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Jafari SH, Lajevardi ZS, Zamani Fard MM, Jafari A, Naghavi S, Ravaei F, Taghavi SP, Mosadeghi K, Zarepour F, Mahjoubin-Tehran M, Rahimian N, Mirzaei H. Imaging Techniques and Biochemical Biomarkers: New Insights into Diagnosis of Pancreatic Cancer. Cell Biochem Biophys 2024; 82:3123-3144. [PMID: 39026059 DOI: 10.1007/s12013-024-01437-z] [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] [Accepted: 07/12/2024] [Indexed: 07/20/2024]
Abstract
Pancreatic cancer (PaC) incidence is increasing, but our current screening and diagnostic strategies are not very effective. However, screening could be helpful in the case of PaC, as recent evidence shows that the disease progresses gradually. Unfortunately, there is no ideal screening method or program for detecting PaC in its early stages. Conventional imaging techniques, such as abdominal ultrasound, CT, MRI, and EUS, have not been successful in detecting early-stage PaC. On the other hand, biomarkers may be a more effective screening tool for PaC and have greater potential for further evaluation compared to imaging. Recent studies on biomarkers and artificial intelligence (AI)-enhanced imaging have shown promising results in the early diagnosis of PaC. In addition to proteins, non-coding RNAs are also being studied as potential biomarkers for PaC. This review consolidates the current literature on PaC screening modalities to provide an organized framework for future studies. While conventional imaging techniques have not been effective in detecting early-stage PaC, biomarkers and AI-enhanced imaging are promising avenues of research. Further studies on the use of biomarkers, particularly non-coding RNAs, in combination with imaging modalities may improve the accuracy of PaC screening and lead to earlier detection of this deadly disease.
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Affiliation(s)
- Seyed Hamed Jafari
- Medical Imaging Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
- Department of Radiology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Zahra Sadat Lajevardi
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Mohammad Masoud Zamani Fard
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Ameneh Jafari
- Chronic Respiratory Diseases Research Center, NRITLD, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Soroush Naghavi
- Student Research Committee, Iran University of Medical Sciences, Tehran, Iran
| | - Fatemeh Ravaei
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Seyed Pouya Taghavi
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Kimia Mosadeghi
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Fatemeh Zarepour
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | | | - Neda Rahimian
- Endocrine Research Center, Institute of Endocrinology and Metabolism, Iran University of Medical Sciences (IUMS), Tehran, Iran; Department of Internal Medicine, School of Medicine, Firoozgar Hospital, Iran University of Medical Sciences, Tehran, Iran.
| | - Hamed Mirzaei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran.
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Bhattacharjya D, Sivalingam N. Mechanism of 5-fluorouracil induced resistance and role of piperine and curcumin as chemo-sensitizers in colon cancer. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2024; 397:8445-8475. [PMID: 38878089 DOI: 10.1007/s00210-024-03189-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/20/2024] [Accepted: 05/27/2024] [Indexed: 10/30/2024]
Abstract
Among cancer-related deaths worldwide, colorectal cancer ranks second, accounting for 1.2% of deaths in those under 50 years and 0.6% of deaths in those between 50 and 54 years. The anticancer drug 5-fluorouracil is widely used to treat colorectal cancer. Due to a better understanding of the drug's mechanism of action, its anticancer activity has been increased through a variety of therapeutic alternatives. Clinical use of 5-FU has been severely restricted due to drug resistance. The chemoresistance mechanism of 5-FU is challenging to overcome because of the existence of several drug efflux transporters, DNA repair enzymes, signaling cascades, classical cellular processes, cancer stem cells, metastasis, and angiogenesis. Curcumin, a potent phytocompound derived from Curcuma longa, functions as a nuclear factor (NF)-κB inhibitor and sensitizer to numerous chemotherapeutic drugs. Piperine, an alkaloid found in Piper longum, inhibits cancer cell growth, causing cell cycle arrest and apoptosis. This review explores the mechanism of 5-FU-induced chemoresistance in colon cancer cells and the role of curcumin and piperine in enhancing the sensitivity of 5-FU-based chemotherapy. CLINICAL TRIAL REGISTRATION: Not applicable.
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Affiliation(s)
- Dorothy Bhattacharjya
- Department of Biotechnology, School of Bioengineering, College of Engineering and Technology, Faculty of Engineering and Technology, SRM Institute of Science and Technology, SRM Nagar, Kattankulathur, 603 203, Chengalpattu District, Tamil Nadu, India
| | - Nageswaran Sivalingam
- Department of Biotechnology, School of Bioengineering, College of Engineering and Technology, Faculty of Engineering and Technology, SRM Institute of Science and Technology, SRM Nagar, Kattankulathur, 603 203, Chengalpattu District, Tamil Nadu, India.
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Han F, Xu Y, Li X, Song Z, Xie J, Yao J. Clinicopathological features and prognosis analysis of proximal colonic mucinous adenocarcinoma. Sci Rep 2024; 14:18682. [PMID: 39134655 PMCID: PMC11319726 DOI: 10.1038/s41598-024-69916-0] [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: 11/14/2023] [Accepted: 08/09/2024] [Indexed: 08/15/2024] Open
Abstract
Mucinous adenocarcinoma (MAC) is a distinct subtype of colorectal cancer. Previous studies have confirmed the poor prognosis of rectal or left-sided colon MAC, while the prognosis and response to chemotherapy in proximal colon MAC remains controversial. The aim of this study was to investigate the clinicopathological characteristics, prognosis, response to chemotherapy, and risk prediction factors of proximal colon MAC. Patients with proximal colon MAC and non-mucinous adenocarcinoma (NMAC) were retrospectively analyzed in this study. The analyzed variables included gender, age, smoking, drinking, chemotherapy, metastasis, pathological stage, and tumor size. Overall survival (OS) was the primary outcome. Kaplan-Meier analysis was used to assess the impact of mucinous subtype and chemotherapy on OS. We conducted univariate and multivariate Cox regression analyses to determine prognosis factors for proximal colon MAC and NMAC. A total of 284 cases of proximal colon MAC and 1384 cases of NMAC were included in the study. Compared to NMAC, proximal colon MAC was diagnosed at a younger age. The proportion of synchronous and metachronous metastasis was also higher, as well as the pathological stage and tumor size. Proximal colon MAC had a worse prognosis than NMAC, especially in stage 3. Moreover, the prognosis of proximal colon NMAC improved after chemotherapy, while MAC showed no improvement in prognosis after chemotherapy. Advanced age, N1 and N2 stage were independent prognostic factors for adverse outcomes in MAC. For proximal colon adenocarcinoma, the independent predictors of adverse outcomes included mucinous subtype, order age, N1 and N2 stages, and pathological stage 4. Proximal colon MAC had a worse prognosis compared to NMAC. Chemotherapy did not improve the prognosis of proximal colon mucinous adenocarcinoma.
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Affiliation(s)
- Fei Han
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe East Road of Erqi District, Zhengzhou, 450052, China
| | - Yue Xu
- Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Xiangyu Li
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe East Road of Erqi District, Zhengzhou, 450052, China
| | - Zhaoxiang Song
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe East Road of Erqi District, Zhengzhou, 450052, China
| | - Jinlin Xie
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe East Road of Erqi District, Zhengzhou, 450052, China
| | - Jianning Yao
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe East Road of Erqi District, Zhengzhou, 450052, China.
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Mogal H, Shen P. Top Peritoneal Surface Malignancy Articles from 2022 to Inform your Cancer Practice. Ann Surg Oncol 2024; 31:5361-5369. [PMID: 38700798 DOI: 10.1245/s10434-024-15304-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2023] [Accepted: 04/01/2024] [Indexed: 07/13/2024]
Abstract
Over the last few decades, the role of cytoreductive surgery (CRS) with or without regional-based peritoneal therapies such as hyperthermic intraperitoneal chemotherapy (HIPEC) has evolved in the management of patients with peritoneal surface malignances (PSMs). Despite the benefit of CRS in improving oncologic outcomes, significant challenges remain in the treatment of patients with advanced PSMs, and the role of HIPEC continues to be questioned. Additionally, while there has been improvement in perioperative outcomes, long-term survival remains poor. As a result, there is much need to improve our understanding of the processes that drive tumor biology, thereby improving patient selection for various treatment approaches. Additionally, newer therapies are needed for patients who remain poor surgical candidates and who progress on systemic therapy. This article highlights recently published studies that we consider impactful in the care of patients with PSMs.
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Affiliation(s)
- Harveshp Mogal
- Department of Surgery, Division of General Surgery, University of Washington/Fred Hutch Cancer Center, Seattle, WA, USA.
| | - Perry Shen
- Department of Surgery, Division of Surgical Oncology, Atrium Health Wake Forest Baptist, Winston Salem, NC, USA
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Ho V, Chung L, Wilkinson K, Ma Y, Rutland T, Lea V, Lim SH, Abubakar A, Ng W, Lee M, Roberts TL, Becker TM, Mackenzie S, Chua W, Lee CS. Microsatellite Instability Testing and Prognostic Implications in Colorectal Cancer. Cancers (Basel) 2024; 16:2005. [PMID: 38893125 PMCID: PMC11171323 DOI: 10.3390/cancers16112005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2024] [Revised: 05/16/2024] [Accepted: 05/22/2024] [Indexed: 06/21/2024] Open
Abstract
Given the crucial predictive implications of microsatellite instability (MSI) in colorectal cancer (CRC), MSI screening is commonly performed in those with and at risk for CRC. Here, we compared results from immunohistochemistry (IHC) and the droplet digital PCR (ddPCR) MSI assay on formalin-fixed paraffin-embedded tumor samples from 48 patients who underwent surgery for colon and rectal cancer by calculating Cohen's kappa measurement (k), revealing high agreement between the methods (k = 0.915). We performed Kaplan-Meier survival analyses and univariate and multivariate Cox regression to assess the prognostic significance of ddPCR-based MSI and to identify clinicopathological features associated with CRC outcome. Patients with MSI-high had better overall survival (OS; p = 0.038) and disease-free survival (DFS; p = 0.049) than those with microsatellite stability (MSS). When stratified by primary tumor location, right-sided CRC patients with MSI-high showed improved DFS, relative to those with MSS (p < 0.001), but left-sided CRC patients did not. In multivariate analyses, MSI-high was associated with improved OS (hazard ratio (HR) = 0.221, 95% confidence interval (CI): 0.026-0.870, p = 0.042), whereas the loss of DNA mismatch repair protein MutL homolog 1 (MLH1) expression was associated with worse OS (HR = 0.133, 95% CI: 0.001-1.152, p = 0.049). Our results suggest ddPCR is a promising tool for MSI detection. Given the opposing effects of MSI-high and MLH1 loss on OS, both ddPCR and IHC may be complementary for the prognostic assessment of CRC.
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Affiliation(s)
- Vincent Ho
- School of Medicine, Western Sydney University, Penrith, NSW 2751, Australia (Y.M.); (T.R.); (V.L.); (A.A.); (T.L.R.); (T.M.B.); (S.M.); (W.C.); (C.S.L.)
- Ingham Institute for Applied Medical Research, Liverpool, NSW 2170, Australia; (K.W.); (S.H.L.)
| | - Liping Chung
- School of Medicine, Western Sydney University, Penrith, NSW 2751, Australia (Y.M.); (T.R.); (V.L.); (A.A.); (T.L.R.); (T.M.B.); (S.M.); (W.C.); (C.S.L.)
- Ingham Institute for Applied Medical Research, Liverpool, NSW 2170, Australia; (K.W.); (S.H.L.)
| | - Kate Wilkinson
- Ingham Institute for Applied Medical Research, Liverpool, NSW 2170, Australia; (K.W.); (S.H.L.)
- Department of Anatomical Pathology, Liverpool Hospital, Liverpool, NSW 2170, Australia
| | - Yafeng Ma
- School of Medicine, Western Sydney University, Penrith, NSW 2751, Australia (Y.M.); (T.R.); (V.L.); (A.A.); (T.L.R.); (T.M.B.); (S.M.); (W.C.); (C.S.L.)
- Ingham Institute for Applied Medical Research, Liverpool, NSW 2170, Australia; (K.W.); (S.H.L.)
- South Western Sydney Clinical School, University of New South Wales, Liverpool Hospital, Liverpool, NSW 2170, Australia
| | - Tristan Rutland
- School of Medicine, Western Sydney University, Penrith, NSW 2751, Australia (Y.M.); (T.R.); (V.L.); (A.A.); (T.L.R.); (T.M.B.); (S.M.); (W.C.); (C.S.L.)
