, CSS by regimens did not significantly differ between these groups. Adjuvant chemotherapy was associated with the longer relapse-free survival of stage III CRC patients in the <70 years group (p = 0.005). Although adjuvant chemotherapy was associated with a favourable CSS regardless of age, the implementation rate of adjuvant chemotherapy for elderly CRC patients was low, which may explain shorter CSS in stage III CRC patients the ≥70 years group than in the <70 years group.
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Affiliation(s)
- Kazuaki Okamoto
- Department of Surgical Oncology, The University of Tokyo, Tokyo, Japan
| | - Hiroaki Nozawa
- Department of Surgical Oncology, The University of Tokyo, Tokyo, Japan
| | - Shigenobu Emoto
- Department of Surgical Oncology, The University of Tokyo, Tokyo, Japan
| | - Koji Murono
- Department of Surgical Oncology, The University of Tokyo, Tokyo, Japan
| | - Kazuhito Sasaki
- Department of Surgical Oncology, The University of Tokyo, Tokyo, Japan
| | - Soichiro Ishihara
- Department of Surgical Oncology, The University of Tokyo, Tokyo, Japan
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Norollahi SE, Babaei K, Vahidi S, Motaz SJH, Tarbeghan MK, Khaleghipour M, Gharakhyli EA, Mirhafez SR, Samadani AA. Evaluation of Fluctuations of BRAF Gene Expression and its Polymorphism at rs1267623 in Colorectal Cancer. Microrna 2024; 13:202-210. [PMID: 39005128 DOI: 10.2174/0122115366286360240625095932] [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: 12/20/2023] [Revised: 05/25/2024] [Accepted: 05/27/2024] [Indexed: 07/16/2024]
Abstract
BACKGROUND Molecular markers in Colorectal Cancer (CRC) are needed for more accurate classification and personalized treatment. In this way, we investigated the effects of the BRAF gene on clinical outcomes of its expression fluctuations and its polymorphism at rs1267623 in CRC. METHODS In this study, 36.36 percent of patients with CRC were women, and 63.63 percent were men. After the pathology department confirmed the tumor of the samples, the stage and grade of the tumor were determined according to the TNM system. Real-time PCR was used to check the expression of the BRAF gene in tumor and non-tumor tissues, and its polymorphism in rs1267623 was also checked using the Tetra-ARMs PCR technique. RESULTS The expression of BRAF in tumor tissues was significantly higher than in non-tumoral tissues (P = 0.001), indicating an upregulation of BRAF gene expression in tumoral tissues. The user's text is empty. Furthermore, there was a significant correlation between BRAF expression and tumor stage (P = 0.001), as well as tumor grade (P = 0.003). However, no significant link was found between lymph node metastasis and distant metastasis of BRAF gene expression (P = 0.3). Additionally, no mutation was detected in the investigation of rs1267623 polymorphism. CONCLUSION The BRAF gene was upregulated in tumoral tissues. Remarkably, no mutation was found in the rs1267623 polymorphism. As a result, this gene can be used as a biomarker in the diagnosis and treatment of CRC.
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Affiliation(s)
- Seyedeh Elham Norollahi
- Cancer Research Center and Department of Immunology, Semnan University of Medical Sciences, Semnan, Iran
| | - Kosar Babaei
- Noncommunicable Diseases Research Center, Neyshabur University of Medical Sciences, Neyshabur, Iran
| | - Sogand Vahidi
- Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | | | | | - Mostafa Khaleghipour
- Noncommunicable Diseases Research Center, Neyshabur University of Medical Sciences, Neyshabur, Iran
| | | | - Seyed Reza Mirhafez
- Noncommunicable Diseases Research Center, Neyshabur University of Medical Sciences, Neyshabur, Iran
| | - Ali Akbar Samadani
- Noncommunicable Diseases Research Center, Neyshabur University of Medical Sciences, Neyshabur, Iran
- Guilan Road Trauma Research Center, Trauma Institute, Guilan University of Medical Sciences, Rasht, Iran
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Chen T, Chu Y, Xu H, Dai H, Zhou Y, Du H, Zhu W. Kinesin superfamily member KIFC2 as an independent prognostic biomarker of colon adenocarcinoma associated with poor immune response. Medicine (Baltimore) 2023; 102:e35491. [PMID: 37904433 PMCID: PMC10615560 DOI: 10.1097/md.0000000000035491] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2023] [Accepted: 09/13/2023] [Indexed: 11/01/2023] Open
Abstract
Clinical outcomes of colon adenocarcinoma (COAD) exhibit heterogeneity among different patients, highlighting the need for novel prognostic biomarkers. Kinesin superfamily members have been shown to play a crucial role in tumors and can predict cancer diagnosis and prognosis. However, the role of kinesin family member C2 (KIFC2) in tumors, particularly its prognostic value in COAD, remains poorly understood. Our bioinformatics analysis of the cancer genome atlas and GEO databases revealed significantly higher expression of KIFC2 in COAD, correlating with a worse prognosis in the cancer genome atlas-COAD and GSE17536 cohorts. Additionally, differentially expressed genes in COAD were enriched in immune-related pathways, and patients with higher KIFC2 expression showed fewer activated CD4 + T cells. These findings suggest KIFC2 as a potential prognostic biomarker for COAD, warranting further validation in clinical studies.
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Affiliation(s)
- Tao Chen
- Department of Gastrointestinal Surgery, The Affiliated Changzhou No.2 People’s Hospital with Nanjing Medical University, Changzhou, Jiangsu, China
| | - Yunqian Chu
- Cancer Center, The Affiliated Changzhou No. 2 People’s Hospital with Nanjing Medical University, Changzhou, Jiangsu, China
| | - Haiyuan Xu
- Department of Medical Oncology, Kunshan First People’s Hospital Affiliated to Jiangsu University, Kunshan, Jiangsu, China
| | - Hanjue Dai
- Cancer Center, The Affiliated Changzhou No. 2 People’s Hospital with Nanjing Medical University, Changzhou, Jiangsu, China
| | - Yuxi Zhou
- Burning Rock Biotech, Guangzhou, China
| | - Haiwei Du
- Burning Rock Biotech, Guangzhou, China
| | - Wenyu Zhu
- Cancer Center, The Affiliated Changzhou No. 2 People’s Hospital with Nanjing Medical University, Changzhou, Jiangsu, China
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Giammanco A, Anzalone R, Serra N, Graceffa G, Vieni S, Scibetta N, Rea T, Capra G, Fasciana T. Helicobacter pylori and Epstein-Barr Virus Co-Infection in Gastric Disease: What Is the Correlation with p53 Mutation, Genes Methylation and Microsatellite Instability in a Cohort of Sicilian Population? Int J Mol Sci 2023; 24:ijms24098104. [PMID: 37175810 PMCID: PMC10179236 DOI: 10.3390/ijms24098104] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Revised: 04/06/2023] [Accepted: 04/10/2023] [Indexed: 05/15/2023] Open
Abstract
Genetic predisposition, environmental factors, and infectious agents interact in the development of gastric diseases. Helicobacter pylori (Hp) and Epstein-Barr virus (EBV) infection has recently been shown to be correlated with these diseases. A cross-sectional study was performed on 100 hospitalized Italian patients with and without gastric diseases. The patients were stratified into four groups. Significant methylation status differences among CDH1, DAPK, COX2, hMLH1 and CDKN2A were observed for coinfected (Hp-EBV group) patients; particularly, a significant presence of COX2 (p = 0.0179) was observed. For microsatellite instability, minor stability was described in the Hp-HBV group (69.23%, p = 0.0456). Finally, for p53 mutation in the EBV group, exon 6 was, significantly, most frequent in comparison to others (p = 0.0124), and in the Hp-EBV group exon 8 was, significantly, most frequent in comparison to others (p < 0.0001). A significant positive relationship was found between patients with infection (Hp, EBV or both) and p53 mutation (rho = 0.383, p = 0.0001), methylation status (rho = 0.432, p < 0.0001) and microsatellite instability (rho = 0.285, p = 0.004). Finally, we observed among infection and methylation status, microsatellite instability, and p53 mutation a significant positive relationship only between infection and methylation status (OR = 3.78, p = 0.0075) and infection and p53 mutation (OR = 6.21, p = 0.0082). According to our analysis, gastric disease in the Sicilian population has different pathways depending on the presence of various factors, including infectious agents such as Hp and EBV and genetic factors of the subject.
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Affiliation(s)
- Anna Giammanco
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, University of Palermo, 90127 Palermo, Italy
| | - Rita Anzalone
- Department of Surgical Oncological and Oral Sciences, University of Palermo, 90133 Palermo, Italy
| | - Nicola Serra
- Department of Public Health, University Federico II of Naples, 80138 Napoli, Italy
| | - Giuseppa Graceffa
- Department of Surgical Oncological and Oral Sciences, University of Palermo, 90133 Palermo, Italy
| | - Salvatore Vieni
- Department of Surgical Oncological and Oral Sciences, University of Palermo, 90133 Palermo, Italy
| | - Nunzia Scibetta
- Anatomopathology Unit, Arnas Civico Di Cristina Benfratelli Hospital, 90127 Palermo, Italy
| | - Teresa Rea
- Public Health Department, Federico II University Hospital, 80131 Naples, Italy
| | - Giuseppina Capra
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, University of Palermo, 90127 Palermo, Italy
| | - Teresa Fasciana
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, University of Palermo, 90127 Palermo, Italy
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11
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Amodio V, Lamba S, Chilà R, Cattaneo CM, Mussolin B, Corti G, Rospo G, Berrino E, Tripodo C, Pisati F, Bartolini A, Aquilano MC, Marsoni S, Mauri G, Marchiò C, Abrignani S, Di Nicolantonio F, Germano G, Bardelli A. Genetic and pharmacological modulation of DNA mismatch repair heterogeneous tumors promotes immune surveillance. Cancer Cell 2023; 41:196-209.e5. [PMID: 36584674 PMCID: PMC9833846 DOI: 10.1016/j.ccell.2022.12.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2022] [Revised: 03/23/2022] [Accepted: 12/06/2022] [Indexed: 12/31/2022]
Abstract
Patients affected by colorectal cancer (CRC) with DNA mismatch repair deficiency (MMRd), often respond to immune checkpoint blockade therapies, while those with mismatch repair-proficient (MMRp) tumors generally do not. Interestingly, a subset of MMRp CRCs contains variable fractions of MMRd cells, but it is unknown how their presence impacts immune surveillance. We asked whether modulation of the MMRd fraction in MMR heterogeneous tumors acts as an endogenous cancer vaccine by promoting immune surveillance. To test this hypothesis, we use isogenic MMRp (Mlh1+/+) and MMRd (Mlh1-/-) mouse CRC cells. MMRp/MMRd cells mixed at different ratios are injected in immunocompetent mice and tumor rejection is observed when at least 50% of cells are MMRd. To enrich the MMRd fraction, MMRp/MMRd tumors are treated with 6-thioguanine, which leads to tumor rejection. These results suggest that genetic and pharmacological modulation of the DNA mismatch repair machinery potentiate the immunogenicity of MMR heterogeneous tumors.
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Affiliation(s)
- Vito Amodio
- Department of Oncology, University of Torino, 10060 Candiolo, TO, Italy; Candiolo Cancer Institute, FPO - IRCCS, 10060 Candiolo, TO, Italy
| | - Simona Lamba
- Candiolo Cancer Institute, FPO - IRCCS, 10060 Candiolo, TO, Italy
| | - Rosaria Chilà
- Department of Oncology, University of Torino, 10060 Candiolo, TO, Italy; IFOM ETS - The AIRC Institute of Molecular Oncology, 20139 Milan, Italy
| | - Chiara M Cattaneo
- IFOM ETS - The AIRC Institute of Molecular Oncology, 20139 Milan, Italy
| | | | - Giorgio Corti
- Department of Oncology, University of Torino, 10060 Candiolo, TO, Italy; Candiolo Cancer Institute, FPO - IRCCS, 10060 Candiolo, TO, Italy
| | - Giuseppe Rospo
- Department of Oncology, University of Torino, 10060 Candiolo, TO, Italy; Candiolo Cancer Institute, FPO - IRCCS, 10060 Candiolo, TO, Italy
| | - Enrico Berrino
- Candiolo Cancer Institute, FPO - IRCCS, 10060 Candiolo, TO, Italy; Department of Medical Sciences, University of Torino, Torino, Italy
| | - Claudio Tripodo
- IFOM ETS - The AIRC Institute of Molecular Oncology, 20139 Milan, Italy; Tumor Immunology Unit, Department of Health Sciences, University of Palermo, 90127 Palermo, Italy
| | - Federica Pisati
- Histopathology Unit, Cogentech S.C.a.R.L., 20139, Milan, Italy
| | - Alice Bartolini
- Candiolo Cancer Institute, FPO - IRCCS, 10060 Candiolo, TO, Italy
| | - Maria Costanza Aquilano
- Department of Hematology, Oncology, and Molecular Medicine, ASST Grande Ospedale Metropolitano Niguarda, 20162 Milan, Italy
| | - Silvia Marsoni
- IFOM ETS - The AIRC Institute of Molecular Oncology, 20139 Milan, Italy
| | - Gianluca Mauri
- IFOM ETS - The AIRC Institute of Molecular Oncology, 20139 Milan, Italy; Department of Oncology and Hemato-Oncology, University of Milan, 20162 Milan, Italy
| | - Caterina Marchiò
- Candiolo Cancer Institute, FPO - IRCCS, 10060 Candiolo, TO, Italy; Department of Medical Sciences, University of Torino, Torino, Italy
| | - Sergio Abrignani
- Istituto Nazionale Genetica Molecolare INGM 'Romeo ed Enrica Invernizzi', 20122 Milan, Italy; Department of Clinical Sciences and Community Health, University of Milan, 20122 Milan, Italy
| | - Federica Di Nicolantonio
- Department of Oncology, University of Torino, 10060 Candiolo, TO, Italy; Candiolo Cancer Institute, FPO - IRCCS, 10060 Candiolo, TO, Italy
| | - Giovanni Germano
- Department of Oncology, University of Torino, 10060 Candiolo, TO, Italy; Candiolo Cancer Institute, FPO - IRCCS, 10060 Candiolo, TO, Italy.
| | - Alberto Bardelli
- Department of Oncology, University of Torino, 10060 Candiolo, TO, Italy; Candiolo Cancer Institute, FPO - IRCCS, 10060 Candiolo, TO, Italy.
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12
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Sfakianaki M, Tzardi M, Tsantaki K, Koutoulaki C, Messaritakis I, Datseri G, Moustou E, Mavroudis D, Souglakos J. Evaluation of Microsatellite Instability Molecular Analysis versus Immuno-Histochemical Interpretation in Malignant Neoplasms with Different Localizations. Cancers (Basel) 2023; 15:cancers15020353. [PMID: 36672302 PMCID: PMC9856558 DOI: 10.3390/cancers15020353] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2022] [Revised: 12/09/2022] [Accepted: 01/03/2023] [Indexed: 01/06/2023] Open
Abstract
MMR gene germline mutations are considered a major genetic disorder in patients with hereditary nonpolyposis colon cancer (HNPCC) or Lynch syndrome; A total of 15% of sporadic colon carcinomas are MSI-High. MSI has also been observed in other cancers, such as endometrial, gastric, and ovarian cancer. The aim of the current study was to correlate and outline the optimal method between the molecular testing of the instability of microsatellite DNA regions (MSI status) and the loss of protein expression by immunehistochemistry (MMR). A total of 242 paraffin-embedded tissues from gastrointestinal, gynecological, genitourinary, lung, breast, and unknown primary cancer patients were analyzed for the expression of MLH1/MSH2/MSH6/PMS2 by immunohistochemistry, as well as for the molecular analysis of MSI status using PCR-based molecular fragment analysis. A total of 29 MSI-High patients were detected molecularly, while 23 patients were detected by immunohistochemistry, with rates that are comparable according to the literature. Based on the agreement coefficient of the two methods, a substantial agreement emerged (Kappa = 0.675 with standard error = 0.081, p < 0.001). Despite the substantial agreement, both methods ought to be established to determine MSI-H/dMMR status in all cancer types as a first-line screening test.
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Affiliation(s)
- Maria Sfakianaki
- Laboratory of Translational Oncology, School of Medicine, University of Crete, 71003 Heraklion, Greece
- Correspondence: (M.S.); (I.M.); Tel.: +30-281-039-4926 (I.M.)
| | - Maria Tzardi
- Department of Pathology, University General Hospital of Heraklion, 71110 Heraklion, Greece
| | - Konstantina Tsantaki
- Laboratory of Translational Oncology, School of Medicine, University of Crete, 71003 Heraklion, Greece
| | - Chara Koutoulaki
- Laboratory of Translational Oncology, School of Medicine, University of Crete, 71003 Heraklion, Greece
| | - Ippokratis Messaritakis
- Laboratory of Translational Oncology, School of Medicine, University of Crete, 71003 Heraklion, Greece
- Correspondence: (M.S.); (I.M.); Tel.: +30-281-039-4926 (I.M.)
| | - Galateia Datseri
- Department of Pathology, University General Hospital of Heraklion, 71110 Heraklion, Greece
| | - Eleni Moustou
- Department of Pathology, University General Hospital of Heraklion, 71110 Heraklion, Greece
| | - Dimitrios Mavroudis
- Laboratory of Translational Oncology, School of Medicine, University of Crete, 71003 Heraklion, Greece
- Department of Medical Oncology, University General Hospital of Heraklion, 71500 Iraklio, Greece
| | - John Souglakos
- Laboratory of Translational Oncology, School of Medicine, University of Crete, 71003 Heraklion, Greece
- Department of Medical Oncology, University General Hospital of Heraklion, 71500 Iraklio, Greece
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13
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Tabernero J, Ros J, Élez E. The Evolving Treatment Landscape in BRAF-V600E-Mutated Metastatic Colorectal Cancer. Am Soc Clin Oncol Educ Book 2022; 42:1-10. [PMID: 35503983 DOI: 10.1200/edbk_349561] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Between 8% and 12% of patients with metastatic colorectal cancer (mCRC) harbor a BRAF-V600E mutation in their tumors, which is associated with a poor response to standard chemotherapy and short overall survival. Moreover, nearly 30% of BRAF-V600E mCRC tumors also have microsatellite instability. Transcriptomic signatures suggest a strong immunogenic biologic background for most of these tumors. In contrast to the melanoma context, single-agent BRAF inhibition does not achieve clinical benefit in BRAF-V600E mCRC. Different preclinical/translational studies have elucidated that, in this context, upon BRAF inhibition, there is immediate signal upregulation via the EGFR, and therefore an anti-EGFR treatment should be added to the BRAF inhibitor. Several phase II studies have confirmed the activity of BRAF inhibitors combined with EGFR-directed monoclonal antibodies in patients with BRAF-V600E mCRC. The role of other mitogen-activated protein kinase inhibitors, such as mitogen-activated protein kinase kinase or PI3K inhibitors, remains unclear. The phase III BEACON clinical trial confirmed the BRAF/EGFR inhibitor combination of encorafenib/cetuximab as the new standard of care for BRAF-V600E mCRC after at least one previous line of systemic therapy. Novel approaches for managing BRAF-V600E mCRC include, among others, triple combinations of BRAF inhibitors and anti-EGFR antibodies combined with immune checkpoint inhibitors in the microsatellite instability population and evaluation of the encorafenib/cetuximab treatment in combination with standard chemotherapy with bevacizumab in the first-line setting.
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Affiliation(s)
- Josep Tabernero
- Medical Oncology Department, Vall d'Hebron University Hospital, Barcelona, Spain.,Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
| | - Javier Ros
- Medical Oncology Department, Vall d'Hebron University Hospital, Barcelona, Spain.,Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
| | - Elena Élez
- Medical Oncology Department, Vall d'Hebron University Hospital, Barcelona, Spain.,Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
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Sadahiro S, Sakamoto K, Tsuchiya T, Takahashi T, Ohge H, Sato T, Kondo K, Ogata Y, Baba H, Itabashi M, Ikeda M, Hamada M, Maeda K, Masuko H, Takahashi K, Sakamoto J, Kusano M, Hyodo I, Taguri M, Morita S. Prospective observational study of the efficacy of oral uracil and tegafur plus leucovorin for stage II colon cancer with risk factors for recurrence using propensity score matching (JFMC46-1201). BMC Cancer 2022; 22:170. [PMID: 35168560 PMCID: PMC8845390 DOI: 10.1186/s12885-022-09267-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Accepted: 01/31/2022] [Indexed: 11/24/2022] Open
Abstract
Background The efficacy of adjuvant chemotherapy for high-risk stage II colon cancer (CC) has not been well established. We compared the effects of surgery with and without oral uracil and tegafur plus leucovorin (UFT/LV) in patients with high-risk stage II CC, adjusting for potential risk factors. Methods We enrolled patients with histologically confirmed stage II colon adenocarcinoma with at least one of the following conditions: T4 disease, perforation/penetration, poorly differentiated adenocarcinoma/mucinous carcinoma, or < 12 dissected lymph nodes. Patients chose to be non-randomized or randomized to undergo surgery alone (NR-Group S or R-Group S) or surgery followed by 6 months of UFT/LV (NR-Group U or R-Group U). The primary endpoint was disease-free survival (DFS) after adjusting for previously reported risk factors using propensity score matching (1:2) and inverse probability of treatment weighting (IPTW) in the non-randomized arm. Results Overall, 1,902 (98%) and 36 (2%) patients were enrolled in the non-randomized and randomized arms, respectively. There were too few patients in the randomized arm and these were therefore excluded from the analysis. Of the 1,902 patients, 402 in NR-Group S and 804 in NR-Group U were propensity score-matched. The 3-year DFS rate (95% confidence interval) was significantly higher in NR-Group U (80.9% [77.9%–83.4%]) than in NR-Group S (74.0% [69.3%–78.0%]) (hazard ratio, 0.64 [0.50–0.83]; P = 0.0006). The 3-year overall survival rate was not significantly different between NR-Group S and NR-Group U. Significantly higher 3-year DFS (P = 0.0013) and overall survival (P = 0.0315) rates were observed in NR-Group U compared with NR-Group S using IPTW. Conclusions Adjuvant chemotherapy with UFT/LV showed a significant survival benefit over surgery alone in patients with high-risk stage II CC characterized by at least one of the following conditions: T4 disease, perforation/penetration, poorly differentiated adenocarcinoma/mucinous carcinoma, or < 12 dissected lymph nodes. Trial registration Japan Registry of Clinical Trials: jRCTs031180155 (date of registration: 25/02/2019) (UMIN Clinical Trials Registry: UMIN000007783, date of registration: 18/04/2012). Supplementary Information The online version contains supplementary material available at 10.1186/s12885-022-09267-z.
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Affiliation(s)
- Sotaro Sadahiro
- Department of Surgery, Tokai University, 143 Shimokasuya, Isehara, Kanagawa, 259-1193, Japan.
| | - Kazuhiro Sakamoto
- Department of Coloproctological Surgery, Juntendo University, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan
| | - Takashi Tsuchiya
- Department of Surgery, Sendai City Medical Center, 5-22-1 Tsurugaya, Miyagino-ku, Sendai, Miyagi, 983-0824, Japan
| | - Takao Takahashi
- Department of Digestive Surgery, Gifu University Hospital, 1-1 Yanagido, Gifu, 501-1194, Japan
| | - Hiroki Ohge
- Department of Infectious Diseases, Hiroshima University Hospital, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Toshihiko Sato
- Department of Surgery, Yamagata Prefectural Central Hospital, 1800 Aoyagi, Yamagata, 990-2292, Japan
| | - Ken Kondo
- Department of Surgery, Nagoya Medical Center, 4-1-1 Sannomaru, Naka-ku, Nagoya, Aichi, 460-0001, Japan
| | - Yutaka Ogata
- Department of Surgery, Kurume University Hospital Cancer Center, 67 Asahi-machi, Kurume, Fukuoka, 830-0011, Japan
| | - Hideo Baba
- Department of Gastroenterological Surgery, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan
| | - Michio Itabashi
- Department of Surgery, Division of Inflammatory Bowel Disease Surgery, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, 162-8666, Japan
| | - Masataka Ikeda
- Department of Gastroenterological Surgery, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan
| | - Madoka Hamada
- Division of Gastrointestinal Surgery, Kansai Medical University Hospital, 2-3-1 Shinmachi Hirakata, Osaka, 573-1191, Japan
| | - Kiyoshi Maeda
- Department of Gastroenterological Surgery, Osaka City General Hospital, 2-13-22 Miyakojimahondori, Miyakojima-ku, Osaka, 534-0021, Japan
| | - Hiroyuki Masuko
- Department of Surgery, Nikko Memorial Hospital, 1-5-13 Shintomi-cho, Muroran, Hokkaido, 051-8501, Japan
| | - Keiichi Takahashi
- Tokyo Metropolitan Health and Hospitals Corporation Ohkubo Hospital, 2-44-1 Kabuki-cho, Shinjuku-ku, Tokyo, 160-8488, Japan
| | - Junichi Sakamoto
- Tokai Central Hospital, 4-6-2 Sohara Higashijima-cho, Kakamigahara, Gifu, 504-8601, Japan
| | - Mitsuo Kusano
- Department of Physical Medicine, Yoichi Hospital, 19-1-1 Kurokawa-cho Yoichi, Hokkaido, 046-0003, Japan
| | - Ichinosuke Hyodo
- Department of Gastrointestinal Medical Oncology, National Hospital Organization Shikoku Cancer Center, 160 Kou, Minamiumemoto, Matsuyama, Ehime, 791-0280, Japan
| | - Masataka Taguri
- Department of Data Science, Yokohama City University, 22-2 Seto, Kanazawa-ku, Yokohama, Kanagawa, 236-0027, Japan
| | - Satoshi Morita
- Department of Biomedical Statistics and Bioinformatics, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan
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15
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Lim JH, Huh JW, Lee WY, Yun SH, Kim HC, Cho YB, Park YA, Shin JK. Comparison of Long-Term Survival Outcomes of T4a and T4b Colorectal Cancer. Front Oncol 2022; 11:780684. [PMID: 35070985 PMCID: PMC8770269 DOI: 10.3389/fonc.2021.780684] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Accepted: 12/13/2021] [Indexed: 12/02/2022] Open
Abstract
Background Although T4b is known to have worse oncologic outcomes, it is unclear whether it truly shows a worse prognosis. This study aims to compare the survival differences between T4a and T4b. Methods Patients who were pathologically diagnosed with T3 and T4 colorectal adenocarcinoma from 2010 to 2014 were included (T3, n = 1822; T4a, n = 424; T4b, n = 67). Overall survival (OS) and cancer-specific survival (CSS) were compared between T4a and T4b using the Kaplan-Meier method and log-rank test. Results In stage II, T4a had better OS and CSS than T4b (5-year OS, 89.5% vs. 72.6%; 5-year CSS, 94.4% vs. 81.7%, all p < 0.05), however, in stage III, there were no significant differences in survivals between groups (all p > 0.05). In multivariable analysis, T classification was not an independent risk factor for OS (p > 0.05). However, for CSS, when respectively compared to T3, T4b (HR 3.53, p < 0.001) showed a relatively higher hazard ratio than T4a (HR 2.27, p < 0.001). Conclusions T4a showed more favorable OS and CSS than T4b, especially in stage II. Our findings support the current AJCC guidelines, in which T4b is presented as a more advanced stage than T4a.