- Department of Anatomical Pathology, Liverpool Hospital, Liverpool, NSW 2170, Australia
| | - Vivienne Lea
- School of Medicine, Western Sydney University, Penrith, NSW 2751, Australia (Y.M.); (T.R.); (V.L.); (A.A.); (T.L.R.); (T.M.B.); (S.M.); (W.C.); (C.S.L.)
- Department of Anatomical Pathology, Liverpool Hospital, Liverpool, NSW 2170, Australia
| | - Stephanie H. Lim
- Ingham Institute for Applied Medical Research, Liverpool, NSW 2170, Australia; (K.W.); (S.H.L.)
- Macarthur Cancer Therapy Centre, Campbelltown Hospital, Campbelltown, NSW 2560, Australia
- Department of Medical Oncology, Liverpool Hospital, Liverpool, NSW 2170, Australia;
| | - Askar Abubakar
- School of Medicine, Western Sydney University, Penrith, NSW 2751, Australia (Y.M.); (T.R.); (V.L.); (A.A.); (T.L.R.); (T.M.B.); (S.M.); (W.C.); (C.S.L.)
- Ingham Institute for Applied Medical Research, Liverpool, NSW 2170, Australia; (K.W.); (S.H.L.)
| | - Weng Ng
- Department of Medical Oncology, Liverpool Hospital, Liverpool, NSW 2170, Australia;
| | - Mark Lee
- Department of Radiation Oncology, Liverpool Hospital, Liverpool, NSW 2170, Australia;
| | - Tara L. Roberts
- School of Medicine, Western Sydney University, Penrith, NSW 2751, Australia (Y.M.); (T.R.); (V.L.); (A.A.); (T.L.R.); (T.M.B.); (S.M.); (W.C.); (C.S.L.)
- Ingham Institute for Applied Medical Research, Liverpool, NSW 2170, Australia; (K.W.); (S.H.L.)
- South Western Sydney Clinical School, University of New South Wales, Liverpool Hospital, Liverpool, NSW 2170, Australia
| | - Therese M. Becker
- School of Medicine, Western Sydney University, Penrith, NSW 2751, Australia (Y.M.); (T.R.); (V.L.); (A.A.); (T.L.R.); (T.M.B.); (S.M.); (W.C.); (C.S.L.)
- Ingham Institute for Applied Medical Research, Liverpool, NSW 2170, Australia; (K.W.); (S.H.L.)
- South Western Sydney Clinical School, University of New South Wales, Liverpool Hospital, Liverpool, NSW 2170, Australia
| | - Scott Mackenzie
- School of Medicine, Western Sydney University, Penrith, NSW 2751, Australia (Y.M.); (T.R.); (V.L.); (A.A.); (T.L.R.); (T.M.B.); (S.M.); (W.C.); (C.S.L.)
- Department of Colorectal Surgery, Liverpool Hospital, Liverpool, NSW 2170, Australia
| | - Wei Chua
- School of Medicine, Western Sydney University, Penrith, NSW 2751, Australia (Y.M.); (T.R.); (V.L.); (A.A.); (T.L.R.); (T.M.B.); (S.M.); (W.C.); (C.S.L.)
- Department of Medical Oncology, Liverpool Hospital, Liverpool, NSW 2170, Australia;
- Discipline of Medical Oncology, School of Medicine, Western Sydney University, Liverpool, NSW 2170, Australia
| | - Cheok Soon Lee
- School of Medicine, Western Sydney University, Penrith, NSW 2751, Australia (Y.M.); (T.R.); (V.L.); (A.A.); (T.L.R.); (T.M.B.); (S.M.); (W.C.); (C.S.L.)
- Ingham Institute for Applied Medical Research, Liverpool, NSW 2170, Australia; (K.W.); (S.H.L.)
- Department of Anatomical Pathology, Liverpool Hospital, Liverpool, NSW 2170, Australia
- Discipline of Pathology, School of Medicine, Western Sydney University, Campbelltown, NSW 2560, Australia
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Skouteris N, Papageorgiou G. PARP Inhibitors in Colorectal Malignancies: A 2023 Update. Rev Recent Clin Trials 2024; 19:101-108. [PMID: 38058097 DOI: 10.2174/0115748871260815231116060817] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2023] [Revised: 09/06/2023] [Accepted: 09/28/2023] [Indexed: 12/08/2023]
Abstract
BACKGROUND Colorectal carcinoma (CRC) is one of the most common malignancies in the Western world, and metastatic disease is associated with a dismal prognosis. Poly-ADpribose polymerase (PARP) inhibitors gain increasing attention in the field of medical oncology, as they lead to synthetic lethality in malignancies with preexisting alterations in the DNA damage repair (DDR) pathway. As those alterations are frequently seen in CRC, a targeted approach through PARP inhibitors is expected to benefit these patients, both alone and in combination with other agents like chemotherapy, immunotherapy, antiangiogenics, and radiation. OBJECTIVE This review article aims to better clarify the role of PARP inhibitors as a treatment option in patients with metastatic CRC with alterations in the DDR pathway. METHODS We used the PubMed database to retrieve journal articles and the inclusion criteria were all human studies that illustrated the effective role of PARP inhibitors in patients with metastatic CRC with homologous repair deficiency (HRD) and the correct line of therapy. RESULTS Current evidence supports the utilization of PARP inhibitors in CRC subgroups, as monotherapy and in combination with other agents. Up to now, data are insufficient to support a formal indication, and further research is needed. CONCLUSION Efforts to precisely define the homologous repair deficiency (HRD) in CRC - and eventually the subgroup of patients that are expected to benefit the most - are also underway.
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Affiliation(s)
- Nikolaos Skouteris
- Division of Medical Oncology & Hematopoietic Cell Transplant Unit, Department of Medicine, "Metaxa" Cancer Hospital, 51 Botassi Street, 18537 Piraeus, Greece
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Kim S, Lee JH, Park EJ, Lee HS, Baik SH, Jeon TJ, Lee KY, Ryu YH, Kang J. Prediction of Microsatellite Instability in Colorectal Cancer Using a Machine Learning Model Based on PET/CT Radiomics. Yonsei Med J 2023; 64:320-326. [PMID: 37114635 PMCID: PMC10151228 DOI: 10.3349/ymj.2022.0548] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Revised: 03/11/2023] [Accepted: 03/20/2023] [Indexed: 04/29/2023] Open
Abstract
PURPOSE We investigated the feasibility of preoperative 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) radiomics with machine learning to predict microsatellite instability (MSI) status in colorectal cancer (CRC) patients. MATERIALS AND METHODS Altogether, 233 patients with CRC who underwent preoperative FDG PET/CT were enrolled and divided into training (n=139) and test (n=94) sets. A PET-based radiomics signature (rad_score) was established to predict the MSI status in patients with CRC. The predictive ability of the rad_score was evaluated using the area under the receiver operating characteristic curve (AUROC) in the test set. A logistic regression model was used to determine whether the rad_score was an independent predictor of MSI status in CRC. The predictive performance of rad_score was compared with conventional PET parameters. RESULTS The incidence of MSI-high was 15 (10.8%) and 10 (10.6%) in the training and test sets, respectively. The rad_score was constructed based on the two radiomic features and showed similar AUROC values for predicting MSI status in the training and test sets (0.815 and 0.867, respectively; p=0.490). Logistic regression analysis revealed that the rad_score was an independent predictor of MSI status in the training set. The rad_score performed better than metabolic tumor volume when assessed using the AUROC (0.867 vs. 0.794, p=0.015). CONCLUSION Our predictive model incorporating PET radiomic features successfully identified the MSI status of CRC, and it also showed better performance than the conventional PET image parameters.
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Affiliation(s)
- Soyoung Kim
- Department of Nuclear Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Jae-Hoon Lee
- Department of Nuclear Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea.
| | - Eun Jung Park
- Department of Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Hye Sun Lee
- Biostatistics Collaboration Unit, Yonsei University College of Medicine, Seoul, Korea
| | - Seung Hyuk Baik
- Department of Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Tae Joo Jeon
- Department of Nuclear Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Kang Young Lee
- Department of Surgery, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Young Hoon Ryu
- Department of Nuclear Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Jeonghyun Kang
- Department of Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea.
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Zhang L, Liu Y, Ding Y, Deng Y, Chen H, Hu F, Fan J, Lan X, Cao W. Predictive value of intratumoral-metabolic heterogeneity derived from 18F-FDG PET/CT in distinguishing microsatellite instability status of colorectal carcinoma. Front Oncol 2023; 13:1065744. [PMID: 37182124 PMCID: PMC10173881 DOI: 10.3389/fonc.2023.1065744] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Accepted: 01/30/2023] [Indexed: 05/16/2023] Open
Abstract
Purpose/background Microsatellite instability (MSI) status is a significant biomarker for the response to immune checkpoint inhibitors, response to 5-fluorouracil-based adjuvant chemotherapy, and prognosis in colorectal carcinoma (CRC). This study investigated the predictive value of intratumoral-metabolic heterogeneity (IMH) and conventional metabolic parameters derived from 18F-FDG PET/CT for MSI in patients with stage I-III CRC. Methods This study was a retrospective analysis of 152 CRC patients with pathologically proven MSI who underwent 18F-FDG PET/CT examination from January 2016 to May 2022. Intratumoral-metabolic heterogeneity (including heterogeneity index [HI] and heterogeneity factor [HF]) and conventional metabolic parameters (standardized uptake value [SUV], metabolic tumor volume [MTV], and total lesion glycolysis [TLG]) of the primary lesions were determined. MTV and SUVmean were calculated on the basis of the percentage threshold of SUVs at 30%-70%. TLG, HI, and HF were obtained on the basis of the above corresponding thresholds. MSI was determined by immunohistochemical evaluation. Differences in clinicopathologic and various metabolic parameters between MSI-High (MSI-H) and microsatellite stability (MSS) groups were assessed. Potential risk factors for MSI were assessed by logistic regression analyses and used for construction of the mathematical model. Area under the curve (AUC) were used to evaluate the predictive ability of factors for MSI. Results This study included 88 patients with CRC in stages I-III, including 19 (21.6%) patients with MSI-H and 69 (78.4%) patients with MSS. Poor differentiation, mucinous component, and various metabolic parameters including MTV30%, MTV40%, MTV50%, and MTV60%, as well as HI50%, HI60%, HI70%, and HF in the MSI-H group were significantly higher than those in the MSS group (all P < 0.05). In multivariate logistic regression analyses, post-standardized HI60% by Z-score (P = 0.037, OR: 2.107) and mucinous component (P < 0.001, OR:11.394) were independently correlated with MSI. AUC of HI60% and our model of the HI60% + mucinous component was 0.685 and 0.850, respectively (P = 0.019), and the AUC of HI30% in predicting the mucinous component was 0.663. Conclusions Intratumoral-metabolic heterogeneity derived from 18F-FDG PET/CT was higher in MSI-H CRC and predicted MSI in stage I-III CRC patients preoperatively. HI60% and mucinous component were independent risk factors for MSI. These findings provide new methods to predict the MSI and mucinous component for patients with CRC.
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Affiliation(s)
- Li Zhang
- Department of Nuclear Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Molecular Imaging, Wuhan, China
| | - Yu Liu
- Department of Nuclear Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Molecular Imaging, Wuhan, China
| | - Ying Ding
- Department of Nuclear Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Molecular Imaging, Wuhan, China
| | - Yinqian Deng
- Department of Nuclear Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Molecular Imaging, Wuhan, China
| | - Huanyu Chen
- Department of Nuclear Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Molecular Imaging, Wuhan, China
| | - Fan Hu
- Department of Nuclear Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Molecular Imaging, Wuhan, China
| | - Jun Fan
- Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaoli Lan
- Department of Nuclear Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Molecular Imaging, Wuhan, China
| | - Wei Cao
- Department of Nuclear Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Molecular Imaging, Wuhan, China
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Kavun A, Veselovsky E, Lebedeva A, Belova E, Kuznetsova O, Yakushina V, Grigoreva T, Mileyko V, Fedyanin M, Ivanov M. Microsatellite Instability: A Review of Molecular Epidemiology and Implications for Immune Checkpoint Inhibitor Therapy. Cancers (Basel) 2023; 15:cancers15082288. [PMID: 37190216 DOI: 10.3390/cancers15082288] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Revised: 04/10/2023] [Accepted: 04/11/2023] [Indexed: 05/17/2023] Open
Abstract
Microsatellite instability (MSI) is one of the most important molecular characteristics of a tumor, which occurs among various tumor types. In this review article, we examine the molecular characteristics of MSI tumors, both sporadic and Lynch-associated. We also overview the risks of developing hereditary forms of cancer and potential mechanisms of tumor development in patients with Lynch syndrome. Additionally, we summarize the results of major clinical studies on the efficacy of immune checkpoint inhibitors for MSI tumors and discuss the predictive role of MSI in the context of chemotherapy and checkpoint inhibitors. Finally, we briefly discuss some of the underlying mechanisms causing therapy resistance in patients treated with immune checkpoint inhibitors.