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Affiliation(s)
- Ji Ha Lim
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Jung Wook Huh
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Woo Yong Lee
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Seong Hyeon Yun
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Hee Cheol Kim
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Yong Beom Cho
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Yoon Ah Park
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Jung Kyong Shin
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
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16
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Grothey A, Fakih M, Tabernero J. Management of BRAF-mutant metastatic colorectal cancer: a review of treatment options and evidence-based guidelines. Ann Oncol 2021; 32:959-967. [PMID: 33836264 DOI: 10.1016/j.annonc.2021.03.206] [Citation(s) in RCA: 109] [Impact Index Per Article: 27.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Revised: 03/24/2021] [Accepted: 03/25/2021] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Colorectal cancer (CRC) is still a leading cause of cancer-related deaths in the United States and worldwide, despite recent improvements in cancer management. CRC, like many malignancies, is a heterogeneous disease, with subtypes characterized by genetic alterations. One common mutation in CRC is in the BRAF gene (most commonly V600E substitution). This occurs in ∼10% of patients with metastatic CRC (mCRC) and is a marker of poor prognosis. DESIGN Herein, we review the clinical and translational literature on the role of the BRAF V600E mutation in the pathogenesis of mCRC, its mechanisms as a prognostic marker, and its potential utility as a predictive marker of treatment response. We then summarize the current evidence-based recommendations for management of BRAF V600E-mutated mCRC, with a focus on recent clinical research advances in this setting. RESULTS The current standard therapies for first-line treatment of BRAF-mutated mCRC are chemotherapy with bevacizumab as well as 5-fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) plus bevacizumab in patients with a good performance status. Combination strategies involving mitogen-activated protein kinase (MAPK) pathway blockade have shown promising results for the treatment of patients with BRAF V600E-mutated mCRC. The Binimetinib, Encorafenib, And Cetuximab cOmbiNed to treat BRAF-mutant ColoRectal Cancer (BEACON CRC) study represents the largest study in this population to date and has given strong clinical evidence to support BRAF and epidermal growth factor receptor inhibition with the combination of encorafenib plus cetuximab. CONCLUSIONS The treatment of BRAF-mutated mCRC has evolved rapidly over the last several years. Recently, combination strategies involving MAPK pathway blockade have shown promising results in BRAF V600E-mutated mCRC, and other potential targets continue to be explored. In addition, a greater understanding of the role of BRAF V600E mutation in the pathogenesis of CRC should also continue to fuel advances in the management of patients with mCRC harboring this genetic aberration.
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Affiliation(s)
- A Grothey
- West Cancer Center and Research Institute, OneOncology, Germantown, USA
| | - M Fakih
- Department of Medical Oncology, City of Hope National Medical Center, Duarte, USA
| | - J Tabernero
- Vall d'Hebron Hospital Campus, Vall d'Hebron Institute of Oncology, UVIC-UCC, IOB-Quiron, Barcelona, Spain.
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17
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Gilson P, Merlin JL, Harlé A. Detection of Microsatellite Instability: State of the Art and Future Applications in Circulating Tumour DNA (ctDNA). Cancers (Basel) 2021; 13:cancers13071491. [PMID: 33804907 PMCID: PMC8037825 DOI: 10.3390/cancers13071491] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Revised: 03/15/2021] [Accepted: 03/22/2021] [Indexed: 12/11/2022] Open
Abstract
Simple Summary Microsatellite instability (MSI) is a molecular fingerprint for defects in the mismatch repair system (dMMR) and is associated with higher risks of cancers. MSI/dMMR tumours are characterized by the accumulation of mutations throughout the genome, and particularly in microsatellite (MS) DNA repeat sequences. MSI stands as a major biomarker for familial cancer risk assessment, cancer prognosis, and therapeutic choices. Standard-of-care classification of MSI/dMMR tumours is most frequently achieved using immunohistochemistry or PCR-based assay directed against a set of five MS regions. However, novel molecular methods based on tumour tissue or plasma samples have been developed and could enter in the future trends of MSI testing. Here, we provide insights into these emerging approaches and discuss their advantages and limitations. Abstract Microsatellite instability (MSI) is a molecular scar resulting from a defective mismatch repair system (dMMR) and associated with various malignancies. MSI tumours are characterized by the accumulation of mutations throughout the genome and particularly clustered in highly repetitive microsatellite (MS) regions. MSI/dMMR status is routinely assessed in solid tumours for the initial screening of Lynch syndrome, the evaluation of cancer prognosis, and treatment decision-making. Currently, pentaplex PCR-based methods and MMR immunohistochemistry on tumour tissue samples are the standard diagnostic methods for MSI/dMMR. Other tissue methods such as next-generation sequencing or real-time PCR-based systems have emerged and represent viable alternatives to standard MSI testing in specific settings. The evolution of the standard molecular techniques has offered the opportunity to extend MSI determination to liquid biopsy based on the analysis of cell-free DNA (cfDNA) in plasma. This review aims at synthetizing the standard and emerging techniques used on tumour tissue samples for MSI/dMMR determination. We also provide insights into the MSI molecular techniques compatible with liquid biopsy and the potential clinical consequences for patients with solid cancers.
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Affiliation(s)
- Pauline Gilson
- Correspondence: ; Tel.: +33-(0)3-8365-6035; Fax: +33-(0)3-8365-6152
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18
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Nelson DW, Merritt C, Chang SC, Grunkemeier G, Steele SR, Goldfarb M. Development of a Risk Score and Nomogram to Predict Individual Benefit Attained from the Addition of Adjuvant Chemotherapy in the Treatment of Stage II Colon Cancer. J Gastrointest Surg 2021; 25:220-232. [PMID: 32748339 DOI: 10.1007/s11605-020-04757-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2020] [Accepted: 07/19/2020] [Indexed: 01/31/2023]
Abstract
BACKGROUND Current guidelines recommend considering adjuvant chemotherapy (AC) for stage II colon cancer (CC) with poor prognostic clinicopathologic and molecular features. However, the relative impact of individual or constellations of high-risk features remains undefined. We developed an individualized point-of-care tool to predict survival benefit attained from the addition of AC. METHODS The National Cancer Database was queried for all patients with resected stage II CC from 2004 to 2015. A prognostic risk score and nomogram were constructed using twelve clinicopathologic and molecular prognostic factors associated with outcomes for CC. Overall survival (OS) was compared between surgery alone and AC groups. The nomogram was validated for discrimination and calibration using bootstrap-adjusted Harrell's concordance index (C-index). For population-level estimation, OS was compared based on quartiles. RESULTS Of 132,666 patients with stage II CC, 16.8% received AC. The calibration curve of the constructed nomogram showed a good agreement between predicted and observed median and 3-, 5-, and 10-year survival (bootstrap-adjusted C-index 0.699, CI: 0.698-0.703). Population-level risk score analysis (median [Q1, Q3]; 4.9 [4.6, 5.5]) demonstrated that patients with scores > 3.34 had significantly decreased risk of death with the addition of AC (all p < 0.001). No survival advantage was associated with AC among patients with low risk scores (risk score < 3.34: HR: 0.94, 95% CI: 0.80-1.11, p = 0.47). DISCUSSION A composite weighted risk score is critical to individualizing AC in select high-risk patients. Our nomogram provides individualized prognostication and estimation of benefit attained from AC. This may better inform treatment decisions and aid future trial design.
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Affiliation(s)
- Daniel W Nelson
- Department of Surgery, William Beaumont Army Medical Center, 5005 N. Piedras St., El Paso, TX, 79920, USA.
| | - Clay Merritt
- Department of Surgery, William Beaumont Army Medical Center, 5005 N. Piedras St., El Paso, TX, 79920, USA
| | - Shu-Ching Chang
- Medical Data Research Center, Providence St. Joseph Health, Portland, OR, USA
| | - Gary Grunkemeier
- Medical Data Research Center, Providence St. Joseph Health, Portland, OR, USA
| | - Scott R Steele
- Department of Colorectal Surgery, Cleveland Clinic, Cleveland, OH, USA
| | - Melanie Goldfarb
- Division of Surgical Oncology, John Wayne Cancer Institute at Providence Saint John's Health Center, Santa Monica, CA, USA.,Center for Endocrine Tumors and Disorders, John Wayne Cancer Institute at Providence Saint John's Health Center, Santa Monica, CA, USA
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19
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Taghizadeh H, Mader RM, Müllauer L, Erhart F, Kautzky-Willer A, Prager GW. Precision Medicine for the Management of Therapy Refractory Colorectal Cancer. J Pers Med 2020; 10:jpm10040272. [PMID: 33322358 PMCID: PMC7768503 DOI: 10.3390/jpm10040272] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Revised: 12/07/2020] [Accepted: 12/09/2020] [Indexed: 12/30/2022] Open
Abstract
In this analysis, we examined the efficacy, feasibility, and limitations of molecular-based targeted therapies in heavily pretreated metastatic colorectal cancer (mCRC) patients after failure of all standard treatments. In this single-center, real-world retrospective analysis of our platform for precision medicine, we mapped the molecular profiles of 60 mCRC patients. Tumor samples of the patients were analyzed using next-generation sequencing panels of mutation hotspots, microsatellite instability testing, and immunohistochemistry. All profiles were reviewed by a multidisciplinary team to provide a targeted treatment recommendation after consensus discussion. In total, we detected 166 mutations in 53 patients. The five most frequently found mutations were TP53, KRAS, APC, PIK3CA, and PTEN. In 28 cases (47% of all patients), a molecularly targeted therapy could be recommended. Eventually, 12 patients (20%) received the recommended therapy. Six patients (10%) had a clinical benefit. The median time to treatment failure was 3.1 months. Our study demonstrates the feasibility and applicability of using targeted therapies in daily clinical practice for heavily pretreated mCRC patients. This could be used as a targeted treatment option in half of the patients.
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Affiliation(s)
- Hossein Taghizadeh
- Department of Medicine I, Clinical Division of Oncology, Medical University of Vienna, 1090 Vienna, Austria; (H.T.); (R.M.M.)
- Comprehensive Cancer Center Vienna, 1090 Vienna, Austria;
| | - Robert M. Mader
- Department of Medicine I, Clinical Division of Oncology, Medical University of Vienna, 1090 Vienna, Austria; (H.T.); (R.M.M.)
- Comprehensive Cancer Center Vienna, 1090 Vienna, Austria;
| | - Leonhard Müllauer
- Comprehensive Cancer Center Vienna, 1090 Vienna, Austria;
- Clinical Institute of Pathology, Medical University Vienna, 1090 Vienna, Austria
| | - Friedrich Erhart
- Department of Internal Medicine, Amstetten Region State Clinic, 3300 Amstetten, Austria;
| | - Alexandra Kautzky-Willer
- Department of Medicine III, Gender Medicine Unit, Medical University of Vienna, 1090 Vienna, Austria;
| | - Gerald W. Prager
- Department of Medicine I, Clinical Division of Oncology, Medical University of Vienna, 1090 Vienna, Austria; (H.T.); (R.M.M.)
- Comprehensive Cancer Center Vienna, 1090 Vienna, Austria;
- Correspondence: ; Tel.: +43-1-40400-44500
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20
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Li L, Zhou W, Li Q, Li P, Yang L, Xia X, Yi X, Wan D. Tumor-derived mutations in postoperative plasma of colorectal cancer with microsatellite instability. Transl Oncol 2020; 14:100945. [PMID: 33190041 PMCID: PMC7674603 DOI: 10.1016/j.tranon.2020.100945] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Revised: 10/22/2020] [Accepted: 11/04/2020] [Indexed: 11/16/2022] Open
Abstract
The mutation in postoperative plasma (molecular residues) was an independently prognostic factor in colorectal cancer (CRC). The status of postoperative plasma mutation of microsatellite instability (MSI) CRC has not been systematically examined. In this study, we enrolled 30 MSI and 46 microsatellite stability (MSS) CRCs, and performed next generation sequencing on surgical tissues, postoperative plasma, and plasma during follow-up. Compared with MSS, MSI tumors had dissimilar genomic profiles, higher tumor mutation burden (TMB), and more frameshift mutations. In the postoperative plasma, more MSI CRCs were detected with tumor-derived mutations (77% in MSI vs 33% in MSS, p < 0.001). The numbers of postoperative mutations were proportional to MSI tissues (Spearman r = 0.47, p = 0.023), while not for MSS. More proportion of postoperative plasma samples of MSI CRCs harbored frameshift mutations than MSS (p = 0.007). For the follow-up plasma, 93% (14 out of 15) MSI CRCs harbored tumor-derived mutations; 33% (4/12) MSS were mutation-positive, lower than MSI (p = 0.003). Thus, considering that MSI CRC had extremely distinct mutational characteristics in tumor and postoperative plasma compared with MSS CRC, we propose that the prognostic value of molecular residue identification in postoperative plasma needs to be independently evaluated in MSI and MSS CRCs.
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Affiliation(s)
- Liren Li
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, Guangdong 510060, P. R. China; Department of Colorectal Surgery, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, P. R. China.
| | - Wenhao Zhou
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, Guangdong 510060, P. R. China; Department of Colorectal Surgery, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, P. R. China.
| | - Qian Li
- Geneplus-Beijing, Beijing 102206, P. R. China.
| | - Pansong Li
- Geneplus-Beijing, Beijing 102206, P. R. China.
| | - Ling Yang
- Geneplus-Beijing, Beijing 102206, P. R. China.
| | - Xuefeng Xia
- Geneplus-Beijing, Beijing 102206, P. R. China.
| | - Xin Yi
- Geneplus-Beijing, Beijing 102206, P. R. China.
| | - Desen Wan
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, Guangdong 510060, P. R. China; Department of Colorectal Surgery, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, P. R. China.
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21
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Evaluation of 3 molecular-based assays for microsatellite instability detection in formalin-fixed tissues of patients with endometrial and colorectal cancers. Sci Rep 2020; 10:16386. [PMID: 33009475 PMCID: PMC7532161 DOI: 10.1038/s41598-020-73421-5] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Accepted: 09/14/2020] [Indexed: 12/24/2022] Open
Abstract
Microsatellite instability (MSI) status is routinely assessed in patients with colorectal and endometrial cancers as it contributes to Lynch syndrome initial screening, tumour prognosis and selecting patients for immunotherapy. Currently, standard reference methods recommended for MSI/dMMR (deficient MisMatch Repair) testing consist of immunohistochemistry and pentaplex PCR-based assays, however, novel molecular-based techniques are emerging. Here, we aimed to evaluate the performance of a custom capture-based NGS method and the Bio-Rad ddPCR and Idylla approaches for the determination of MSI status for theranostic purposes in 30 formalin-fixed paraffin embedded (FFPE) tissue samples from patients with endometrial (n = 15) and colorectal (n = 15) cancers. All samples were previously characterised using IHC and Promega MSI Analysis System and these assays set as golden standard. Overall agreement, sensitivity and specificity of our custom-built NGS panel were 93.30%, 93.75% and 92.86% respectively. Overall agreement, sensitivity and specificity were 100% with the Idylla MSI system. The Bio-Rad ddPCR MSI assay showed a 100% concordance, sensitivity and specificity. The custom capture-based NGS, Bio-Rad ddPCR and Idylla approaches represent viable and complementary options to IHC and Promega MSI Analysis System for the detection of MSI. Bio-Rad ddPCR and Idylla MSI assays accounts for easy and fast screening assays while the NGS approach offers the advantages to simultaneously detect MSI and clinically relevant genomic alterations.
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22
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Prognostic implications of EGFR protein expression in sporadic colorectal tumors: Correlation with copy number status, mRNA levels and miRNA regulation. Sci Rep 2020; 10:4662. [PMID: 32170146 PMCID: PMC7070091 DOI: 10.1038/s41598-020-61688-7] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2019] [Accepted: 02/26/2020] [Indexed: 11/10/2022] Open
Abstract
Sporadic colorectal cancer (sCRC) is the third most frequent cancer worldwide and the second most common cause of cancer-related deaths (mainly due metastatic dissemination). We investigated the immunohistochemical expression of frequently altered proteins in primary tumors from 51 patients (25 liver metastatic and 26 non-metastatic cases) with a median 103 months follow-up (103 months). We evaluated EGFR copy number (using SNP arrays and FISH) and its expression and regulation (by mRNA and miRNA arrays). We found differences between metastatic and non-metastatic sCRCs for MLH1 (p = 0.05), PMS2 (p = 0.02), CEA (p < 0.001) and EGFR (p < 0.001) expression. EGFR expression was associated with lymph node metastases (p = 0.001), liver metastases at diagnosis (p < 0.001), and advanced stage (p < 0.001). There were associations between EGFR expression-, EGFR gene copy number- and EGFR mRNA levels. We found potential interactions of two miRNAs targeting EGFR expression, (miR-134 and miR-4328, in non-metastatic and metastatic tumors, respectively). EGFR expression was associated with a worse outcome (p = 0.005). Multivariate analysis of prognostic factors for overall survival identified that, the expression of EGFR expression (p = 0.047) and pTNM stage (p < 0.001) predicted an adverse outcome. EGFR expression could be regulated by amplification or polysomies (in metastatic tumors), or miRNAs (miRNA-134, in non-metastatic tumors). EGFR expression in sCRC appears to be related to metastases and poor outcome.
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23
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Paulose RR, Ail DA, Biradar S, Vasudevan A, Sundaram KR. Prognostic and predictive significance of microsatellite instability in stage II colorectal carcinoma: An 8-year study from a tertiary center in South India. Indian J Cancer 2020; 56:302-308. [PMID: 31607697 DOI: 10.4103/ijc.ijc_365_18] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
BACKGROUND Microsatellite instability (MSI) accounts for 15-20% of colorectal cancer (CRC) and is considered to have favorable stage-adjusted prognosis compared to Microsatellite stable (MSS) CRCs. Determination of MSI in stage II CRC is important for management decisions regarding adjuvant chemotherapy administration. The aim of this study was to determine the prognostic and predictive significance of MSI in stage 2 CRC in the Indian scenario. MATERIALS AND METHODS A total of 195 patients who underwent curative surgery for stage II CRC from 2010 to 2017 were included. MSI testing by immunohistochemistry (DNA MisMatch Repair proteins) was performed in all. Various clinicopathological factors and disease-free survival and overall survival were assessed between MSI and MSS groups. The effect of treatment in terms of survival benefits with adjuvant therapy in the MSI group was also assessed. RESULTS 27.1% of the CRCs' showed MSI. Younger age (<50 years), family history of cancer, synchronous/metachronous malignancies, proximal (right sided) location, poor morphological tumour differentiation, mucin production, and presence of peritumoral (Crohn's-like) lymphocytic response showed statistically significant association with MSI. Majority (56%) of our patients showed combined loss of MLH1 and PMS2. Overall, survival among the MSI patients was significantly higher (76.6 ± 4.149 months) than the MSS patients (65.05 ± 3.555)P= 0.04. MSI patients did not show any differences in survival with or without treatment. CONCLUSION This study highlights the distinct clinicopathological features of MSI-related CRC and the relevance of MSI testing of stage II CRC for management decisions and prognostication.
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Affiliation(s)
- Roopa R Paulose
- Department of Pathology, Amrita Institute of Medical Sciences, Kochi, Kerala, India
| | - Divya A Ail
- Department of Pathology, Amrita Institute of Medical Sciences, Kochi, Kerala, India
| | - Shital Biradar
- Department of Pathology, Amrita Institute of Medical Sciences, Kochi, Kerala, India
| | - Anu Vasudevan
- Department of Biostatistics, Amrita Institute of Medical Sciences, Kochi, Kerala, India
| | - K R Sundaram
- Department of Biostatistics, Amrita Institute of Medical Sciences, Kochi, Kerala, India
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24
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Stobbe MD, Thun GA, Diéguez-Docampo A, Oliva M, Whalley JP, Raineri E, Gut IG. Recurrent somatic mutations reveal new insights into consequences of mutagenic processes in cancer. PLoS Comput Biol 2019; 15:e1007496. [PMID: 31765368 PMCID: PMC6901237 DOI: 10.1371/journal.pcbi.1007496] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2019] [Revised: 12/09/2019] [Accepted: 10/22/2019] [Indexed: 12/12/2022] Open
Abstract
The sheer size of the human genome makes it improbable that identical somatic mutations at the exact same position are observed in multiple tumours solely by chance. The scarcity of cancer driver mutations also precludes positive selection as the sole explanation. Therefore, recurrent mutations may be highly informative of characteristics of mutational processes. To explore the potential, we use recurrence as a starting point to cluster >2,500 whole genomes of a pan-cancer cohort. We describe each genome with 13 recurrence-based and 29 general mutational features. Using principal component analysis we reduce the dimensionality and create independent features. We apply hierarchical clustering to the first 18 principal components followed by k-means clustering. We show that the resulting 16 clusters capture clinically relevant cancer phenotypes. High levels of recurrent substitutions separate the clusters that we link to UV-light exposure and deregulated activity of POLE from the one representing defective mismatch repair, which shows high levels of recurrent insertions/deletions. Recurrence of both mutation types characterizes cancer genomes with somatic hypermutation of immunoglobulin genes and the cluster of genomes exposed to gastric acid. Low levels of recurrence are observed for the cluster where tobacco-smoke exposure induces mutagenesis and the one linked to increased activity of cytidine deaminases. Notably, the majority of substitutions are recurrent in a single tumour type, while recurrent insertions/deletions point to shared processes between tumour types. Recurrence also reveals susceptible sequence motifs, including TT[C>A]TTT and AAC[T>G]T for the POLE and 'gastric-acid exposure' clusters, respectively. Moreover, we refine knowledge of mutagenesis, including increased C/G deletion levels in general for lung tumours and specifically in midsize homopolymer sequence contexts for microsatellite instable tumours. Our findings are an important step towards the development of a generic cancer diagnostic test for clinical practice based on whole-genome sequencing that could replace multiple diagnostics currently in use.
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Affiliation(s)
- Miranda D. Stobbe
- CNAG-CRG, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona, Spain
| | - Gian A. Thun
- CNAG-CRG, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona, Spain
| | - Andrea Diéguez-Docampo
- CNAG-CRG, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona, Spain
| | - Meritxell Oliva
- CNAG-CRG, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona, Spain
| | - Justin P. Whalley
- CNAG-CRG, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona, Spain
| | - Emanuele Raineri
- CNAG-CRG, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona, Spain
| | - Ivo G. Gut
- CNAG-CRG, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona, Spain
- Universitat Pompeu Fabra (UPF), Barcelona, Spain
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25
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Park YY, An CH, Oh ST, Chang ED, Lee J. Expression of CD133 is associated with poor prognosis in stage II colorectal carcinoma. Medicine (Baltimore) 2019; 98:e16709. [PMID: 31393377 PMCID: PMC6708874 DOI: 10.1097/md.0000000000016709] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/26/2023] Open
Abstract
CD133 is currently believed to be one of the best colorectal cancer stem cell markers. This study aimed to evaluate prognostic significance of CD133 expression in colorectal cancer patients.A total of 303 patients with stage I to III colorectal cancer who underwent curative surgical resection from 2003 to 2008 at a single institution were included. CD133 expression was evaluated using immunohistochemical staining, and clinicopathological data were retrospectively reviewed. The patients were dichotomized after scoring CD133 expression (0 to 2+: low CD133 expression vs 3+ to 4+: high CD133 expression) according to the extent of area of CD133 positive tumor cells (<50% vs ≥50%) and pattern of staining (membranous staining of the luminal surface and/or staining of cellular debris in the tumor glands and cytoplasm).The 5-year overall survival (OS) (61.9% vs 80.2%, P = .001) and disease-free survival (64.8% vs 75.8%, P = .026) were poorer in the high CD133 expression group than the low CD133 expression group. In the multivariate analysis for risk factors of OS in the whole population, higher nodal stage (N2 compared to N0: hazard ratio [HR] 3.141; 95% confidence interval [CI] 1.718-5.744, P < .001), perineural invasion (HR 2.262; 95% CI 1.347-3.798, P = .002) and high CD133 expression (HR 1.929; 95% CI 1.221-3.048, P = .005) were independent poor prognostic factors of OS. Subgroup analyses according to each TNM stage revealed that CD133 expression was associated with OS only within the stage II patients (HR 3.167 95% CI 1.221-8.216, P = .018). Furthermore, the stage II patients demonstrating the high CD133 expression showed survival benefit of adjuvant chemotherapy, regardless of high-risk feature positivity (HR 0.201 95% CI 0.054-0.750, P = .017).High CD133 expression is correlated with poor prognosis in colorectal cancer patients after radical resection. The CD133 expression may serve as a more potent and informative biomarker for prognosis than conventional high-risk features in the stage II colorectal cancer patients.