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Affiliation(s)
| | - Egor Veselovsky
- OncoAtlas LLC, 119049 Moscow, Russia
- Department of Evolutionary Genetics of Development, Koltzov Institute of Developmental Biology of the Russian Academy of Sciences, 119334 Moscow, Russia
| | | | - Ekaterina Belova
- OncoAtlas LLC, 119049 Moscow, Russia
- Faculty of Physics, Lomonosov Moscow State University, 119991 Moscow, Russia
| | - Olesya Kuznetsova
- OncoAtlas LLC, 119049 Moscow, Russia
- N.N. Blokhin Russian Cancer Research Center, 115478 Moscow, Russia
| | - Valentina Yakushina
- OncoAtlas LLC, 119049 Moscow, Russia
- Laboratory of Epigenetics, Research Centre for Medical Genetics, 115522 Moscow, Russia
| | - Tatiana Grigoreva
- OncoAtlas LLC, 119049 Moscow, Russia
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, 117997 Moscow, Russia
| | | | - Mikhail Fedyanin
- N.N. Blokhin Russian Cancer Research Center, 115478 Moscow, Russia
- State Budgetary Institution of Health Care of the City of Moscow "Moscow Multidisciplinary Clinical Center" "Kommunarka" of the Department of Health of the City of Moscow, 142770 Moscow, Russia
- Federal State Budgetary Institution "National Medical and Surgical Center named after N.I. Pirogov" of the Ministry of Health of the Russian Federation, 105203 Moscow, Russia
| | - Maxim Ivanov
- OncoAtlas LLC, 119049 Moscow, Russia
- Moscow Institute of Physics and Technology, 141701 Dolgoprudny, Russia
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10
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Muacevic A, Adler JR, Courtney E. Operative and Pathological Factors in Right-Sided Colon Cancers: How Can We Improve the Outcomes? Cureus 2023; 15:e33832. [PMID: 36819408 PMCID: PMC9930915 DOI: 10.7759/cureus.33832] [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] [Accepted: 12/26/2022] [Indexed: 01/18/2023] Open
Abstract
INTRODUCTION Though the tumour-node-metastasis staging classification is the standard approach to risk stratification in patients with colorectal cancer, several other important variables including the presence of extramural venous invasion (EMVI), the tumour mismatch repair status, as well as surgical technique and its influence on lymph node yield all have an impact on long-term survival. This study aims to review both the impact of the type of operation on lymph node yield: complete mesocolic excision (CME) versus right hemicolectomy, and the impact of EMVI and microsatellite instability in predicting overall survival in patients undergoing a right hemicolectomy for colon cancer. METHODS Data of all patients who underwent an elective or emergency right hemicolectomy with curative intent for colon cancer between January 2013 and June 2022 (inclusive) was collected for this single-centre retrospective study. Kaplan-Meier survival curves were calculated using the Statistical Package for the Social Sciences (SPSS version 28, IBM Corp., Armonk, NY) software, and the log-rank (Mantel-Cox) test was used to compare survival distribution between different groups. RESULTS A total of 421 patients underwent a right hemicolectomy for colon cancer with curative intent during the study period. EMVI was present in 173 (41%) tumours. Survival analysis showed significantly reduced cancer-related survival in patients with EMVI-positive tumours (p < 0.001), with five-year survival rates of 70% in EMVI-positive groups versus 96% in EMVI-negative groups. Subgroup analysis showed a significant difference in survival between node-positive and node-negative tumours in cancers found to have EMVI (p < 0.001). Mean lymph node yield was significantly higher in the CME group versus the standard right hemicolectomy group (p < 0.001). We found no significant difference in survival between patients with microsatellite instability-high (MSI-H) tumours and microsatellite stable (MSS) tumours (p = 0.432). CONCLUSION Consideration of tumour biology and adopting the optimum surgical technique are factors that may influence long-term survival in patients with colorectal cancer. Extramural venous invasion is an important prognostic indicator of adverse outcomes in patients with right-sided colon cancer. Our study demonstrates a reduction in survival in patients with EMVI-positive tumours when undertaking subgroup analysis by the presence or absence of nodal disease. Further research needs to be undertaken to compare the relative efficacy of neoadjuvant versus adjuvant chemotherapy in right-sided cancers known to be EMVI-positive as some patients will fail to have adjuvant chemotherapy due to postoperative complications, thereby delaying recovery and missing the optimum window for treatment.
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11
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Crutcher M, Waldman S. Biomarkers in the development of individualized treatment regimens for colorectal cancer. Front Med (Lausanne) 2022; 9:1062423. [DOI: 10.3389/fmed.2022.1062423] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2022] [Accepted: 11/14/2022] [Indexed: 12/05/2022] Open
Abstract
IntroductionColorectal cancer (CRC) is the third most common and second most deadly malignancy in the world with an estimated 1. 9 million cases and 0.9 million deaths in 2020. The 5-year overall survival for stage I disease is 92% compared to a dismal 11% in stage IV disease. At initial presentation, up to 35% of patients have metastatic colorectal cancer (mCRC), and 20–50% of stage II and III patients eventually progress to mCRC. These statistics imply both that there is a proportion of early stage patients who are not receiving adequate treatment and that we are not adequately treating mCRC patients.BodyTargeted therapies directed at CRC biomarkers are now commonly used in select mCRC patients. In addition to acting as direct targets, these biomarkers also could help stratify which patients receive adjuvant therapies and what types. This review discusses the role of RAS, microsatellite instability, HER2, consensus molecular subtypes and ctDNA/CTC in targeted therapy and adjuvant chemotherapy.DiscussionGiven the relatively high recurrence rate in early stage CRC patients as well as the continued poor survival in mCRC patients, additional work needs to be done beyond surgical management to limit recurrence and improve survival. Biomarkers offer both a potential target and a predictive method of stratifying patients to determine those who could benefit from adjuvant treatment.
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12
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Huang B, Deng W, Chen P, Mao Q, Chen H, Zhuo Z, Huang Z, Chen K, Huang J, Luo Y. Development and validation of a novel ubiquitination-related gene prognostic signature based on tumor microenvironment for colon cancer. Transl Cancer Res 2022; 11:3724-3740. [PMID: 36388031 PMCID: PMC9641125 DOI: 10.21037/tcr-22-607] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Accepted: 07/22/2022] [Indexed: 11/30/2024]
Abstract
BACKGROUND Colon cancer (CC) is one of the most common cancers with high morbidity globally. Ubiquitination is involved in the characterization of multiple biological processes, and some ubiquitinated enzymes are associated with the prognosis of CC. However, the prognostic model associated with ubiquitination-related genes (URGs) for CC is unavailable. METHODS Gene expression data, somatic mutations, transcriptome profiles, microsatellite instability status (MSI) status, and clinical information for CC were obtained from The Cancer Genome Atlas (TCGA) dataset. Seven URGs were used for establishing a prognostic prediction model, which was constructed and validated in GSE17538. Besides, genomic variance analysis (GSVA) was used to explore further the differences in biological pathway activation status between the high-risk and low-risk groups. Finally, the single-sample gene set enrichment analysis (ssGSEA) and ESTIMATE algorithm analysis were used to characterize the cellular infiltration in the microenvironment. RESULTS A seven-URG prognostic signature was established, based on which patients in the training and test groups could be divided into high-risk and low-risk groups. The results demonstrated that the model has a solid ability to predict the prognosis of CC patients. CONCLUSIONS We established a prognostic prediction model for CC based on ubiquitination. Then we analyzed the genetic characteristics associated with ubiquitination and the tumor microenvironment (TME) cell infiltration in CC. These results are worthy of exploring new clinical treatment strategies for CC.
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Affiliation(s)
- Baoyi Huang
- Department of Clinical Medicine, The Second Clinical College of Guangzhou Medical University, Guangzhou, China
| | - Weiping Deng
- Guangdong Provincial Geriatrics Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Pengfei Chen
- Department of Laboratory Medicine, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Qiuxian Mao
- Prenatal Diagnostic Department, Guangdong Second Provincial General Hospital, Guangzhou, China
| | - Hao Chen
- Department of Gastroenterology, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Zewei Zhuo
- Department of Gastroenterology, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Zena Huang
- Department of General Medicine, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Kequan Chen
- Department of Gastroenterology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Jiayu Huang
- Department of Otorhinolaryngology-Head and Neck Surgery, Huizhou Municipal Central People’s Hospital, Huizhou, China
| | - Yujun Luo
- Department of Gastroenterology, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
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13
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Detection of Microsatellite Instability in Colonoscopic Biopsies and Postal Urine Samples from Lynch Syndrome Cancer Patients Using a Multiplex PCR Assay. Cancers (Basel) 2022; 14:cancers14153838. [PMID: 35954501 PMCID: PMC9367254 DOI: 10.3390/cancers14153838] [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] [Received: 05/31/2022] [Revised: 07/15/2022] [Accepted: 07/21/2022] [Indexed: 11/16/2022] Open
Abstract
Identification of mismatch repair (MMR)-deficient colorectal cancers (CRCs) is recommended for Lynch syndrome (LS) screening, and supports targeting of immune checkpoint inhibitors. Microsatellite instability (MSI) analysis is commonly used to test for MMR deficiency. Testing biopsies prior to tumour resection can inform surgical and therapeutic decisions, but can be limited by DNA quantity. MSI analysis of voided urine could also provide much needed surveillance for genitourinary tract cancers in LS. Here, we reconfigure an existing molecular inversion probe-based MSI and BRAF c.1799T > A assay to a multiplex PCR (mPCR) format, and demonstrate that it can sample >140 unique molecules per marker from <1 ng of DNA and classify CRCs with 96−100% sensitivity and specificity. We also show that it can detect increased MSI within individual and composite CRC biopsies from LS patients, and within preoperative urine cell free DNA (cfDNA) from two LS patients, one with an upper tract urothelial cancer, the other an undiagnosed endometrial cancer. Approximately 60−70% of the urine cfDNAs were tumour-derived. Our results suggest that mPCR sequence-based analysis of MSI and mutation hotspots in CRC biopsies could facilitate presurgery decision making, and could enable postal-based screening for urinary tract and endometrial tumours in LS patients.
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14
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Microsatellite Instability: From the Implementation of the Detection to a Prognostic and Predictive Role in Cancers. Int J Mol Sci 2022; 23:ijms23158726. [PMID: 35955855 PMCID: PMC9369169 DOI: 10.3390/ijms23158726] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Revised: 07/26/2022] [Accepted: 08/03/2022] [Indexed: 02/07/2023] Open
Abstract
Microsatellite instability (MSI) has been identified in several tumors arising from either germline or somatic aberration. The presence of MSI in cancer predicts the sensitivity to immune checkpoint inhibitors (ICIs), particularly PD1/PD-L1 inhibitors. To date, the predictive role of MSI is currently used in the selection of colorectal cancer patients for immunotherapy; moreover, the expansion of clinical trials into other cancer types may elucidate the predictive value of MSI for non-colorectal tumors. In clinical practice, several assays are used for MSI testing, including immunohistochemistry (IHC), polymerase chain reaction (PCR) and next-generation sequencing (NGS). In this review, we provide an overview of MSI in various cancer types, highlighting its potential predictive/prognostic role and the clinical trials performed. Finally, we focus on the comparison data between the different assays used to detect MSI in clinical practice.
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15
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Wang H, Gao Y, Vafaei S, Yu Q, Zhang J, Wang L. A chemoresistance lncRNA signature for recurrence risk stratification of colon cancer patients with chemotherapy. MOLECULAR THERAPY. NUCLEIC ACIDS 2022; 27:427-438. [PMID: 35036055 PMCID: PMC8733234 DOI: 10.1016/j.omtn.2021.12.015] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Accepted: 12/09/2021] [Indexed: 02/07/2023]
Abstract
Chemotherapy is considered the nonsurgical treatment of choice for colon cancer patients. However, no precise molecular markers are available to determine which patients can actually benefit from it. In this study, we identified 55 chemotherapy-specific long non-coding RNAs (lncRNAs) of colon cancer patients through a systematic assessment of lncRNA expression profiles from a public database. These were taken from multiple cohorts of colon cancer patients who had received chemotherapy, or not. Based on these data, a chemoresistance lncRNA signature, named CRLSig, was constructed and successfully applied to divide chemotherapy patients into two groups with different recurrence-free survival (RFS) rates. Gene set enrichment analysis revealed that patients with low CRLSig had more infiltrating CD8+ T cells and macrophages, while those with high CRLSig had more infiltrating natural killer T cells. KEGG pathway analysis revealed that the low CRLSig group had more activated metabolic pathways compared with those in the high CRLSig group, indicating better response to chemotherapy. Single-cell sequencing analysis revealed that stromal cells and epithelial cells had higher CRLSig. Thus, we have constructed an auxiliary prognostic tool, CRLSig, able to discriminate patients at high risk of RFS, despite having received standard adjuvant chemotherapy treatment.
A CRLSig was constructed for the first time CRLSig revealed chemotherapy patients with different RFS rates Low CRLSig group had more activated metabolic pathways ScRNA-seq analysis revealed stromal cells and epithelial cells had higher CRLSig
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Affiliation(s)
- Hao Wang
- Department of Gastroenterology, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, China.,Institution of Gastroenterology, Zhejiang University, Hangzhou, Zhejiang, China
| | - Yuzhen Gao
- Department of Clinical Laboratory, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310016, China.,Biomedical Research Center, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310013, China
| | - Somayeh Vafaei
- Department of Molecular Medicine, Faculty of advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Qiaoyan Yu
- Department of Gastroenterology, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, China.,Institution of Gastroenterology, Zhejiang University, Hangzhou, Zhejiang, China
| | - Jun Zhang
- Department of Clinical Laboratory, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310016, China.,Biomedical Research Center, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310013, China
| | - Liangjing Wang
- Department of Gastroenterology, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, China.,Institution of Gastroenterology, Zhejiang University, Hangzhou, Zhejiang, China
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16
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A Prediction Model for Tumor Recurrence in Stage II–III Colorectal Cancer Patients: From a Machine Learning Model to Genomic Profiling. Biomedicines 2022; 10:biomedicines10020340. [PMID: 35203549 PMCID: PMC8961774 DOI: 10.3390/biomedicines10020340] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Revised: 01/27/2022] [Accepted: 01/28/2022] [Indexed: 01/27/2023] Open
Abstract
Background: Colorectal cancer (CRC) is one of the most prevalent malignant diseases worldwide. Risk prediction for tumor recurrence is important for making effective treatment decisions and for the survival outcomes of patients with CRC after surgery. Herein, we aimed to explore a prediction algorithm and the risk factors for postoperative tumor recurrence using a machine learning (ML) approach with standardized pathology reports for patients with stage II and III CRC. Methods: Pertinent clinicopathological features were compiled from medical records and standardized pathology reports of patients with stage II and III CRC. Four ML models based on logistic regression (LR), random forest (RF), classification and regression decision trees (CARTs), and support vector machine (SVM) were applied for the development of the prediction algorithm. The area under the curve (AUC) of the ML models was determined in order to compare the prediction accuracy. Genomic studies were performed using a panel-targeted next-generation sequencing approach. Results: A total of 1073 patients who received curative intent surgery at the National Cheng Kung University Hospital between January 2004 and January 2019 were included. Based on conventional statistical methods, chemotherapy (p = 0.003), endophytic tumor configuration (p = 0.008), TNM stage III disease (p < 0.001), pT4 (p < 0.001), pN2 (p < 0.001), increased numbers of lymph node metastases (p < 0.001), higher lymph node ratios (LNR) (p < 0.001), lymphovascular invasion (p < 0.001), perineural invasion (p < 0.001), tumor budding (p = 0.004), and neoadjuvant chemoradiotherapy (p = 0.025) were found to be correlated with the tumor recurrence of patients with stage II–III CRC. While comparing the performance of different ML models for predicting cancer recurrence, the AUCs for LR, RF, CART, and SVM were found to be 0.678, 0.639, 0.593, and 0.581, respectively. The LR model had a better accuracy value of 0.87 and a specificity value of 1 in the testing set. Two prognostic factors, age and LNR, were selected by multivariable analysis and the four ML models. In terms of age, older patients received fewer cycles of chemotherapy and radiotherapy (p < 0.001). Right-sided colon tumors (p = 0.002), larger tumor sizes (p = 0.008) and tumor volumes (p = 0.049), TNM stage II disease (p < 0.001), and advanced pT3–4 stage diseases (p = 0.04) were found to be correlated with the older age of patients. However, pN2 diseases (p = 0.005), lymph node metastasis number (p = 0.001), LNR (p = 0.004), perineural invasion (p = 0.018), and overall survival rate (p < 0.001) were found to be decreased in older patients. Furthermore, PIK3CA and DNMT3A mutations (p = 0.032 and 0.039, respectively) were more frequently found in older patients with stage II–III CRC compared to their younger counterparts. Conclusions: This study demonstrated that ML models have a comparable predictive power for determining cancer recurrence in patients with stage II–III CRC after surgery. Advanced age and high LNR were significant risk factors for cancer recurrence, as determined by ML algorithms and multivariable analyses. Distinctive genomic profiles may contribute to discrete clinical behaviors and survival outcomes between patients of different age groups. Studies incorporating complete molecular and genomic profiles in cancer prediction models are beneficial for patients with stage II–III CRC.
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17
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Aggarwal N, Quaglia A, McPhail MJW, Monahan KJ. Systematic review and meta-analysis of tumour microsatellite-instability status as a predictor of response to fluorouracil-based adjuvant chemotherapy in colorectal cancer. Int J Colorectal Dis 2022; 37:35-46. [PMID: 34677685 PMCID: PMC8760189 DOI: 10.1007/s00384-021-04046-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/01/2021] [Indexed: 02/04/2023]
Abstract
PURPOSE Colorectal cancer (CRC) can be classified according to the chromosomal-instability pathway (a microsatellite-stable (MSS) pathway) and the microsatellite-instability (MSI) pathway. Adjuvant therapy after surgery in advanced CRC is usually based on fluoropyrimidine 5-fluorouracil (5-FU) alone or combined with other agents. Controversy however remains on the use of 5-FU-based regimens in treating MSI-related tumours. AIMS To systematically investigate the relationship between tumour microsatellite profile and 5-year overall survival in patients with CRC treated with 5-FU. METHODS A systematic literature review of PubMed and Embase databases was conducted. Pre-specified criteria determined study inclusion/exclusion. The PRISMA and QUADAS-2 criteria were used to assess study suitability and quality respectively. Patients were categorised as having either MSI or MSS CRC. Overall 5-year survival was estimated from Kaplan-Meier curves. Publication bias was assessed using funnel-plots and Egger's test. RESULTS 1807 studies were identified, with meta-analysis performed using nine studies. 5-FU treated individuals with CRC who died at 5 years were found to be 0.31 times less likely to have MSI than those who were alive, although this was not statistically significant. There was an insufficient number of studies to enable subgroup analysis by stage. CONCLUSIONS In this meta-analysis, MSI status does not alter 5-year survival of patients with CRC patients treated with adjuvant 5-FU, however there is significant heterogeneity in the design of individual studies in the data synthesis. More studies are necessary to clarify whether CRC patients with MSI CRC, in particular early stage, should be offered 5-FU based adjuvant chemotherapy.
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Affiliation(s)
- Nikhil Aggarwal
- Internal Medicine, St Thomas’ Hospital, London, United Kingdom
| | - Alberto Quaglia
- Department of Cellular Pathology, Royal Free London NHS Foundation Trust, London, United Kingdom ,UCL Cancer Institute, University College London, London, United Kingdom
| | - Mark J. W. McPhail
- Institute of Liver Studies, Kings College London, London, United Kingdom
| | - Kevin J. Monahan
- Imperial College London, London, United Kingdom ,Lynch Syndrome & Family Cancer Clinic, St Mark’s Hospital, London, United Kingdom
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18
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Jaffrelot M, Farés N, Brunac AC, Laurenty AP, Danjoux M, Grand D, Icher S, Meilleroux J, Mery E, Buscail E, Maulat C, Toulas C, Vande Perre P, Chipoulet E, Bonnet D, Staub A, Guimbaud R, Selves J. An unusual phenotype occurs in 15% of mismatch repair-deficient tumors and is associated with non-colorectal cancers and genetic syndromes. Mod Pathol 2022; 35:427-437. [PMID: 34545179 PMCID: PMC8860743 DOI: 10.1038/s41379-021-00918-3] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 08/21/2021] [Accepted: 08/27/2021] [Indexed: 02/07/2023]
Abstract
Immunohistochemistry (IHC) and/or MSI-PCR (microsatellite instability-polymerase chain reaction) tests are performed routinely to detect mismatch repair deficiency (MMR-D). Classical MMR-D tumors present a loss of MLH1/PMS2 or MSH2/MSH6 with MSI-High. Other profiles of MMR-D tumors have been described but have been rarely studied. In this study, we established a classification of unusual MMR-D tumors and determined their frequency and clinical impact. All MMR-D tumors identified between 2007 and 2017 were selected. Any profile besides the classical MMR-D phenotype was defined as unusual. For patients with unusual MMR-D tumors, IHC, and PCR data were reviewed, the tumor mutation burden (TMB) was evaluated and clinical and genetic features were collected. Of the 4948 cases of MMR testing, 3800 had both the available IHC and MSI-PCR results and 585 of these had MMR-D. After reviewing the IHC and PCR, 21% of the cases initially identified as unusual MMR-D were reclassified, which resulted in a final identification of 89 unusual MMR-D tumors (15%). Unusual MMR-D tumors were more often associated with non-CRC than classical MMR-D tumors. Unusual MMR-D tumors were classified into four sub-groups: i) isolated loss of PMS2 or MSH6, ii) classical loss of MLH1/PMS2 or MSH2/MSH6 without MSI, iii) four MMR proteins retained with MSI and, iv) complex loss of MMR proteins, with clinical characteristics for each sub-group. TMB-high or -intermediate was shown in 96% of the cancers studied (24/25), which confirmed MMR deficiency. Genetic syndromes were identified in 44.9% (40/89) and 21.4% (106/496) of patients with unusual and classical MMR-D tumors, respectively (P < 0.001). Five patients treated with an immune checkpoint inhibitor (ICI) had a prolonged clinical benefit. Our classification of unusual MMR-D phenotype helps to identify MMR deficiency. Unusual MMR-D phenotype occurs in 15% of MMR-D tumors. A high frequency of genetic syndromes was noted in these patients who could benefit from ICI.
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Affiliation(s)
- Marion Jaffrelot
- grid.411175.70000 0001 1457 2980Department of Digestive Oncology, Centre Hospitalier Universitaire (CHU), Toulouse, France
| | - Nadim Farés
- grid.411175.70000 0001 1457 2980Department of Digestive Oncology, Centre Hospitalier Universitaire (CHU), Toulouse, France ,grid.15781.3a0000 0001 0723 035XUniversité Fédérale Toulouse Midi-Pyrénées, Université Toulouse III Paul Sabatier, INSERM, CRCT, 31330 Toulouse, France ,grid.411175.70000 0001 1457 2980Department of Digestive Surgery, Centre Hospitalier Universitaire (CHU), Toulouse, France
| | - Anne Cécile Brunac
- grid.411175.70000 0001 1457 2980Department of Pathology, Institut Universitaire du Cancer-Oncopole de Toulouse; Centre Hospitalier Universitaire (CHU), Toulouse, France
| | - Anne Pascale Laurenty
- grid.411175.70000 0001 1457 2980Department of Digestive Oncology, Centre Hospitalier Universitaire (CHU), Toulouse, France
| | - Marie Danjoux
- grid.411175.70000 0001 1457 2980Department of Pathology, Institut Universitaire du Cancer-Oncopole de Toulouse; Centre Hospitalier Universitaire (CHU), Toulouse, France
| | - David Grand
- grid.411175.70000 0001 1457 2980Department of Pathology, Institut Universitaire du Cancer-Oncopole de Toulouse; Centre Hospitalier Universitaire (CHU), Toulouse, France
| | - Samira Icher
- grid.411175.70000 0001 1457 2980Department of Pathology, Institut Universitaire du Cancer-Oncopole de Toulouse; Centre Hospitalier Universitaire (CHU), Toulouse, France
| | - Julie Meilleroux
- grid.411175.70000 0001 1457 2980Department of Pathology, Institut Universitaire du Cancer-Oncopole de Toulouse; Centre Hospitalier Universitaire (CHU), Toulouse, France
| | - Eliane Mery
- grid.411175.70000 0001 1457 2980Department of Pathology, Institut Universitaire du Cancer-Oncopole de Toulouse; Centre Hospitalier Universitaire (CHU), Toulouse, France
| | - Etienne Buscail
- grid.411175.70000 0001 1457 2980Department of Oncogenetics, Institut Universitaire du Cancer-Oncopole de Toulouse, Institut Claudius Regaud and Centre Hospitalier Universitaire (CHU), Toulouse, France
| | - Charlotte Maulat
- grid.411175.70000 0001 1457 2980Department of Oncogenetics, Institut Universitaire du Cancer-Oncopole de Toulouse, Institut Claudius Regaud and Centre Hospitalier Universitaire (CHU), Toulouse, France
| | - Christine Toulas
- grid.411175.70000 0001 1457 2980Department of Oncogenetics, Institut Universitaire du Cancer-Oncopole de Toulouse, Institut Claudius Regaud and Centre Hospitalier Universitaire (CHU), Toulouse, France
| | - Pierre Vande Perre
- grid.411175.70000 0001 1457 2980Department of Oncogenetics, Institut Universitaire du Cancer-Oncopole de Toulouse, Institut Claudius Regaud and Centre Hospitalier Universitaire (CHU), Toulouse, France
| | - Edith Chipoulet
- grid.411175.70000 0001 1457 2980Department of Oncogenetics, Institut Universitaire du Cancer-Oncopole de Toulouse, Institut Claudius Regaud and Centre Hospitalier Universitaire (CHU), Toulouse, France
| | - Delphine Bonnet
- grid.411175.70000 0001 1457 2980Department of Oncogenetics, Institut Universitaire du Cancer-Oncopole de Toulouse, Institut Claudius Regaud and Centre Hospitalier Universitaire (CHU), Toulouse, France
| | - Anne Staub
- grid.411175.70000 0001 1457 2980Department of Oncogenetics, Institut Universitaire du Cancer-Oncopole de Toulouse, Institut Claudius Regaud and Centre Hospitalier Universitaire (CHU), Toulouse, France
| | - Rosine Guimbaud
- grid.411175.70000 0001 1457 2980Department of Digestive Oncology, Centre Hospitalier Universitaire (CHU), Toulouse, France ,grid.15781.3a0000 0001 0723 035XUniversité Fédérale Toulouse Midi-Pyrénées, Université Toulouse III Paul Sabatier, INSERM, CRCT, 31330 Toulouse, France ,grid.411175.70000 0001 1457 2980Department of Digestive Surgery, Centre Hospitalier Universitaire (CHU), Toulouse, France
| | - Janick Selves
- Université Fédérale Toulouse Midi-Pyrénées, Université Toulouse III Paul Sabatier, INSERM, CRCT, 31330, Toulouse, France. .,Department of Digestive Surgery, Centre Hospitalier Universitaire (CHU), Toulouse, France.