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Affiliation(s)
| | | | | | - Eun Deock Chang
- Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
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26
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Ramaswamy A, Kothari R, Desouza A, Gupta T, Bairwa S, Kapoor A, Kumar A, Ventrapati P, Ramadwar M, Mandavkar S, Chavan N, Saklani A, Ostwal V. Adjuvant chemotherapy in stage II-III operated colon cancer patients from a nontrial cohort in a low colon cancer prevalence country with predominant use of modified CAPOX. South Asian J Cancer 2019; 8:160-165. [PMID: 31489288 PMCID: PMC6699238 DOI: 10.4103/sajc.sajc_176_18] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
BACKGROUND Data regarding the practice of adjuvant chemotherapy, specifically with modified CAPOX, and survival outcomes in operated colon cancer patients from a nontrial cohort in a lower-middle income and low prevalence nation like India is scarce. MATERIALS AND METHODS Patients who underwent upfront curative resection for colon cancer from January 2013 to December 2016 were analyzed for baseline variables and outcomes. RESULTS A total of 491 patients underwent curative resection in the predefined time period. The median age of the patients was 53 years (range: 17-87). Patients with Stage I, Stage II, and Stage III disease comprised 7.9%, 44.8%, and 45.4% of the entire cohort, respectively. Patients with Stage I cancer were observed. Adjuvant chemotherapy was planned for 384 patients (78.2%), with the doublet regimens (capecitabine-oxaliplatin, or 5-fluorouracil-oxaliplatin) being used commonly (77.6%). Common toxicities were Hand-foot syndrome (Grade 2/3 - 21.4%) and peripheral neuropathy (Grade 2/3 - 20.1%). About 85% of patients receiving monotherapy (capecitabine or 5 fluorouracil) and 81.2% of patients receiving doublet chemotherapy (mCAPOX or modified FOLFOX-7) completed their planned adjuvant treatment. With a median follow-up of 22 months, estimated 3 years event-free survival was 86%, and overall survival (OS) was 93.6%. Stage, younger age (<50 years), underlying cardiovascular abnormalities, need for dose reductions and noncompletion of planned chemotherapy predicted for inferior estimated 3-year OS on multivariate analysis. CONCLUSIONS Adjuvant chemotherapy especially with modified CAPOX appears well tolerated in the Indian population and early survival outcomes appear to be comparable to published literature.
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Affiliation(s)
- Anant Ramaswamy
- Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India
| | - Rushabh Kothari
- Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India
| | - Ashwin Desouza
- Department of Surgical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India
| | - Tarachand Gupta
- Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India
| | - Sandeep Bairwa
- Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India
| | - Akhil Kapoor
- Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India
| | - Amit Kumar
- Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India
| | - Pradeep Ventrapati
- Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India
| | - Mukta Ramadwar
- Department of Pathology, Tata Memorial Hospital, Mumbai, Maharashtra, India
| | - Sarika Mandavkar
- Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India
| | - Nita Chavan
- Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India
| | - Avanish Saklani
- Department of Surgical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India
| | - Vikas Ostwal
- Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India
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27
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Gan Z, Zou Q, Lin Y, Xu Z, Huang Z, Chen Z, Lv Y. Identification of a 13-gene-based classifier as a potential biomarker to predict the effects of fluorouracil-based chemotherapy in colorectal cancer. Oncol Lett 2019; 17:5057-5063. [PMID: 31186717 PMCID: PMC6507297 DOI: 10.3892/ol.2019.10159] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2018] [Accepted: 02/25/2019] [Indexed: 12/14/2022] Open
Abstract
The aim of the current study was to develop a predictor classifier for response to fluorouracil-based chemotherapy in patients with advanced colorectal cancer (CRC) using microarray gene expression profiles of primary CRC tissues. Using two expression profiles downloaded from the Gene Expression Omnibus database, differentially expressed genes (DEGs) between responders and non-responders to fluorouracil-based chemotherapy were identified. A total of 791 DEGs, including 303 that were upregulated and 488 that were downregulated in responders, were identified. Functional enrichment analysis revealed that the DEGs were primarily involved in 'cell mitosis', 'DNA replication' and 'cell cycle' signaling pathways. Following feature selection using two methods, a random forest classifier for response to fluorouracil-based chemotherapy with 13 DEGs was constructed. The accuracy of the 13-gene classifier was 0.930 in the training set and 0.810 in the validation set. The receiver operating characteristic curve analysis revealed that the area under the curve was 1.000 in the training set and 0.873 in the validation set (P=0.227). The 13-gene-based classifier described in the current study may be used as a potential biomarker to predict the effects of fluorouracil-based chemotherapy in patients with CRC.
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Affiliation(s)
- Zuhuan Gan
- Department of Medical Oncology, Affiliated Langdong Hospital of Guangxi Medical University, Guangxi Medical University Kaiyuan Langdong Hospital, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Qiyuan Zou
- Department of Medicine, Affiliated Langdong Hospital of Guangxi Medical University, Guangxi Medical University Kaiyuan Langdong Hospital, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Yan Lin
- Department of Medical Oncology, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Zihai Xu
- Department of Medical Oncology, Affiliated Langdong Hospital of Guangxi Medical University, Guangxi Medical University Kaiyuan Langdong Hospital, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Zhong Huang
- Department of Medical Oncology, Affiliated Langdong Hospital of Guangxi Medical University, Guangxi Medical University Kaiyuan Langdong Hospital, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Zhichao Chen
- Department of Medical Oncology, Affiliated Langdong Hospital of Guangxi Medical University, Guangxi Medical University Kaiyuan Langdong Hospital, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Yufeng Lv
- Department of Medical Oncology, Affiliated Langdong Hospital of Guangxi Medical University, Guangxi Medical University Kaiyuan Langdong Hospital, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
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28
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Yozu M, Kumarasinghe MP, Brown IS, Gill AJ, Rosty C. Australasian Gastrointestinal Pathology Society (AGPS) consensus guidelines for universal defective mismatch repair testing in colorectal carcinoma. Pathology 2019; 51:233-239. [DOI: 10.1016/j.pathol.2018.11.014] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2018] [Revised: 11/18/2018] [Accepted: 11/25/2018] [Indexed: 01/28/2023]
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29
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Fischer J, Walker LC, Robinson BA, Frizelle FA, Church JM, Eglinton TW. Clinical implications of the genetics of sporadic colorectal cancer. ANZ J Surg 2019; 89:1224-1229. [PMID: 30919552 DOI: 10.1111/ans.15074] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2018] [Revised: 12/17/2018] [Accepted: 12/22/2018] [Indexed: 01/07/2023]
Abstract
Colorectal cancer (CRC) is common and at least 80% of cases are sporadic, without any significant family history. Prognostication and treatment have been relatively empirical for what has become increasingly identified as a genetically heterogeneous disease. There are three main genetic pathways in sporadic CRC: the chromosomal instability pathway, the microsatellite instability pathway and the CpG island methylator phenotype pathway. There is significant overlap between these complex molecular pathways and this limits the clinical application of CRC genetics. Recent Australian and New Zealand guidelines recommend routine testing of mismatch repair (MMR) status for new cases of CRC and selective KRAS and BRAF testing on the basis of diagnostic, prognostic and therapeutic implications. It is important that all clinicians treating CRC have an understanding of the importance of and basis for identifying key genetic features of CRC. It is likely that in the future better molecular characterization such as that allowed by the consensus molecular subtype classification will allow improved prognostication and targeted therapy in order to deliver more personalized treatment for CRC.
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Affiliation(s)
- Jesse Fischer
- Department of Surgery, University of Otago, Christchurch, New Zealand
| | - Logan C Walker
- Department of Pathology, University of Otago, Christchurch, New Zealand
| | - Bridget A Robinson
- Department of Medicine, University of Otago, Christchurch, New Zealand.,Oncology Service, Christchurch Hospital, Christchurch, New Zealand
| | - Frank A Frizelle
- Department of Surgery, University of Otago, Christchurch, New Zealand.,Department of Surgery, Canterbury District Health Board, Christchurch, New Zealand
| | - James M Church
- Department of Colorectal Surgery, Cleveland Clinic Foundation, Cleveland, Ohio, USA
| | - Tim W Eglinton
- Department of Surgery, University of Otago, Christchurch, New Zealand.,Department of Surgery, Canterbury District Health Board, Christchurch, New Zealand
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30
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Pinto JC, Rosa I, Martins C, Marques I, da Silva JP, Fonseca R, Freire J, Pereira AD. Colon Adenocarcinoma Stage IIA-Can We Predict Relapse? J Gastrointest Cancer 2019; 51:116-120. [PMID: 30834501 DOI: 10.1007/s12029-019-00218-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
PURPOSE To determine prognostic factors for stage IIA colon cancer (CC) recurrence in patients undergoing curative intent surgery without adjuvant treatment. METHODS Single-centre cohort study. All patients with stage IIA CC discussed in a multidisciplinary colorectal cancer clinic from January 2010 to December 2012 were evaluated. Clinical data, laboratory data and tumour features, including expression of DNA repair proteins (EDRP), were analysed. Assessment of overall and disease free survival, recurrence, recurrence site and recurrence's method of diagnosis was performed. The associations between variables were tested through the Fisher's exact test (SPSS 23). RESULTS Fifty-five patients were included (55% male gender; mean age at diagnosis was 70.3 years (42-88)). CC was in the left colon in 62%, high grade in 7% and had lymphovascular invasion in 7% of the cases. Only one patient was submitted to emergent surgery for obstructive symptoms. In 55% of cases ≥ 12 lymph nodes were collected. There was EDRP loss in nine patients (MLH1/PMS2: six; MSH2/MSH6: three)-only two fulfilled revised Bethesda criteria. Recurrence occurred in five patients (8.9%), and it was diagnosed through surveillance in all of them. No variable showed a statistically significant association with recurrence; however, there were no recurrences in patients with EPRD loss (p = 0.209). Mean follow-up time was 43 months (2-70). In those with recurrence, mean disease-free survival was 23.4 months. CONCLUSIONS The overall good prognosis and absence of recurrence predictive factors were confirmed, validating the decision of not to submit stage IIA CC patients to chemotherapy risks.
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Affiliation(s)
- João Cortez Pinto
- Serviço de Gastrenterologia, Instituto Português de Oncologia de Lisboa Francisco Gentil (IPOLFG) EPE, 1099-023, Lisbon, Portugal.
| | - Isadora Rosa
- Serviço de Gastrenterologia, Instituto Português de Oncologia de Lisboa Francisco Gentil (IPOLFG) EPE, 1099-023, Lisbon, Portugal
| | - Catarina Martins
- Serviço de Gastrenterologia, Instituto Português de Oncologia de Lisboa Francisco Gentil (IPOLFG) EPE, 1099-023, Lisbon, Portugal
| | - Inês Marques
- Serviço de Gastrenterologia, Instituto Português de Oncologia de Lisboa Francisco Gentil (IPOLFG) EPE, 1099-023, Lisbon, Portugal
| | - João Pereira da Silva
- Serviço de Gastrenterologia, Instituto Português de Oncologia de Lisboa Francisco Gentil (IPOLFG) EPE, 1099-023, Lisbon, Portugal
| | - Ricardo Fonseca
- Serviço de Anatomia Patológica, Instituto Português de Oncologia de Lisboa Francisco Gentil (IPOLFG) EPE, 1099-023, Lisbon, Portugal
| | - João Freire
- Serviço de Oncologia, Instituto Português de Oncologia de Lisboa Francisco Gentil (IPOLFG) EPE, 1099-023, Lisbon, Portugal
| | - António Dias Pereira
- Serviço de Gastrenterologia, Instituto Português de Oncologia de Lisboa Francisco Gentil (IPOLFG) EPE, 1099-023, Lisbon, Portugal
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Otto W, Macrae F, Sierdziński J, Smaga J, Król M, Wilińska E, Zieniewicz K. Microsatellite instability and manifestations of angiogenesis in stage IV of sporadic colorectal carcinoma. Medicine (Baltimore) 2019; 98:e13956. [PMID: 30608431 PMCID: PMC6344194 DOI: 10.1097/md.0000000000013956] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2018] [Revised: 11/05/2018] [Accepted: 12/11/2018] [Indexed: 12/20/2022] Open
Abstract
Angiogenesis represents one of the critical mechanisms that facilitates carcinoma development. The study objective was to evaluate whether the microsatellite instability of colorectal carcinoma has impact on the angiogenesis activity in liver metastases.In a cohort of 80 randomly selected patients with stage IV colorectal carcinoma, 30% were recognized as microsatellite unstable (Microsatellite instability high-frequency (MSI-H)). The endothelial progenitor cell fraction (CD309+) was counted within the subpopulation of CD34+CD45+ cell and CD34+CD45- cells by flow cytometer. vascular endothelial growth factor (VEGF) factor levels were quantified in serum samples by enzyme-linked immunosorbent assay (ELISA). A control group consisted of 36 healthy volunteers. The relationship of genomic instability to angiogenesis activity was evaluated by multivariate analysis in comparison to the controls, adopting a P < .05 value as statistically significant.The expression of endothelial progenitor cells (EPCs) and VEGF was significantly higher in MSI-H compared to both microsatellite stability (MSS) patients and healthy controls (P < .008). Multi-parametric analysis showed microsatellite instability (OR=9.12, P < .01), metastases in both lobes (OR = 32.83, P < .001) and simultaneous metastases outside liver (OR = 8.32, P < .01), as independent factors associated with increased angiogenesis as assessed by measures of EPC and VEGF. A higher percentage of EPCs within the white blood cell fraction (total % EPCs / white blood cells (WBC)) and higher serum concentrations of VEGF were present in patients with MSI-H colorectal cancer, and not with MSS cancers (P < .001).MSI-H patients with colorectal cancer metastases are associated with the overexpression of circulating EPCs and VEGF, potentially driving angiogenesis. This should be considered in therapeutic decision-making.