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Tonello M, Baratti D, Sammartino P, Di Giorgio A, Robella M, Sassaroli C, Framarini M, Valle M, Macrì A, Graziosi L, Coccolini F, Lippolis PV, Roberta G, Deraco M, Biacchi D, Santullo F, Vaira M, Di Lauro K, D'Acapito F, Carboni F, Giuffrè G, Donini A, Fugazzola P, Faviana P, Lorena S, Scapinello A, Del Bianco P, Sommariva A. Microsatellite and RAS/RAF Mutational Status as Prognostic Factors in Colorectal Peritoneal Metastases Treated with Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy (HIPEC). Ann Surg Oncol 2021; 29:3405-3417. [PMID: 34783946 DOI: 10.1245/s10434-021-11045-3] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Accepted: 10/20/2021] [Indexed: 12/16/2022]
Abstract
BACKGROUND Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) leads to prolonged survival for selected patients with colorectal (CRC) peritoneal metastases (PM). This study aimed to analyze the prognostic role of micro-satellite (MS) status and RAS/RAF mutations for patients treated with CRS. METHODS Data were collected from 13 Italian centers with PM expertise within a collaborative group of the Italian Society of Surgical Oncology. Clinical and pathologic variables and KRAS/NRAS/BRAF mutational and MS status were correlated with overall survival (OS) and disease-free survival (DFS). RESULTS The study enrolled 437 patients treated with CRS-HIPEC. The median OS was 42.3 months [95% confidence interval (CI), 33.4-51.2 months], and the median DFS was 13.6 months (95% CI, 12.3-14.9 months). The local (peritoneal) DFS was 20.5 months (95% CI, 16.4-24.6 months). In addition to the known clinical factors, KRAS mutations (p = 0.005), BRAF mutations (p = 0.01), and MS status (p = 0.04) were related to survival. The KRAS- and BRAF-mutated patients had a shorter survival than the wild-type (WT) patients (5-year OS, 29.4% and 26.8% vs 51.5%, respectively). The patients with micro-satellite instability (MSI) had a longer survival than the patients with micro-satellite stability (MSS) (5-year OS, 58.3% vs 36.7%). The MSI/WT patients had the best prognosis. The MSS/WT and MSI/mutated patients had similar survivals, whereas the MSS/mutated patients showed the worst prognosis (5-year OS, 70.6%, 48.1%, 23.4%; p = 0.0001). In the multivariable analysis, OS was related to the Peritoneal Cancer Index [hazard ratio (HR), 1.05 per point], completeness of cytoreduction (CC) score (HR, 2.8), N status (HR, 1.6), signet-ring (HR, 2.4), MSI/WT (HR, 0.5), and MSS/WT-MSI/mutation (HR, 0.4). Similar results were obtained for DFS. CONCLUSION For patients affected by CRC-PM who are eligible for CRS, clinical and pathologic criteria need to be integrated with molecular features (KRAS/BRAF mutation). Micro-satellite status should be strongly considered because MSI confers a survival advantage over MSS, even for mutated patients.
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Affiliation(s)
- Marco Tonello
- Unit of Surgical Oncology of the Esophagus and Digestive Tract, Surgical Oncology Department, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy
| | - Dario Baratti
- Peritoneal Surface Malignancy Unit, Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Paolo Sammartino
- Cytoreductive Surgery and HIPEC Unit, Department of Surgery "Pietro Valdoni", Sapienza University of Rome, Rome, Italy
| | - Andrea Di Giorgio
- Surgical Unit of Peritoneum and Retroperitoneum, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
| | - Manuela Robella
- Surgical Oncology Unit, Candiolo Cancer Institute, Candiolo, Turin, Italy
| | - Cinzia Sassaroli
- Colorectal Surgical Oncology, Abdominal Oncology Department, Fondazione Giovanni Pascale" IRCCS, Naples, Italy
| | - Massimo Framarini
- General and Oncologic Surgery, Morgagni-Pierantoni Hospital, AUSL Romagna, Forlì, Italy
| | - Mario Valle
- Peritoneal Malignancies Unit, INT "Regina Elena", Rome, Italy
| | - Antonio Macrì
- Peritoneal Surface Malignancy and Soft Tissue Sarcoma Program, University of Messina, Messina, Italy
| | - Luigina Graziosi
- General and Emergency Surgery Department, Santa Maria della Misericordia Hospital, University of Perugia, Perugia, Italy
| | - Federico Coccolini
- General Emergency and Trauma Surgery, Bufalini Hospital, Cesena, Italy.,General Emergency and Trauma Surgery, Pisa University Hospital, Pisa, Italy
| | - Piero Vincenzo Lippolis
- General and Peritoneal Surgery, Department of Surgery, Hospital University Pisa (AOUP), Pisa, Italy
| | - Gelmini Roberta
- General and Oncological Surgery Unit, AOU of Modena University of Modena and Reggio Emilia, Modena, Italy
| | - Marcello Deraco
- Peritoneal Surface Malignancy Unit, Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Daniele Biacchi
- Cytoreductive Surgery and HIPEC Unit, Department of Surgery "Pietro Valdoni", Sapienza University of Rome, Rome, Italy
| | - Francesco Santullo
- Surgical Unit of Peritoneum and Retroperitoneum, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
| | - Marco Vaira
- Surgical Oncology Unit, Candiolo Cancer Institute, Candiolo, Turin, Italy
| | - Katia Di Lauro
- Department of Advanced Biomedical Sciences, "Federico II" University, Naples, Italy
| | - Fabrizio D'Acapito
- General and Oncologic Surgery, Morgagni-Pierantoni Hospital, AUSL Romagna, Forlì, Italy
| | - Fabio Carboni
- Peritoneal Malignancies Unit, INT "Regina Elena", Rome, Italy
| | - Giuseppe Giuffrè
- Department of Human Pathology in Adult and Developmental Age 'Gaetano Barresi', Section of Pathology, University of Messina, Messina, Italy
| | - Annibale Donini
- General and Emergency Surgery Department, Santa Maria della Misericordia Hospital, University of Perugia, Perugia, Italy
| | - Paola Fugazzola
- General Emergency and Trauma Surgery, Bufalini Hospital, Cesena, Italy
| | - Pinuccia Faviana
- Pathological Anatomy III, Laboratory Medicine Department, Hospital University Pisa (AOUP), Pisa, Italy
| | - Sorrentino Lorena
- General and Oncological Surgery Unit, AOU of Modena University of Modena and Reggio Emilia, Modena, Italy
| | | | - Paola Del Bianco
- Clinical Research Unit, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy
| | - Antonio Sommariva
- Unit of Surgical Oncology of the Esophagus and Digestive Tract, Surgical Oncology Department, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy.
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Zaborowski AM, Winter DC, Lynch L. The therapeutic and prognostic implications of immunobiology in colorectal cancer: a review. Br J Cancer 2021; 125:1341-1349. [PMID: 34302062 PMCID: PMC8575924 DOI: 10.1038/s41416-021-01475-x] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Revised: 05/13/2021] [Accepted: 06/17/2021] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer represents the second leading cause of cancer-related death worldwide. The therapeutic field of immuno-oncology has rapidly gained momentum, with strikingly promising results observed in clinical practice. Increasing emphasis has been placed on the role of the immune response in tumorigenesis, therapy and predicting prognosis. Enhanced understanding of the dynamic and complex tumour-immune microenvironment has enabled the development of molecularly directed, individualised treatment. Analysis of intra-tumoural lymphocyte infiltration and the dichotomisation of colorectal cancer into microsatellite stable and unstable disease has important therapeutic and prognostic implications, with potential to capitalise further on this data. This review discusses the latest evidence surrounding the tumour biology and immune landscape of colorectal cancer, novel immunotherapies and the interaction of the immune system with each apex of the tripartite of cancer management (oncotherapeutics, radiotherapy and surgery). By utilising the synergy of chemotherapeutic agents and immunotherapies, and identifying prognostic and predictive immunological biomarkers, we may enter an era of unprecedented disease control, survivorship and cure rates.
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Affiliation(s)
- Alexandra M. Zaborowski
- grid.412751.40000 0001 0315 8143Centre for Colorectal Disease, St. Vincent’s University Hospital, Dublin 4, Ireland ,grid.8217.c0000 0004 1936 9705School of Biochemistry and Immunology, Trinity College Dublin, Dublin, Ireland
| | - Des C. Winter
- grid.412751.40000 0001 0315 8143Centre for Colorectal Disease, St. Vincent’s University Hospital, Dublin 4, Ireland ,grid.7886.10000 0001 0768 2743School of Medicine, University College Dublin, Dublin 4, Ireland
| | - Lydia Lynch
- grid.8217.c0000 0004 1936 9705School of Biochemistry and Immunology, Trinity College Dublin, Dublin, Ireland ,grid.38142.3c000000041936754XHarvard Institutes of Medicine, Harvard Medical School, Boston, MA USA
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21
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Toh JWT, Phan K, Reza F, Chapuis P, Spring KJ. Rate of dissemination and prognosis in early and advanced stage colorectal cancer based on microsatellite instability status: systematic review and meta-analysis. Int J Colorectal Dis 2021; 36:1573-1596. [PMID: 33604737 DOI: 10.1007/s00384-021-03874-1] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/27/2021] [Indexed: 02/04/2023]
Abstract
INTRODUCTION For the past two decades, microsatellite instability (MSI) has been reported as a robust clinical biomarker associated with survival advantage attributed to its immunogenicity. However, MSI is also associated with high-risk adverse pathological features (poorly differentiated, mucinous, signet cell, higher grade) and exhibits a double-edged sword phenomenon. We performed a systematic review and meta-analysis to evaluate the rate of dissemination and the prognosis of early and advanced stage colorectal cancer based on MSI status. METHODS A systematic literature search of original studies was performed on Ovid searching MEDLINE, Embase, Cochrane Database of Systematic Reviews, American College of Physicians ACP Journal Club, Database of Abstracts of Reviews of Effects DARE, Clinical Trials databases from inception of database to June 2019. Colorectal cancer, microsatellite instability, genomic instability and DNA mismatch repair were used as key words or MeSH terms. The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline was followed. Data were pooled using a random-effects model with odds ratio (OR) as the effect size. Statistical analysis was performed using RevMan ver 5.3 Cochrane Collaboration. RESULTS From 5288 studies, 136 met the inclusion criteria (n = 92,035; MSI-H 11,746 (13%)). Overall, MSI-H was associated with improved OS (OR, 0.81; 95% CI 0.73-0.90), DFS (OR, 0.73; 95% CI 0.66-0.81) and DSS (OR, 0.69; 95% CI 0.52-0.90). Importantly, MSI-H had a protective effect against dissemination with a significantly lower rate of lymph node and distant metastases. By stage, the protective effect of MSI-H in terms of OS and DFS was observed clearly in stage II and stage III. Survival in stage I CRC was excellent irrespective of MSI status. In stage IV CRC, without immunotherapy, MSI-H was not associated with any survival benefit. CONCLUSIONS MSI-H CRC was associated with an overall survival benefit with a lower rate of dissemination. Survival benefit was clearly evident in both stage II and III CRC, but MSI-H was neither a robust prognostic marker in stage I nor stage IV CRC without immunotherapy.