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Affiliation(s)
| | - Finlay Macrae
- Department of Colorectal Medicine and Genetics, The Royal Melbourne Hospital, and Department of Medicine, The University of Melbourne, Australia
| | | | | | - Maria Król
- Department of Oncology, Hematology & Internal Medicine
| | - Ewa Wilińska
- Department of Pathology Central Teaching Hospital, Medical University of Warsaw, Banacha 1a, 02-097 Warsaw, Poland
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Next Generation Sequencing (NGS): A Revolutionary Technology in Pharmacogenomics and Personalized Medicine in Cancer. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1168:9-30. [DOI: 10.1007/978-3-030-24100-1_2] [Citation(s) in RCA: 65] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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Narayanan S, Gabriel E, Attwood K, Boland P, Nurkin S. Association of Clinicopathologic and Molecular Markers on Stage-specific Survival of Right Versus Left Colon Cancer. Clin Colorectal Cancer 2018; 17:e671-e678. [PMID: 30108021 PMCID: PMC10625797 DOI: 10.1016/j.clcc.2018.07.001] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Revised: 06/23/2018] [Accepted: 07/02/2018] [Indexed: 02/08/2023]
Abstract
BACKGROUND Previous studies have shown that variability in molecular markers correlates with poorer survival outcomes in patients with right-sided colon cancer (RCC) compared with left-sided colon cancer (LCC). However, several studies have shown conflicting results when examined stage for stage. We examined RCC and LCC to assess for differences in histopathologic features and overall survival (OS). MATERIALS AND METHODS The National Cancer Database was used to identify patients with RCC and LCC from 2004 to 2013. A propensity-adjusted analysis evaluating the association between the primary site and OS was performed. RESULTS Of the 422,443 patients identified, 54.7% had RCC and 45.3% had LCC. For all stages, the patients with RCC were older, had more poorly differentiated tumors, and had a greater degree of microsatellite instability compared with those with LCC. Patients with RCC also had more KRAS mutations than did those with LCC. RCC patients had poorer 3- and 5-year OS at all stages, especially stage 3 (62% vs. 73% and 50% vs. 62%, respectively; P < .001). The median OS was 77.5 months for LCC and 62.3 months for RCC (P < .001). CONCLUSION The present study is one of the largest studies demonstrating that RCC and LCC are different biologic entities. Patients with RCC had significantly greater rates of microsatellite instability for all stages, which has been previously shown to be prognostically advantageous. However, the results of the present study showed poorer OS at every disease stage for RCC compared with LCC. These factors have important implications for the further use of targeted therapies in the treatment of advanced colon cancer.
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Affiliation(s)
- Sumana Narayanan
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY
| | - Emmanuel Gabriel
- Section of Surgical Oncology, Department of Surgery, Mayo Clinic, Jacksonville, FL
| | - Kristopher Attwood
- Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center Buffalo, NY
| | - Patrick Boland
- Department of Medicine, Gastrointestinal Center, Roswell Park Comprehensive Cancer Center Buffalo, NY
| | - Steven Nurkin
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY.
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Tan WJ, Hamzah JL, Acharyya S, Foo FJ, Lim KH, Tan IBH, Tang CL, Chew MH. Evaluation of Long-Term Outcomes of Microsatellite Instability Status in an Asian Cohort of Sporadic Colorectal Cancers. J Gastrointest Cancer 2018; 49:311-318. [PMID: 28550452 DOI: 10.1007/s12029-017-9953-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
PURPOSE Microsatellite instability in colorectal cancer (CRC) and its long-term outcomes remains poorly studied in Asians. We investigate the prognostic significance of microsatellite instability in an Asian population and assess its clinical impact in patients who undergo adjuvant chemotherapy. METHODS Six hundred fifty-four consecutive CRC patients who underwent surgical resection between January 2010 and December 2012 were recruited. Survival was estimated using the Kaplan-Meier approach. Univariate Cox proportional hazard models were used to estimate the hazard ratios for variables associated with survival. A subgroup analyses was performed for stage III patients who underwent chemotherapy to evaluate the prognostic significance of microsatellite instability in this group. RESULTS Five hundred ninety-one (90.4%) patients were microsatellite stable (MSS) while 63 (9.6%) were microsatellite instable (MSI). Three years recurrence-free survival (RFS) and disease-specific survival (DSS) were 83.7 versus 73.7% (p = 0.295) and 87.1 versus 91.2% (p = 0.307) in MSS and MSI tumors, respectively. Among stage III patients who received adjuvant therapy, MSI status was found to be an adverse prognostic factor for RFS (HR 2.74 (95% CI 1.43-5.26), p = 0.002). This remained significant on multivariate analysis (HR 2.38 (95% CI 1.15-4.93), p = 0.018). Adjuvant chemotherapy was associated with survival benefit for patients with MSS tumors (HR 0.35, 95% CI 0.17-0.69, p = 0.002) but not MSI tumors (HR 0.67, 95% CI 0.08-8.15, p = 0.750). CONCLUSIONS MSI status is not a prognostic indicator in the general CRC population but appears to be an adverse prognostic indicator for RFS in stage III CRC patients who received adjuvant chemotherapy.
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Affiliation(s)
- Winson Jianhong Tan
- Department of Colorectal Surgery, Singapore General Hospital, 20 College Road, Academia, Singapore, 169856, Singapore.
| | - Julie Liana Hamzah
- Department of Colorectal Surgery, Singapore General Hospital, 20 College Road, Academia, Singapore, 169856, Singapore
| | - Sanchalika Acharyya
- Centre for Qualitative Medicine, DUKE NUS Graduate Medical School, Singapore, Singapore
| | - Fung Joon Foo
- Department of Colorectal Surgery, Singapore General Hospital, 20 College Road, Academia, Singapore, 169856, Singapore
| | - Kiat Hon Lim
- Department of Pathology, Singapore General Hospital, Singapore, Singapore
| | - Iain Bee Huat Tan
- Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore
| | - Choong Leong Tang
- Department of Colorectal Surgery, Singapore General Hospital, 20 College Road, Academia, Singapore, 169856, Singapore
| | - Min Hoe Chew
- Department of Colorectal Surgery, Singapore General Hospital, 20 College Road, Academia, Singapore, 169856, Singapore
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Germano G, Amirouchene-Angelozzi N, Rospo G, Bardelli A. The Clinical Impact of the Genomic Landscape of Mismatch Repair-Deficient Cancers. Cancer Discov 2018; 8:1518-1528. [PMID: 30442708 DOI: 10.1158/2159-8290.cd-18-0150] [Citation(s) in RCA: 91] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2018] [Revised: 06/06/2018] [Accepted: 09/04/2018] [Indexed: 11/16/2022]
Abstract
The mismatch repair (MMR) system which detects and corrects base mismatches and insertions and deletions that occur during DNA synthesis is deregulated in approximately 20% of human cancers. MMR-deficient tumors have peculiar properties, including early-onset metastatic potential but generally favorable prognosis, and remarkable response to immune therapy. The functional basis of these atypical clinical features has recently started to be elucidated. Here, we discuss how the biological and clinical features of MMR-deficient tumors might be traced back to their ability to continuously produce new somatic mutations, leading to increased levels of neoantigens, which in turn stimulate immune surveillance. SIGNIFICANCE: Tumors carrying defects in DNA MMR accumulate high levels of mutations, a feature linked to rapid tumor progression and acquisition of drug resistance but also favorable prognosis and response to immune-checkpoint blockade. We discuss how the genomic landscape of MMR-deficient tumors affects their biological and clinical behaviors.
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Affiliation(s)
- Giovanni Germano
- Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Torino, Italy.,Department of Oncology, University of Torino, Candiolo, Torino, Italy
| | | | | | - Alberto Bardelli
- Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Torino, Italy. .,Department of Oncology, University of Torino, Candiolo, Torino, Italy
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Clinical Targeted Next-Generation Sequencing Shows Increased Mutational Load in Endometrioid-type Endometrial Adenocarcinoma With Deficient DNA Mismatch Repair. Int J Gynecol Pathol 2018; 37:581-589. [DOI: 10.1097/pgp.0000000000000459] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
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Mismatch Repair Protein Defects and Microsatellite Instability in Malignant Pleural Mesothelioma. J Thorac Oncol 2018; 13:1588-1594. [PMID: 30056163 DOI: 10.1016/j.jtho.2018.07.015] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2018] [Revised: 07/11/2018] [Accepted: 07/12/2018] [Indexed: 01/28/2023]
Abstract
INTRODUCTION Malignant pleural mesothelioma is an aggressive malignancy with limited systemic therapy options. Promising results have been reported with use of anti-programmed cell death 1 therapy; however, its benefits appear to be confined to a subgroup of patients. Microsatellite instability (MSI) results from the inactivation of DNA mismatch repair genes and results in a high tumor mutational burden, a phenomenon that has not been seen with mesothelioma. MSI and protein absence have been shown to correlate in colorectal cancer, such that most centers have adopted immunohistochemistry (IHC) to screen for MSI-high colorectal cancers. We profiled a large cohort of patients with mesothelioma to determine the rate of negative IHC staining results the four common mismatch repair proteins. DESIGN A tissue microarray comprising 335 patients with malignant pleural mesothelioma were used. IHC for the four common mismatch repair proteins (mutL homolog 1; PMS1 homolog 2, mismatch repair system component; mutS homolog 2; and mutS homolog 6) was performed. Programmed death ligand 1 IHC staining with the E1L3N clone was also performed. DNA was isolated from IHC equivocal samples and analyzed for microsatellite instability by using the Promega MSI Analysis System (version 1.2, Promega, Madison, WI). RESULTS Of the patients profiled, 329 had intact mismatch repair proteins by IHC. Six samples with IHC testing results indicating absent mismatch repair protein were analyzed for MSI and confirmed to be negative. Of the six IHC-negative samples, five were negative for programmed death ligand 1 staining and one sample had more than 5% staining. CONCLUSION In this large retrospective series, we were unable to identify any patients with malignant pleural mesothelioma with microsatellite instability. Response to anti-programmed cell death 1-based immunotherapy may be driven by other mechanisms.
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Athanasakis E, Xenaki S, Venianaki M, Chalkiadakis G, Chrysos E. Newly recognized extratumoral features of colorectal cancer challenge the current tumor-node-metastasis staging system. Ann Gastroenterol 2018; 31:525-534. [PMID: 30174388 PMCID: PMC6102465 DOI: 10.20524/aog.2018.0284] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/02/2018] [Accepted: 03/13/2018] [Indexed: 12/12/2022] Open
Abstract
One of the most common malignant tumors in humans, colorectal cancer has been extensively studied during the past few decades. Staging colorectal cancer allows clinicians to obtain precise prognostic information and apply specific treatment procedures. Apart from remote metastases, the depth of tumor infiltration and lymph node involvement have traditionally been recognized as the most important factors predicting outcome. Variations in the molecular signature of colorectal cancer have also revealed differences in phenotypic aggressiveness and therapeutic response rates. This article presents a review of the extratumoral environment in colorectal surgery.