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Affiliation(s)
- James W T Toh
- Department of Surgery, Division of Colorectal Surgery, Westmead Hospital, Sydney, NSW, Australia. .,Discipline of Surgery, Sydney Medical School, University of Sydney, Sydney, NSW, Australia. .,Discipline of Surgery, The University of New South Wales, Sydney, NSW, Australia. .,Medical Oncology, Ingham Institute for Applied Medical Research, School of Medicine Western Sydney University and South Western Clinical School, University of New South Wales, NSW, Sydney, Australia.
| | - Kevin Phan
- Department of Surgery, Division of Colorectal Surgery, Westmead Hospital, Sydney, NSW, Australia
| | - Faizur Reza
- Department of Surgery, Division of Colorectal Surgery, Westmead Hospital, Sydney, NSW, Australia
| | - Pierre Chapuis
- Discipline of Surgery, Sydney Medical School, University of Sydney, Sydney, NSW, Australia
| | - Kevin J Spring
- Medical Oncology, Ingham Institute for Applied Medical Research, School of Medicine Western Sydney University and South Western Clinical School, University of New South Wales, NSW, Sydney, Australia
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22
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Li J, Yang Z, Xin B, Hao Y, Wang L, Song S, Xu J, Wang X. Quantitative Prediction of Microsatellite Instability in Colorectal Cancer With Preoperative PET/CT-Based Radiomics. Front Oncol 2021; 11:702055. [PMID: 34367985 PMCID: PMC8339969 DOI: 10.3389/fonc.2021.702055] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Accepted: 06/30/2021] [Indexed: 12/23/2022] Open
Abstract
OBJECTIVES Microsatellite instability (MSI) status is an important hallmark for prognosis prediction and treatment recommendation of colorectal cancer (CRC). To address issues due to the invasiveness of clinical preoperative evaluation of microsatellite status, we investigated the value of preoperative 18F-FDG PET/CT radiomics with machine learning for predicting the microsatellite status of colorectal cancer patients. METHODS A total of 173 patients that underwent 18F-FDG PET/CT scans before operations were retrospectively analyzed in this study. The microsatellite status for each patient was identified as microsatellite instability-high (MSI-H) or microsatellite stable (MSS), according to the test for mismatch repair gene proteins with immunohistochemical staining methods. There were 2,492 radiomic features in total extracted from 18F-FDG PET/CT imaging. Then, radiomic features were selected through multivariate random forest selection and univariate relevancy tests after handling the imbalanced dataset through the random under-sampling method. Based on the selected features, we constructed a BalancedBagging model based on Adaboost classifiers to identify the MSI status in patients with CRC. The model performance was evaluated by the area under the curve (AUC), sensitivity, specificity, and accuracy on the validation dataset. RESULTS The ensemble model was constructed based on two radiomic features and achieved an 82.8% AUC for predicting the MSI status of colorectal cancer patients. The sensitivity, specificity, and accuracy were 83.3, 76.3, and 76.8%, respectively. The significant correlation of the selected two radiomic features with multiple effective clinical features was identified (p < 0.05). CONCLUSION 18F-FDG PET/CT radiomics analysis with the machine learning model provided a quantitative, efficient, and non-invasive mechanism for identifying the microsatellite status of colorectal cancer patients, which optimized the treatment decision support.
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Affiliation(s)
- Jiaru Li
- School of Computer Science, The University of Sydney, Sydney, NSW, Australia
| | - Ziyi Yang
- Department of Nuclear Medicine, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Bowen Xin
- School of Computer Science, The University of Sydney, Sydney, NSW, Australia
| | - Yichao Hao
- School of Computer Science, The University of Sydney, Sydney, NSW, Australia
| | - Lisheng Wang
- Department of Automation, Shanghai Jiao Tong University, Shanghai, China
| | - Shaoli Song
- Department of Nuclear Medicine, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Junyan Xu
- Department of Nuclear Medicine, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Xiuying Wang
- School of Computer Science, The University of Sydney, Sydney, NSW, Australia
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23
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Masfarré L, Vidal J, Fernández-Rodríguez C, Montagut C. ctDNA to Guide Adjuvant Therapy in Localized Colorectal Cancer (CRC). Cancers (Basel) 2021; 13:2869. [PMID: 34201274 PMCID: PMC8226638 DOI: 10.3390/cancers13122869] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2021] [Revised: 05/30/2021] [Accepted: 06/02/2021] [Indexed: 12/15/2022] Open
Abstract
Currently, the standard treatment for patients with localized colorectal cancer (CRC) includes surgical resection followed by adjuvant chemotherapy based on clinicopathological features. Recurrence risk stratification in those patients is of utmost importance to guide clinicians to avoid both under- and overtreatment. Recently, the concept of minimal residual disease (MRD) has emerged as the detection of circulating tumor DNA (ctDNA) carrying tumor-specific genomic or epigenomic alterations in the bloodstream of patients after surgery. Emerging studies described how the detection of MRD is a powerful prognostic biomarker to identify patients at higher risk of recurrence and who will potentially benefit the most from a systemic adjuvant treatment. Based on that unprecedented finding, several clinical trials involving stage II and III CRC patients are ongoing evaluating the impact of ctDNA guided treatment by escalating or deescalating adjuvant chemotherapy based on ctDNA MRD detection. This review provides a critical overview of current perspectives of liquid biopsy in early-stage CRC including technical, biological, and clinical key points, as well as ongoing ctDNA-based clinical trials that ultimately aim to improve clinical outcomes of patients with CRC.
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Affiliation(s)
- Laura Masfarré
- Medical Oncology Department, Hospital del Mar, 08003 Barcelona, Spain; (L.M.); (J.V.)
| | - Joana Vidal
- Medical Oncology Department, Hospital del Mar, 08003 Barcelona, Spain; (L.M.); (J.V.)
- Cancer Research Program, FIMIM, Hospital del Mar, 08003 Barcelona, Spain
| | | | - Clara Montagut
- Medical Oncology Department, Hospital del Mar, 08003 Barcelona, Spain; (L.M.); (J.V.)
- Cancer Research Program, FIMIM, Hospital del Mar, 08003 Barcelona, Spain
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24
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Ruiz-Bañobre J, Goel A. Genomic and epigenomic biomarkers in colorectal cancer: From diagnosis to therapy. Adv Cancer Res 2021; 151:231-304. [PMID: 34148615 PMCID: PMC10338180 DOI: 10.1016/bs.acr.2021.02.008] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Colorectal cancer (CRC) is the second leading cause of cancer-related deaths in the United States. Despite ongoing efforts aimed at increasing screening for CRC and early detection, and development of more effective therapeutic regimens, the overall morbidity and mortality from this malignancy remains a clinical challenge. Therefore, identifying and developing genomic and epigenomic biomarkers that can improve CRC diagnosis and help predict response to current therapies are of paramount importance for improving survival outcomes in CRC patients, sparing patients from toxicity associated with current regimens, and reducing the economic burden associated with these treatments. Although efforts to develop biomarkers over the past decades have achieved some success, the recent availability of high-throughput analytical tools, together with the use of machine learning algorithms, will likely hasten the development of more robust diagnostic biomarkers and improved guidance for clinical decision-making in the coming years. In this chapter, we provide a systematic and comprehensive overview on the current status of genomic and epigenomic biomarkers in CRC, and comment on their potential clinical significance in the management of patients with this fatal malignancy, including in the context of precision medicine.
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Affiliation(s)
- Juan Ruiz-Bañobre
- Medical Oncology Department, University Clinical Hospital of Santiago de Compostela, University of Santiago de Compostela (USC), CIBERONC, Santiago de Compostela, Spain; Translational Medical Oncology Group (Oncomet), Health Research Institute of Santiago (IDIS), University Clinical Hospital of Santiago de Compostela, University of Santiago de Compostela (USC), CIBERONC, Santiago de Compostela, Spain
| | - Ajay Goel
- Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute of City of Hope Comprehensive Cancer Center, Duarte, CA, United States.
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25
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Zhang W, Huang Z, Zhao J, He D, Li M, Yin H, Tian S, Zhang H, Song B. Development and validation of magnetic resonance imaging-based radiomics models for preoperative prediction of microsatellite instability in rectal cancer. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:134. [PMID: 33569436 PMCID: PMC7867944 DOI: 10.21037/atm-20-7673] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Background Microsatellite instability (MSI) is a predictive biomarker for response to chemotherapy and a prognostic biomarker for clinical outcomes of rectal cancer. The purpose of this study was to develop and validate radiomics models for preoperative prediction of the MSI status of rectal cancer based on magnetic resonance (MR) images. Methods This study retrospectively recruited 491 rectal cancer patients with pathologically confirmed MSI status. Patients were randomly divided into a training cohort (n=327) and a validation cohort (n=164). The most predictive radiomics features were selected using intraclass correlation coefficient (ICC) analysis, the two-sample t test, and the least absolute shrinkage and selection operator (LASSO) method. XGBoost models were constructed in the training cohort to discriminate the MSI status using clinical factors, radiomics features, or a combined model incorporating both the radiomics signature and independent clinical characteristics. The diagnostic performance of these three models was evaluated in the validation cohort based on their area under the curve (AUC), sensitivity, specificity, and accuracy. Results Among the 491 rectal cancer patients, the prevalence of MSI was 10.39% (51/491). Following ICC analysis, two-sample t test, and LASSO regression, six radiomics features were selected for subsequent analysis. The combined model, which incorporated both the clinical factors and radiomics features achieved an AUC of 0.895 [95% confidence interval (CI), 0.838–0.938] in the validation cohort, and showed better performance in predicting MSI status than the other two models using either clinical factors (P=0.015) or radiomics features (P=0.204) alone. Conclusions Radiomics features based on preoperative T2-weighted MR imaging (MRI) are associated with the MSI status of rectal cancer. Combinational analysis of clinical factors and radiomics features may improve predictive performance and potentially contribute to noninvasive personalized therapy selection.
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Affiliation(s)
- Wei Zhang
- Department of Radiology, West China Hospital, Sichuan University, Chengdu, China.,Department of Radiology, Sichuan Provincial Corps Hospital, Chinese People's Armed Police Forces, Leshan, China
| | - Zixing Huang
- Department of Radiology, West China Hospital, Sichuan University, Chengdu, China
| | - Jian Zhao
- Department of Radiology, West China Hospital, Sichuan University, Chengdu, China.,Department of Radiology, Sichuan Provincial Corps Hospital, Chinese People's Armed Police Forces, Leshan, China
| | - Du He
- Department of Pathology, West China Hospital, Sichuan University, Chengdu, China
| | - Mou Li
- Department of Radiology, West China Hospital, Sichuan University, Chengdu, China
| | - Hongkun Yin
- Institute of Advanced Research, InferVision, Beijing, China
| | - Song Tian
- Institute of Advanced Research, InferVision, Beijing, China
| | - Huiling Zhang
- Institute of Advanced Research, InferVision, Beijing, China
| | - Bin Song
- Department of Radiology, West China Hospital, Sichuan University, Chengdu, China
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Li Z, Liu J, Chen H, Zhang Y, Shi H, Huang L, Tao J, Shen R, Wang T. Ferritin Light Chain (FTL) competes with long noncoding RNA Linc00467 for miR-133b binding site to regulate chemoresistance and metastasis of colorectal cancer. Carcinogenesis 2020; 41:467-477. [PMID: 31675755 DOI: 10.1093/carcin/bgz181] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2019] [Revised: 10/18/2019] [Accepted: 10/25/2019] [Indexed: 12/22/2022] Open
Abstract
Although the colorectal cancer (CRC) mortality rates are decreasing in virtue of CRC screening and improved therapeutic methods, CRC is still a leading cause of cancer deaths. One of the main causes is chemoresistance occurrence in CRC. Understanding of the molecular mechanisms of chemoresistance benefits to CRC diagnosis and treatment. In this study, gene expression was determined by western blot and qRT-PCR. The biological functions of genes in CRC cells were studied by knocking down or overexpressing the gene in CRC cells and then analyzing cell sensitivity to 5-Fu by the MTT assay and the flow cytometry, and analyzing cell migration and invasion by transwell assays. The luciferase reporter assay was used to examine microRNA regulation of target gene expression, and biotin pull-down assay was performed to detect interaction between RNA molecules. This study found that ferritin light chain (FTL) and long intergenic noncoding RNA Linc00467 were both upregulated in CRC tissues and cell lines, and inversely correlated to CRC patient survival. FTL and Linc00467 promoted CRC cells abilities to resistance against 5-fluor-ouracil (5-Fu), migration and invasion. These effects were compromised by miR-133b which targeted both FTL and Linc00467. miR-133b interacted with Linc00467 and miR-133b inhibitor prevented Linc00467 knockdown-induced alternations of FTL expression and biological functions. Both FTL and Linc00467 are oncogenes in CRC. FTL expression upregulated in CRC via Linc00467/ miR-133b axis, and leads to CRC cell resistance against 5-FU treatment and promotes CRC metastasis. FTL expression upregulated in CRC via Linc00467/miR-133b axis, and leads to CRC cell resistance to 5-FU treatment and promotes CRC metastasis.