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Affiliation(s)
- Elias Athanasakis
- Department of General Surgery, University Hospital of Heraklion Crete, Greece
| | - Sofia Xenaki
- Department of General Surgery, University Hospital of Heraklion Crete, Greece
| | - Maria Venianaki
- Department of General Surgery, University Hospital of Heraklion Crete, Greece
| | - George Chalkiadakis
- Department of General Surgery, University Hospital of Heraklion Crete, Greece
| | - Emmanuel Chrysos
- Department of General Surgery, University Hospital of Heraklion Crete, Greece
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Clinical Signatures of Mucinous and Poorly Differentiated Subtypes of Colorectal Adenocarcinomas by a Propensity Score Analysis of an Independent Patient Database from Three Phase III Trials. Dis Colon Rectum 2018. [PMID: 29521828 DOI: 10.1097/dcr.0000000000001022] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND Although colorectal cancer comprises several histological subtypes, the influences of histological subtypes on disease progression and treatment responses remain controversial. OBJECTIVE We sought to evaluate the prognostic relevance of mucinous and poorly differentiated histological subtypes of colorectal cancer by the propensity score weighting analysis of prospectively collected data from multi-institute phase III trials. DESIGN Independent patient data analysis of a pooled database from 3 phase III trials was performed. SETTINGS An integrated database of 3 multicenter prospective clinical trials (the Japanese Foundation for Multidisciplinary Treatment of Cancer 7, 15, and 33) was the source of study data. INTERVENTIONS Surgery alone or postoperative adjuvant chemotherapy was offered in patients with resectable colorectal cancer. MAIN OUTCOME MEASURES To balance essential variables more strictly for the comparison analyses, propensity score weighting was conducted with the use of a multinomial logistic regression model. We evaluated the clinical signatures of mucinous and poorly differentiated subtypes with regard to postoperative survival, recurrence, and chemosensitivity. RESULTS Of 5489 patients, 136 (2.5%) and 155 (2.8%) were pathologically diagnosed with poorly differentiated and mucinous subtypes. The poorly differentiated subtypes were associated with a poorer prognosis than the "others" group (HR, 1.69; 95% CI, 1.00-2.87; p = 0.051), particularly in the patient subgroup of adjuvant chemotherapy (HR, 2.16). Although the mucinous subtype had a marginal prognostic impact among patients with stage I to III colorectal cancer (HR, 1.33; 95% CI, 0.90-1.96), it was found to be an independent prognostic factor in the subpopulation of patients with stage II disease, being associated with a higher prevalence of peritoneal recurrence. LIMITATIONS The treatment regimens of postoperative chemotherapy are now somewhat outdated. CONCLUSIONS Both mucinous and poorly differentiated subtypes have distinct clinical characteristics. Patients with the mucinous subtype require special attention during follow-up, even for stage II disease, because of the risk of peritoneal or local recurrence. See Video Abstract at http://links.lww.com/DCR/A531.
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Wang ZN, Liu D, Yin B, Ju WY, Qiu HZ, Xiao Y, Chen YJ, Peng XZ, Lu CM. High expression of PTBP1 promote invasion of colorectal cancer by alternative splicing of cortactin. Oncotarget 2018; 8:36185-36202. [PMID: 28404950 PMCID: PMC5482648 DOI: 10.18632/oncotarget.15873] [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: 06/13/2016] [Accepted: 01/23/2017] [Indexed: 12/22/2022] Open
Abstract
Polypyrimidine tract-binding protein 1 (PTBP1) involving in almost all steps of mRNA regulation including alternative splicing metabolism during tumorigenesis due to its RNA-binding activity. Initially, we found that high expressed PTBP1 and poor prognosis was interrelated in colorectal cancer (CRC) patients with stages II and III CRC, which widely different in prognosis and treatment, by immunohistochemistry. PTBP1 was also upregulated in colon cancer cell lines. In our study, knockdown of PTBP1 by siRNA transfection decreased cell proliferation and invasion in vitro. Denovirus shRNA knockdown of PTBP1 inhibited colorectal cancer growth in vivo. Furthermore, PTBP1 regulates alternative splicing of many target genes involving in tumorgenesis in colon cancer cells. We confirmed that the splicing of cortactin exon 11 which was only contained in cortactin isoform-a, as a PTBP1 target. Knockdown of PTBP1 decreased the expression of cortactin isoform-a by exclusion of exon 11. Also the mRNA levels of PTBP1 and cortactin isoform-a were cooperatively expressed in colorectal cancer tissues. Knocking down cortactin isoform-a significantly decreased cell migration and invasion in colorectal cancer cells. Overexpression of cortactin isoform-a could rescue PTBP1-knockdown effect of cell motility. In summary the study revealed that PTBP1 facilitates colorectal cancer migration and invasion activities by inclusion of cortactin exon 11.
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Affiliation(s)
- Zhi-Na Wang
- Department of Gastroenteology and Hepatology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Dan Liu
- Department of Gastroenteology and Hepatology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.,Department of Gastroenterology and Hepatology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Bin Yin
- National Laboratory of Meidical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Wen-Yi Ju
- National Laboratory of Meidical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Hui-Zhong Qiu
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Yi Xiao
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Yuan-Jia Chen
- Department of Gastroenteology and Hepatology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Xiao-Zhong Peng
- National Laboratory of Meidical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Chong-Mei Lu
- Department of Gastroenteology and Hepatology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
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Oh BY, Kim SY, Lee YS, Hong HK, Kim TW, Kim SH, Lee WY, Cho YB. Twist1-induced epithelial-mesenchymal transition according to microsatellite instability status in colon cancer cells. Oncotarget 2018; 7:57066-57076. [PMID: 27494849 PMCID: PMC5302973 DOI: 10.18632/oncotarget.10974] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2015] [Accepted: 07/18/2016] [Indexed: 12/31/2022] Open
Abstract
Colorectal cancer (CRC) with microsatellite instability (MSI) may exhibit impaired epithelial-mesenchymal transition (EMT), but little is known about the underlying mechanisms of this phenomenon. In this study, we investigated the role of Twist1 and its downstream signaling cascades in EMT induction according to MSI status. To investigate the effects of Twist1 on EMT induction according to MSI status, MSS LS513 and MSI LoVo colon cancer cell lines, which overexpress human Twist1, were generated. Twist1-induced EMT and its downstream signaling pathways were evaluated via in vitro and in vivo experiments. We found that Twist1 induced EMT markers and stem cell-like characteristics via AKT signaling pathways. Twist1 induced activation of AKT and suppression of glycogen synthase kinase (GSK)-3β, which resulted in the activation of β-catenin, increasing CD44 expression. In addition, Twist1 activated the AKT-induced NF-κB pathway, increasing CD44 and CD166 expression. Activation of both the AKT/GSK-3β/β-catenin and AKT/NF-κB pathways occurred in MSS LS513 cells, while only the AKT/GSK-3β/β-catenin pathway was activated in MSI LoVo cells. In conclusion, Twist1 induces stem cell-like characteristics in colon cancer cell lines related to EMT via AKT signaling pathways, and those pathways depend on MSI status.
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Affiliation(s)
- Bo Young Oh
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - So-Young Kim
- Samsung Biomedical Research Institute, Samsung Medical Center, Seoul, Korea
| | - Yeo Song Lee
- Samsung Biomedical Research Institute, Samsung Medical Center, Seoul, Korea
| | - Hye Kyung Hong
- Samsung Biomedical Research Institute, Samsung Medical Center, Seoul, Korea
| | - Tae Won Kim
- Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, Korea
| | - Seok Hyung Kim
- Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Woo Yong Lee
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.,Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, Korea
| | - Yong Beom Cho
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.,Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, Korea.,Department of Medical Device Management & Research, SAIHST, Sungkyunkwan University, Seoul, Korea
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Bramsen JB, Rasmussen MH, Ongen H, Mattesen TB, Ørntoft MBW, Árnadóttir SS, Sandoval J, Laguna T, Vang S, Øster B, Lamy P, Madsen MR, Laurberg S, Esteller M, Dermitzakis ET, Ørntoft TF, Andersen CL. Molecular-Subtype-Specific Biomarkers Improve Prediction of Prognosis in Colorectal Cancer. Cell Rep 2018; 19:1268-1280. [PMID: 28494874 DOI: 10.1016/j.celrep.2017.04.045] [Citation(s) in RCA: 81] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2016] [Revised: 12/28/2016] [Accepted: 04/16/2017] [Indexed: 02/07/2023] Open
Abstract
Colorectal cancer (CRC) is characterized by major inter-tumor diversity that complicates the prediction of disease and treatment outcomes. Recent efforts help resolve this by sub-classification of CRC into natural molecular subtypes; however, this strategy is not yet able to provide clinicians with improved tools for decision making. We here present an extended framework for CRC stratification that specifically aims to improve patient prognostication. Using transcriptional profiles from 1,100 CRCs, including >300 previously unpublished samples, we identify cancer cell and tumor archetypes and suggest the tumor microenvironment as a major prognostic determinant that can be influenced by the microbiome. Notably, our subtyping strategy allowed identification of archetype-specific prognostic biomarkers that provided information beyond and independent of UICC-TNM staging, MSI status, and consensus molecular subtyping. The results illustrate that our extended subtyping framework, combining subtyping and subtype-specific biomarkers, could contribute to improved patient prognostication and may form a strong basis for future studies.
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Affiliation(s)
| | | | - Halit Ongen
- Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva 1211, Switzerland; Institute for Genetics and Genomics in Geneva (iGE3), University of Geneva, Geneva 1211, Switzerland; Swiss Institute of Bioinformatics, Geneva 1211, Switzerland
| | - Trine Block Mattesen
- Department of Molecular Medicine, Aarhus University Hospital, Aarhus 8200, Denmark
| | | | | | - Juan Sandoval
- Cancer Epigenetics and Biology Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet, Barcelona 08908, Catalonia, Spain
| | - Teresa Laguna
- Cancer Epigenetics and Biology Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet, Barcelona 08908, Catalonia, Spain
| | - Søren Vang
- Department of Molecular Medicine, Aarhus University Hospital, Aarhus 8200, Denmark
| | - Bodil Øster
- Department of Molecular Medicine, Aarhus University Hospital, Aarhus 8200, Denmark
| | - Philippe Lamy
- Department of Molecular Medicine, Aarhus University Hospital, Aarhus 8200, Denmark
| | | | - Søren Laurberg
- Section of Coloproctology, Aarhus University Hospital, Aarhus 8000, Denmark
| | - Manel Esteller
- Cancer Epigenetics and Biology Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet, Barcelona 08908, Catalonia, Spain; Physiological Sciences Department, School of Medicine and Health Sciences, University of Barcelona, Barcelona 08907, Catalonia, Spain; Institucio Catalana de Recerca i Estudis Avancats (ICREA), Barcelona 08010, Catalonia, Spain
| | - Emmanouil Theophilos Dermitzakis
- Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva 1211, Switzerland; Institute for Genetics and Genomics in Geneva (iGE3), University of Geneva, Geneva 1211, Switzerland; Swiss Institute of Bioinformatics, Geneva 1211, Switzerland
| | - Torben Falck Ørntoft
- Department of Molecular Medicine, Aarhus University Hospital, Aarhus 8200, Denmark
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Lin HH, Wei NC, Chou TY, Lin CC, Lan YT, Chang SC, Wang HS, Yang SH, Chen WS, Lin TC, Lin JK, Jiang JK. Building personalized treatment plans for early-stage colorectal cancer patients. Oncotarget 2017; 8:13805-13817. [PMID: 28099153 PMCID: PMC5355140 DOI: 10.18632/oncotarget.14638] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2016] [Accepted: 01/06/2017] [Indexed: 12/12/2022] Open
Abstract
We developed a series of models to predict the likelihood of recurrence and the response to chemotherapy for the personalized treatment of stage I and II colorectal cancer patients. A recurrence prediction model was developed from 235 stage I/II patients. The model successfully distinguished between high-risk and low-risk groups, with a hazard ratio of recurrence of 4.66 (p < 0.0001). More importantly, the model was accurate for both stage I (hazard ratio = 5.87, p = 0.0006) and stage II (hazard ratio = 4.30, p < 0.0001) disease. This model performed much better than the Oncotype and ColoPrint commercial services in identifying patients at high risk for stage II recurrence. And unlike the commercial services, the robust model included recurrence prediction for stage I patients. As stage I/II CRC patients usually do not receive chemotherapy, we generated chemotherapy efficacy prediction models with data from 358 stage III patients. The predictions were highly accurate: the hazard ratio of recurrence for responders vs. non-responders was 4.13 for those treated with FOLFOX (p < 0.0001), and 3.16 (p = 0.0012) for those treated with fluorouracil. We have thus created a prognostic model that accurately identifies patients at high risk for recurrence, and the first accurate chemotherapy efficacy prediction model for individual patients. In the future, complete personalized treatment plans for stage I/II patients may be developed if the drug prediction models generated from stage III patients are verified to be effective for stage I and II patients in prospective studies.
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Affiliation(s)
- Hung-Hsin Lin
- Division of Colon and Rectal Surgery, Department of Surgery, Taipei Veterans General Hospital, Taiwan.,Department of Surgery, School of Medicine, National Yang-Ming University, Taiwan
| | | | - Teh-Ying Chou
- Division of Molecular Pathology, Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.,Institute of Clinical Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Chun-Chi Lin
- Division of Colon and Rectal Surgery, Department of Surgery, Taipei Veterans General Hospital, Taiwan.,Department of Surgery, School of Medicine, National Yang-Ming University, Taiwan
| | - Yuan-Tsu Lan
- Division of Colon and Rectal Surgery, Department of Surgery, Taipei Veterans General Hospital, Taiwan.,Department of Surgery, School of Medicine, National Yang-Ming University, Taiwan
| | - Shin-Ching Chang
- Division of Colon and Rectal Surgery, Department of Surgery, Taipei Veterans General Hospital, Taiwan.,Department of Surgery, School of Medicine, National Yang-Ming University, Taiwan
| | - Huann-Sheng Wang
- Division of Colon and Rectal Surgery, Department of Surgery, Taipei Veterans General Hospital, Taiwan.,Department of Surgery, School of Medicine, National Yang-Ming University, Taiwan
| | - Shung-Haur Yang
- Division of Colon and Rectal Surgery, Department of Surgery, Taipei Veterans General Hospital, Taiwan.,Department of Surgery, School of Medicine, National Yang-Ming University, Taiwan
| | - Wei-Shone Chen
- Division of Colon and Rectal Surgery, Department of Surgery, Taipei Veterans General Hospital, Taiwan.,Department of Surgery, School of Medicine, National Yang-Ming University, Taiwan
| | - Tzu-Chen Lin
- Division of Colon and Rectal Surgery, Department of Surgery, Taipei Veterans General Hospital, Taiwan.,Department of Surgery, School of Medicine, National Yang-Ming University, Taiwan
| | - Jen-Kou Lin
- Division of Colon and Rectal Surgery, Department of Surgery, Taipei Veterans General Hospital, Taiwan.,Department of Surgery, School of Medicine, National Yang-Ming University, Taiwan
| | - Jeng-Kai Jiang
- Division of Colon and Rectal Surgery, Department of Surgery, Taipei Veterans General Hospital, Taiwan.,Department of Surgery, School of Medicine, National Yang-Ming University, Taiwan
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Strickler JH, Wu C, Bekaii-Saab T. Targeting BRAF in metastatic colorectal cancer: Maximizing molecular approaches. Cancer Treat Rev 2017; 60:109-119. [PMID: 28946014 DOI: 10.1016/j.ctrv.2017.08.006] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2017] [Revised: 08/08/2017] [Accepted: 08/11/2017] [Indexed: 02/07/2023]
Abstract
Oncogenic mutations in B-type Raf kinase (BRAF) occur in 7-10% of metastatic colorectal cancers (mCRC). Despite recent improvements in survival in the general population of patients with mCRC, patients with BRAF-mutant mCRC continue to have poor response to most systemic therapies, and prognosis remains poor. There is a substantial unmet need for novel therapeutic strategies to treat patients with BRAF-mutant mCRC. This review outlines the epidemiology, molecular pathogenesis, prognosis, and mechanisms of treatment resistance of BRAF-mutated CRC. Additionally, this review highlights novel therapeutic strategies aimed at enhancing response and improving outcomes.
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Affiliation(s)
- John H Strickler
- Duke University School of Medicine, 20 Duke Medicine Circle, Durham, NC 27710, USA
| | - Christina Wu
- Emory University, 1365-C Clifton Rd NE, Atlanta, GA 30322, USA
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Nitsche U, Stöss C, Friess H. Effect of Adjuvant Chemotherapy on Elderly Colorectal Cancer Patients: Lack of Evidence. Gastrointest Tumors 2017; 4:11-19. [PMID: 29071260 DOI: 10.1159/000479318] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2017] [Accepted: 07/06/2017] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Adjuvant chemotherapy has become the standard form of treatment for all patients with stage III colorectal cancer and is also recommended for patients with stage II disease and defined risk factors. However, clinical studies that evaluate the effect of adjuvant treatment regimens have a selection bias in favor of younger patients, so that even retrospective subgroup analyses cannot define the best therapeutic procedure in elderly patients with comorbidities. SUMMARY As long as the role of adjuvant chemotherapy in elderly colorectal cancer patients is not investigated in comprehensive trials, no clear recommendations are possible. KEY MESSAGE An exploratory review of the relevant literature revealed that a formal meta-analysis concerning adjuvant chemotherapy in elderly patients with colorectal cancer is not feasible due to varying definitions of elderly patients, inclusion and exclusion criteria, and a plethora of chemotherapeutic regimens. PRACTICAL IMPLICATIONS Given the high incidence of colorectal cancer and the median age of 68 years for patients at the time of diagnosis, health economic considerations should promote randomized controlled trials regarding the role of adjuvant chemotherapy in the elderly.
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Affiliation(s)
- Ulrich Nitsche
- Klinik und Poliklinik für Chirurgie, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
| | - Christian Stöss
- Klinik und Poliklinik für Chirurgie, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
| | - Helmut Friess
- Klinik und Poliklinik für Chirurgie, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
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Aziz MA, Yousef Z, Saleh AM, Mohammad S, Al Knawy B. Towards personalized medicine of colorectal cancer. Crit Rev Oncol Hematol 2017; 118:70-78. [PMID: 28917272 DOI: 10.1016/j.critrevonc.2017.08.007] [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] [Received: 12/11/2016] [Revised: 04/18/2017] [Accepted: 08/21/2017] [Indexed: 02/07/2023] Open
Abstract
Efforts in colorectal cancer (CRC) research aim to improve early detection and treatment for metastatic stages which could translate into better prognosis of this disease. One of the major challenges that hinder these efforts is the heterogeneous nature of CRC and involvement of diverse molecular pathways. New large-scale 'omics' technologies are making it possible to generate, analyze and interpret biological data from molecular determinants of CRC. The developments of sophisticated computational analyses would allow information from different omics platforms to be integrated, thus providing new insights into the biology of CRC. Together, these technological advances and an improved mechanistic understanding might allow CRC to be clinically managed at the level of the individual patient. This review provides an account of the current challenges in CRC management and an insight into how new technologies could allow the development of personalized medicine for CRC.
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Affiliation(s)
- Mohammad Azhar Aziz
- King Abdullah International Medical Research Center [KAIMRC], King Saud Bin Abdulaziz University for Health Sciences, Colorectal Cancer Research Program, National Guard Health Affairs, P.O. Box 22490, Riyadh 11426, Saudi Arabia.
| | - Zeyad Yousef
- King Abdullah International Medical Research Center [KAIMRC], King Saud Bin Abdulaziz University for Health Sciences, Department of Surgery, National Guard Health Affairs, P.O. Box 22490, Riyadh 11426, Saudi Arabia.
| | - Ayman M Saleh
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud Bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, National Guard Health Affairs, Mail Code 6610, P. O. Box 9515 Jeddah 21423, Saudi Arabia; King Abdullah International Medical Research Center [KAIMRC], King Abdulaziz Medical City, National Guard Health Affairs, P. O. Box 9515, Jeddah 21423, Saudi Arabia.
| | - Sameer Mohammad
- King Abdullah International Medical Research Center [KAIMRC], King Saud Bin Abdulaziz University for Health Sciences, Department of Experimental Medicine, National Guard Health Affairs, P.O. Box 22490, Riyadh 11426, Saudi Arabia.
| | - Bandar Al Knawy
- King Abdullah International Medical Research Center [KAIMRC], King Saud Bin Abdulaziz University for Health Sciences, Office of the Chief Executive Officer, National Guard Health Affairs, P.O. Box 22490, Riyadh 11426, Saudi Arabia.
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The current value of determining the mismatch repair status of colorectal cancer: A rationale for routine testing. Crit Rev Oncol Hematol 2017; 116:38-57. [PMID: 28693799 DOI: 10.1016/j.critrevonc.2017.05.006] [Citation(s) in RCA: 80] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2016] [Revised: 03/02/2017] [Accepted: 05/15/2017] [Indexed: 02/08/2023] Open
Abstract
Colorectal Cancer (CRC) is the third most prevalent cancer in men and women. Up to 15% of CRCs display microsatellite instability (MSI). MSI is reflective of a deficient mismatch repair (MMR) system and is most commonly caused by hypermethylation of the MLH1 promoter. However, it may also be due to autosomal dominant constitutional mutations in DNA MMR, termed Lynch Syndrome. MSI may be diagnosed via polymerase chain reaction (PCR) or alternatively, immunohistochemistry (IHC) can identify MMR deficiency (dMMR). Many institutions now advocate universal tumor screening of CRC via either PCR for MSI or IHC for dMMR to guide Lynch Syndrome testing. The association of sporadic MSI with methylation of the MLH1 promoter and an activating BRAF mutation may offer further exclusion criteria for genetic testing. Aside from screening for Lynch syndrome, MMR testing is important because of its prognostic and therapeutic implications. Several studies have shown MSI CRCs exhibit different clinicopathological features and prognosis compared to microsatellite-stable (MSS) CRCs. For example, response to conventional chemotherapy has been reported to be less in MSI tumours. More recently, MSI tumours have been shown to be responsive to immune-checkpoint inhibition providing a novel therapeutic strategy. This provides a rationale for routine testing for MSI or dMMR in CRC.
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Gonzalez RS, Washington K, Shi C. Current applications of molecular pathology in colorectal carcinoma. ACTA ACUST UNITED AC 2017. [DOI: 10.1186/s41241-017-0020-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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Copija A, Waniczek D, Witkoś A, Walkiewicz K, Nowakowska-Zajdel E. Clinical Significance and Prognostic Relevance of Microsatellite Instability in Sporadic Colorectal Cancer Patients. Int J Mol Sci 2017; 18:ijms18010107. [PMID: 28067827 PMCID: PMC5297741 DOI: 10.3390/ijms18010107] [Citation(s) in RCA: 60] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2016] [Revised: 12/26/2016] [Accepted: 12/30/2016] [Indexed: 02/06/2023] Open
Abstract
Microsatellite instability (MSI) is a marker of the replication error phenotype. It is caused by impaired DNA mismatch repair processes (MMR), resulting in ineffectiveness of the mechanisms responsible for the DNA replication precision and postreplicative DNA repair. MSI underlies the pathogenesis of 10%-20% of colorectal cancer (CRC) cases. The data about the potential value of MMR status as a predictive factor for 5-fluorouracil (FU)-based chemotherapy remain unclear. According to National Comprehensive Cancer Network updated guidelines, MSI testing is recommended for all patients with stage II CRC because patients with MSI-H (high-frequency MSI) tumour may have a good prognosis and obtain no benefit from 5-FU-based adjuvant chemotherapy. The significance of the MSI status as a predictive factor for patients with metastatic disease was not confirmed. The association between the MSI status and the efficacy of the therapy based on anti-programmed death-1 receptor inhibitors requires further studies.
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Affiliation(s)
- Angelika Copija
- Department of Nutrition Related Disease Prevention, School of Public Health in Bytom, Medical University of Silesia, 41-902 Bytom, Poland.
- Department of Clinical Oncology, Regional Specialised Hospital No. 4 in Bytom, 41-900 Bytom, Poland.
| | - Dariusz Waniczek
- Department of Propaedeutics Surgery, Chair of General, Colorectal and Polytrauma Surgery, School of Health Sciences in Katowice, Medical University of Silesia, 41-902 Bytom, Poland.
| | - Andrzej Witkoś
- Department of Clinical Oncology, Regional Specialised Hospital No. 4 in Bytom, 41-900 Bytom, Poland.
| | - Katarzyna Walkiewicz
- Department of Internal Medicine, School of Public Health in Bytom, Medical University of Silesia, 41-902 Bytom, Poland.
| | - Ewa Nowakowska-Zajdel
- Department of Nutrition Related Disease Prevention, School of Public Health in Bytom, Medical University of Silesia, 41-902 Bytom, Poland.
- Department of Clinical Oncology, Regional Specialised Hospital No. 4 in Bytom, 41-900 Bytom, Poland.
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Gómez-Álvarez MA, Lino-Silva LS, Salcedo-Hernández RA, Padilla-Rosciano A, Ruiz-García EB, López-Basave HN, Calderillo-Ruiz G, Aguilar-Romero JM, Domínguez-Rodríguez JA, Herrera-Gómez Á, Meneses-García A. Medullary colonic carcinoma with microsatellite instability has lower survival compared with conventional colonic adenocarcinoma with microsatellite instability. PRZEGLAD GASTROENTEROLOGICZNY 2016; 12:208-214. [PMID: 29123583 PMCID: PMC5672702 DOI: 10.5114/pg.2016.64740] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/01/2015] [Accepted: 02/01/2016] [Indexed: 12/03/2022]
Abstract
INTRODUCTION Colorectal medullary carcinoma (MC) is a rare subtype of poorly differentiated adenocarcinoma (PDA) with unclear prognostic significance. Microsatellite instable (MSI) colorectal carcinomas have demonstrated better prognosis in clinical stage II. AIM To analyze the survival and clinicopathological characteristics of MCs versus PDAs with MSI in clinical stage III. MATERIAL AND METHODS We studied 22 cases of PDAs with MSI versus 10 MCs. RESULTS Of the 10 MCs, 7 patients were men; the mean age was 57.8 ±5.6 years. The mean tumor size was 9.6 ±4.1 cm, and the primary site was the right colon in 9; 7 patients showed lymph node metastases (LNM) and lymphovascular invasion (LVI). Of the 22 PDA cases, 12 (54.5%) were women with a mean age of 75 ±16.1 years. The mean tumor size was 6.4 ±3.2 cm. Twelve (54.5%) presented in the right colon, 21 (95.5%) showed LNM and 7 (31.8%) LVI. Follow-up was 32 ±8 months, with a 5-year overall survival of 42.9% for MCs and 76.6% for PDAs (p = 0.048). Univariate analysis found local recurrence (p = 0.001) and medullary subtype (p = 0.043) associated with lower survival. CONCLUSIONS Medullary carcinomas were of greater tumor size and associated with more LVI and worse survival versus PDAs with MSI in stage III.
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Affiliation(s)
| | - Leonardo S. Lino-Silva
- Department of Anatomic Pathology, Instituto Nacional de Cancerología, México City, Mexico
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