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Affiliation(s)
- Zengyao Li
- Department of General Surgery, and , Wuxi, Jiangsu.,Nanjing Medical University, Nanjing, Jiangsu, China
| | - Jing Liu
- Department of Respiratory, Wuxi People's Hospital, Wuxi, Jiangsu.,Nanjing Medical University, Nanjing, Jiangsu, China
| | - Hang Chen
- Department of General Surgery, and , Wuxi, Jiangsu.,Nanjing Medical University, Nanjing, Jiangsu, China
| | - Ye Zhang
- Department of General Surgery, and , Wuxi, Jiangsu.,Nanjing Medical University, Nanjing, Jiangsu, China
| | - Haoze Shi
- Department of General Surgery, and , Wuxi, Jiangsu.,Nanjing Medical University, Nanjing, Jiangsu, China
| | - Longchang Huang
- Department of General Surgery, and , Wuxi, Jiangsu.,Nanjing Medical University, Nanjing, Jiangsu, China
| | - Jianxin Tao
- Department of General Surgery, and , Wuxi, Jiangsu.,Nanjing Medical University, Nanjing, Jiangsu, China
| | - Renhui Shen
- Department of General Surgery, and , Wuxi, Jiangsu.,Nanjing Medical University, Nanjing, Jiangsu, China
| | - Tong Wang
- Department of General Surgery, and , Wuxi, Jiangsu.,Nanjing Medical University, Nanjing, Jiangsu, China
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Cellular Mechanisms Accounting for the Refractoriness of Colorectal Carcinoma to Pharmacological Treatment. Cancers (Basel) 2020; 12:cancers12092605. [PMID: 32933095 PMCID: PMC7563523 DOI: 10.3390/cancers12092605] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Revised: 09/07/2020] [Accepted: 09/09/2020] [Indexed: 02/06/2023] Open
Abstract
Simple Summary Colorectal cancer (CRC) causes a high number (more than 800,000) of deaths worldwide each year. Better methods for early diagnosis and the development of strategies to enhance the efficacy of the therapeutic approaches used to complement or substitute surgical removal of the tumor are urgently needed. Currently available pharmacological armamentarium provides very moderate benefits to patients due to the high resistance of tumor cells to respond to anticancer drugs. The present review summarizes and classifies into seven groups the cellular and molecular mechanisms of chemoresistance (MOC) accounting for the failure of CRC response to the pharmacological treatment. Abstract The unsatisfactory response of colorectal cancer (CRC) to pharmacological treatment contributes to the substantial global health burden caused by this disease. Over the last few decades, CRC has become the cause of more than 800,000 deaths per year. The reason is a combination of two factors: (i) the late cancer detection, which is being partially solved by the implementation of mass screening of adults over age 50, permitting earlier diagnosis and treatment; (ii) the inadequate response of advanced unresectable tumors (i.e., stages III and IV) to pharmacological therapy. The latter is due to the existence of complex mechanisms of chemoresistance (MOCs) that interact and synergize with each other, rendering CRC cells strongly refractory to the available pharmacological regimens based on conventional chemotherapy, such as pyrimidine analogs (5-fluorouracil, capecitabine, trifluridine, and tipiracil), oxaliplatin, and irinotecan, as well as drugs targeted toward tyrosine kinase receptors (regorafenib, aflibercept, bevacizumab, cetuximab, panitumumab, and ramucirumab), and, more recently, immune checkpoint inhibitors (nivolumab, ipilimumab, and pembrolizumab). In the present review, we have inventoried the genes involved in the lack of CRC response to pharmacological treatment, classifying them into seven groups (from MOC-1 to MOC-7) according to functional criteria to identify cancer cell weaknesses. This classification will be useful to pave the way for developing sensitizing tools consisting of (i) new agents to be co-administered with the active drug; (ii) pharmacological approaches, such as drug encapsulation (e.g., into labeled liposomes or exosomes); (iii) gene therapy interventions aimed at restoring the impaired function of some proteins (e.g., uptake transporters and tumor suppressors) or abolishing that of others (such as export pumps and oncogenes).
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Hu Z, Long T, Ma Y, Zhu J, Gao L, Zhong Y, Wang X, Wang X, Li Z. Downregulation of GLYR1 contributes to microsatellite instability colorectal cancer by targeting p21 via the p38MAPK and PI3K/AKT pathways. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2020; 39:76. [PMID: 32370786 PMCID: PMC7201645 DOI: 10.1186/s13046-020-01578-y] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/01/2020] [Accepted: 04/22/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND GLYR1 has a high mutation frequency in microsatellite instability colorectal cancer (MSI CRC) and is presumed to be a novel tumor suppressor. However, the role of GLYR1 in tumors has never been studied. In particular, the downregulation of GLYR1 in MSI CRC is worthy of further investigation. METHODS Western blot and immunohistochemistry analyses were used to detect GLYR1 protein expression in CRC tissues and cell lines, and the clinical significance of GLYR1 was also analyzed. The relationship between GLYR1 and MLH1 was validated by immunofluorescence, immunoprecipitation and bioinformatics analyses. Western blotting, qRT-PCR, CCK-8 assays, colony formation assays, flow cytometry and Hoechst 33258 staining assays were used to assess the effect of GLYR1 on the cell cycle progression, proliferation, differentiation and apoptosis of CRC cells in vitro. The related mechanisms were initially investigated by Western blotting. RESULTS GLYR1 was significantly downregulated in MSI CRC and its expression was negatively correlated with tumor size and positively correlated with tumor differentiation in CRC patients. In addition, GLYR1 interacted with MLH1 to regulate its nuclear import and expression. Moreover, downregulation of GLYR1 accelerated G1/S phase transition, promoted proliferation and inhibited differentiation of SW480 and SW620 cells in vitro. Furthermore, downregulation of GLYR1 decreased the sensitivity to 5-fluorouracil (5-FU) by inhibiting the mitochondrial apoptosis pathway in CRC cells. Inhibition of the p38 mitogen-activated protein kinase (p38MAPK) and activation of the phosphatidyl 3-kinase/protein kinase B (PI3K/Akt) signaling pathways were involved in the mechanism by which GLYR1 downregulated p21. CONCLUSIONS Ours is the first study to elucidate the role of GLYR1 in tumors and provide evidence for GLYR1 as a biological marker that reflects the degree of malignancy and sensitivity to 5-FU in MSI CRC.
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Affiliation(s)
- Zhiyan Hu
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, China.,Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Molecular tumor Pathology, Guangzhou, China
| | - Ting Long
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Molecular tumor Pathology, Guangzhou, China
| | - Yidan Ma
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Molecular tumor Pathology, Guangzhou, China
| | - Jiaxian Zhu
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Molecular tumor Pathology, Guangzhou, China
| | - Lingfang Gao
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Molecular tumor Pathology, Guangzhou, China
| | - Yan Zhong
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Molecular tumor Pathology, Guangzhou, China
| | - Xia Wang
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, China.,Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Molecular tumor Pathology, Guangzhou, China
| | - Xiaoyan Wang
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, China.,Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Molecular tumor Pathology, Guangzhou, China
| | - Zuguo Li
- Department of Pathology, Shenzhen Hospital of Southern Medical University, Shenzhen, China. .,Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China. .,Guangdong Provincial Key Laboratory of Molecular tumor Pathology, Guangzhou, China.
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Kasi PM, Kamatham S, Shahjehan F, Li Z, Johnson PW, Merchea A, Colibaseanu DT. BRAF-V600E and microsatellite instability prediction through CA-19-9/CEA ratio in patients with colorectal cancer. J Gastrointest Oncol 2020; 11:236-241. [PMID: 32399264 PMCID: PMC7212105 DOI: 10.21037/jgo.2019.12.08] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
BACKGROUND Early identification of colorectal cancer (CRC) patients that are BRAF-V600E mutant and/or microsatellite instability-high (MSI-High), has both prognostic and predictive value. We wanted to highlight an observation of utilizing 2 simple, rapid and universally available lab tests, i.e., carbohydrate cancer antigen 19-9 (CA 19-9) and carcinoembryonic antigen (CEA) tumor markers, the ratio (CA-19-9/CEA) of which can distinctly identify these patients from other molecular subsets of CRC. METHODS All patients with metastatic CRC from December 2016 to February 2019 were identified, and included in the study if they had both CA19-9 and CEA tests available. Circulating tumor DNA (ctDNA) testing and tissue genetic testing results were used to categorize patients into BRAF V600E microsatellite stable (MSS), MSI-High, RAS mutant MSS and RAS/RAF wild type CRCs. Kruskal-Wallis test was used to compare the CA19-9/CEA ratio between mutation types and the pairwise p values were adjusted for multiple comparisons with Holm method. For sensitivity analysis, the same analysis was repeated for the mean and median ratio of each patient. All tests were two-sided with alpha level set at 0.05 for statistical significance. RESULTS BRAF-V600E MSS CRC patients had a discordantly profound elevation in CA-19-9 levels as opposed to the CEA levels. Patients in the BRAF V600E MSS subset had the highest median CA19-9/CEA ratio versus the least median ratio in MSI-High patients. The median of maximum CA-19-9/CEA ratio was 28.92 (range, 2.76-707.27) in BRAF-V600E MSS patients and 4.06 (range, 0.46-166.74) in MSI-High subset of patients. CONCLUSIONS To date, this is the first report utilizing the ratio of tumor markers CA19-9/CEA as a predictive rather than just prognostic tool to identify BRAF-V600E MSS and MSI-High CRC patients.
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Affiliation(s)
- Pashtoon Murtaza Kasi
- Division of Oncology/Hematology, Division of Internal Medicine, University of Iowa, Holden Comprehensive Cancer Center, Iowa City, IA, USA
| | | | - Faisal Shahjehan
- Division of Internal Medicine, Conemaugh Memorial Medical Center, Johnstown, PA, USA
| | - Zhuo Li
- Division of Biomedical Statistics and Informatics, Mayo Clinic, Jacksonville, FL, USA
| | - Patrick W. Johnson
- Division of Biomedical Statistics and Informatics, Mayo Clinic, Jacksonville, FL, USA
| | - Amit Merchea
- Division of Colorectal Surgery, Mayo Clinic, Jacksonville, FL, USA
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30
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Zaborowski AM, Murphy B, Creavin B, Rogers AC, Kennelly R, Hanly A, Martin ST, O'Connell PR, Sheahan K, Winter DC. Clinicopathological features and oncological outcomes of patients with young-onset rectal cancer. Br J Surg 2020; 107:606-612. [PMID: 32149397 DOI: 10.1002/bjs.11526] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2019] [Revised: 11/20/2019] [Accepted: 01/12/2020] [Indexed: 12/30/2022]
Abstract
BACKGROUND The incidence of rectal cancer among adults aged less than 50 years is rising. Survival data are limited and conflicting, and the oncological benefit of standard neoadjuvant and adjuvant therapies is unclear. METHODS Disease-specific outcomes of patients diagnosed with rectal cancer undergoing surgical resection with curative intent between 2006 and 2016 were analysed. RESULTS A total of 797 patients with rectal cancer were identified, of whom 685 had surgery with curative intent. Seventy patients were younger than 50 years and 615 were aged 50 years or more. Clinical stage did not differ between the two age groups. Patients aged less than 50 years were more likely to have microsatellite instability (9 versus 1·6 per cent; P = 0·003) and Lynch syndrome (7 versus 0 per cent; P < 0·001). Younger patients were also more likely to receive neoadjuvant chemoradiotherapy (67 versus 53·3 per cent; P = 0·003) and adjuvant chemotherapy (41 versus 24·2 per cent; P = 0·006). Five-year overall survival was better in those under 50 years old (80 versus 72 per cent; P = 0·013). The 5-year disease-free survival rate was 81 per cent in both age groups (P = 0·711). There were no significant differences in the development of locoregional recurrence or distant metastases. CONCLUSION Despite accessing more treatment, young patients have disease-specific outcomes comparable to those of their older counterparts.
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Affiliation(s)
- A M Zaborowski
- Centre for Colorectal Disease, St Vincent's University Hospital, Dublin, Ireland
| | - B Murphy
- Centre for Colorectal Disease, St Vincent's University Hospital, Dublin, Ireland
| | - B Creavin
- Centre for Colorectal Disease, St Vincent's University Hospital, Dublin, Ireland
| | - A C Rogers
- Centre for Colorectal Disease, St Vincent's University Hospital, Dublin, Ireland
| | - R Kennelly
- Centre for Colorectal Disease, St Vincent's University Hospital, Dublin, Ireland
| | - A Hanly
- Centre for Colorectal Disease, St Vincent's University Hospital, Dublin, Ireland
| | - S T Martin
- Centre for Colorectal Disease, St Vincent's University Hospital, Dublin, Ireland
| | - P R O'Connell
- Centre for Colorectal Disease, St Vincent's University Hospital, Dublin, Ireland.,School of Medicine, University College Dublin, Dublin, Ireland
| | - K Sheahan
- Centre for Colorectal Disease, St Vincent's University Hospital, Dublin, Ireland
| | - D C Winter
- Centre for Colorectal Disease, St Vincent's University Hospital, Dublin, Ireland.,School of Medicine, University College Dublin, Dublin, Ireland
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31
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Zhao H, Su W, Sun Y, Wu Z. WBSCR22 Competes with Long Non-coding RNA Linc00346 for miR-509-5p Binding Site to Regulate Cancer Stem Cell Phenotypes of Colorectal Cancer. Biochem Genet 2020; 58:384-398. [PMID: 32008219 DOI: 10.1007/s10528-020-09949-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2019] [Accepted: 01/23/2020] [Indexed: 12/18/2022]
Abstract
Various Long non-coding RNAs (lncRNAs) and MicroRNAs (miRNAs) have been demonstrated to be involved in colorectal cancer stem cells (CSCs). WBSCR22 is a key gene we previously found that functions in colorectal cancer (CRC). This paper aims to investigate the effects of WBSCR22 and its corresponding miRNA and lncRNA in CRC. The expression of WBSCR22 was detected by Western blot and qRT-PCR analysis. Tumor sphere formation assays, CCK-8 analysis, and Transwell assays were applied to examine the colorectal cancer stem cell properties. Luciferase assay and biotin RNA pulldown assay were used to detect the interaction between miR-509-5p and WBSCR22/Linc00346. WBSCR22 is highly expressed in CRC and correlates with poor prognosis. Knockdown of WBSCR22 decreased the sphere-forming capacities, cell proliferation, and invasion abilities. WBSCR22 was negatively regulated by miR-509-5p. Linc00346 promoted the expression of WBSCR22 by adsorbing miR-509-5p. The Linc00346/miR-509-5p/WBSCR22 signal axis regulated the characteristics of colon cancer stem cells. Linc00346 regulated the expression of WBSCR22 by binding to miR-509-5p, thereby monitoring the characteristics of colorectal cancer stem cells. Thus, WBSCR22, Linc00346, and miR-509-5p might be utilized as potential targets for clinical diagnosis and treatment of CRC.
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Affiliation(s)
- Haiyan Zhao
- Department of Oncology, the Affiliated Hospital of Inner Mongolia Medical University, Huimin District, North Street, Hohhot, 010050, Inner Mongolia, China.
| | - Wuyun Su
- Department of Oncology, the Affiliated Hospital of Inner Mongolia Medical University, Huimin District, North Street, Hohhot, 010050, Inner Mongolia, China
| | - Yushu Sun
- Department of Oncology, Inner Mongolia Autonomous Region Cancer Hospital, Hottot, 010020, China
| | - Zhongjun Wu
- Hepatobiliay Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing, 646000, Sichuan, China
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32
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Costea T, Vlad OC, Miclea LC, Ganea C, Szöllősi J, Mocanu MM. Alleviation of Multidrug Resistance by Flavonoid and Non-Flavonoid Compounds in Breast, Lung, Colorectal and Prostate Cancer. Int J Mol Sci 2020; 21:E401. [PMID: 31936346 PMCID: PMC7013436 DOI: 10.3390/ijms21020401] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2019] [Revised: 01/03/2020] [Accepted: 01/03/2020] [Indexed: 12/12/2022] Open
Abstract
The aim of the manuscript is to discuss the influence of plant polyphenols in overcoming multidrug resistance in four types of solid cancers (breast, colorectal, lung and prostate cancer). Effective treatment requires the use of multiple toxic chemotherapeutic drugs with different properties and targets. However, a major cause of cancer treatment failure and metastasis is the development of multidrug resistance. Potential mechanisms of multidrug resistance include increase of drug efflux, drug inactivation, detoxification mechanisms, modification of drug target, inhibition of cell death, involvement of cancer stem cells, dysregulation of miRNAs activity, epigenetic variations, imbalance of DNA damage/repair processes, tumor heterogeneity, tumor microenvironment, epithelial to mesenchymal transition and modulation of reactive oxygen species. Taking into consideration that synthetic multidrug resistance agents have failed to demonstrate significant survival benefits in patients with different types of cancer, recent research have focused on beneficial effects of natural compounds. Several phenolic compounds (flavones, phenolcarboxylic acids, ellagitannins, stilbens, lignans, curcumin, etc.) act as chemopreventive agents due to their antioxidant capacity, inhibition of proliferation, survival, angiogenesis, and metastasis, modulation of immune and inflammatory responses or inactivation of pro-carcinogens. Moreover, preclinical and clinical studies revealed that these compounds prevent multidrug resistance in cancer by modulating different pathways. Additional research is needed regarding the role of phenolic compounds in the prevention of multidrug resistance in different types of cancer.
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Affiliation(s)
- Teodora Costea
- Department of Pharmacognosy, Phytochemistry and Phytotherapy, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania;
| | - Oana Cezara Vlad
- Department of Biophysics, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania; (O.C.V.); (C.G.)
| | - Luminita-Claudia Miclea
- Department of Biophysics and Cellular Biotechnology, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania;
- Research Excellence Center in Biophysics and Cellular Biotechnology, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania
| | - Constanta Ganea
- Department of Biophysics, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania; (O.C.V.); (C.G.)
| | - János Szöllősi
- Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary;
- MTA-DE Cell Biology and Signaling Research Group, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary
| | - Maria-Magdalena Mocanu
- Department of Biophysics, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania; (O.C.V.); (C.G.)
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33
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Sveen A, Kopetz S, Lothe RA. Biomarker-guided therapy for colorectal cancer: strength in complexity. Nat Rev Clin Oncol 2020; 17:11-32. [PMID: 31289352 PMCID: PMC7577509 DOI: 10.1038/s41571-019-0241-1] [Citation(s) in RCA: 217] [Impact Index Per Article: 43.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/05/2019] [Indexed: 12/16/2022]
Abstract
The number of molecularly stratified treatment options available to patients with colorectal cancer (CRC) is increasing, with a parallel rise in the use of biomarkers to guide prognostication and treatment decision-making. The increase in both the number of biomarkers and their use has resulted in a progressively complex situation, evident both from the extensive interactions between biomarkers and from their sometimes complex associations with patient prognosis and treatment benefit. Current and emerging biomarkers also reflect the genomic complexity of CRC, and include a wide range of aberrations such as point mutations, amplifications, fusions and hypermutator phenotypes, in addition to global gene expression subtypes. In this Review, we provide an overview of current and emerging clinically relevant biomarkers and their role in the management of patients with CRC, illustrating the intricacies of biomarker interactions and the growing treatment opportunities created by the availability of comprehensive molecular profiling.
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Affiliation(s)
- Anita Sveen
- Department of Molecular Oncology, Institute for Cancer Research & K.G. Jebsen Colorectal Cancer Research Centre, Division for Cancer Medicine, Oslo University Hospital, Oslo, Norway.
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
| | - Scott Kopetz
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Ragnhild A Lothe
- Department of Molecular Oncology, Institute for Cancer Research & K.G. Jebsen Colorectal Cancer Research Centre, Division for Cancer Medicine, Oslo University Hospital, Oslo, Norway
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
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34
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Al-Shaheri FN, Al-Shami KM, Gamal EH, Mahasneh AA, Ayoub NM. Association of DNA repair gene polymorphisms with colorectal cancer risk and treatment outcomes. Exp Mol Pathol 2019; 113:104364. [PMID: 31881200 DOI: 10.1016/j.yexmp.2019.104364] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2019] [Revised: 12/16/2019] [Accepted: 12/24/2019] [Indexed: 02/07/2023]
Abstract
Colorectal cancer (CRC) is the third most common carcinoma worldwide. Despite the progress in screening and treatment, CRC remains a leading cause of cancer-related mortality. Alterations to normal nucleic acid processing may drive neoplastic transformation of colorectal epithelium. DNA repair machinery performs an essential function in the protection of genome by reducing the number of genetic polymorphisms/variations that may drive carcinogenicity. Four essential DNA repair systems are known which include nucleotide excision repair (NER), base excision repair (BER), mismatch repair (MMR), and double-strand break repair (DSBR). Polymorphisms of DNA repair genes have been shown to influence the risk of cancer development as well as outcomes of treatment. Several studies demonstrated the association between genetic polymorphism of DNA repair genes and increased risk of CRC in different populations. In this review, we have summarized the impact of DNA repair gene polymorphisms on risk of CRC development and treatment outcomes. Advancements of the current understanding for the impact of DNA repair gene polymorphisms on the risk and treatment of CRC may support diagnostic and predictive roles in patients with CRC.
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Affiliation(s)
- Fawaz N Al-Shaheri
- Division of Functional Genome Analysis, German Cancer Research Center (DKFZ), ImNeuenheimer Feld 580, 69120 Heidelberg, Germany; Medical Faculty Heidelberg, University of Heidelberg, ImNeuenheimer Feld 672, 69120 Heidelberg, Germany; Faculty of Applied Medical Sciences, Department of Medical Laboratory Sciences, Jordan University of Science and Technology, Irbid, Jordan.
| | - Kamal M Al-Shami
- Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, 720 South Donahue Drive, Auburn, Alabama 36849, United States of America; Department of Clinical Pharmacy, Faculty of Pharmacy, Jordan University of Science and Technology, Irbid 22110, Jordan.
| | - Eshrak H Gamal
- Department of Oncology, Collage of Medicine, Bonn University, Germany; Faculty of Applied Medical Sciences, Department of Medical Laboratory Sciences, Jordan University of Science and Technology, Irbid, Jordan.
| | - Amjad A Mahasneh
- Department of Applied Biological Sciences, Faculty of Science and Arts, Jordan University of Science and Technology, Irbid 22110, Jordan.
| | - Nehad M Ayoub
- Department of Clinical Pharmacy, Faculty of Pharmacy, Jordan University of Science and Technology, Irbid 22110, Jordan.
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35
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Pang SW, Awi NJ, Armon S, Lim WWD, Low JSH, Peh KB, Peh SC, Teow SY. Current Update of Laboratory Molecular Diagnostics Advancement in Management of Colorectal Cancer (CRC). Diagnostics (Basel) 2019; 10:E9. [PMID: 31877940 PMCID: PMC7168209 DOI: 10.3390/diagnostics10010009] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2019] [Revised: 11/11/2019] [Accepted: 11/23/2019] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) continues to be one of the most common cancers globally. The incidence has increased in developing countries in the past few decades, this could be partly attributed to aging populations and unhealthy lifestyles. While the treatment of CRC has seen significant improvement since the advent of target-specific therapies and personalized medicine, CRC is oftentimes detected at late or advanced stages, thereby reducing the efficacy of treatment. Hence, screening for early detection is still the key to combat CRC and to increase overall survival (OS). Considering that the field of medical diagnostics is moving towards molecular diagnostics, CRC can now be effectively screened and diagnosed with high accuracy and sensitivity. Depending on the tumor genotype and genetic profile of the individual, personalized treatments including tyrosine kinase inhibitor therapy and immunotherapy can be administered. Notably, there can be no one single treatment that is effective for all CRC patients due to the variation in tumor genetics, which highlights the importance of molecular diagnostics. This review provides insights on therapeutic modalities, molecular biomarkers, advancement of diagnostic technologies, and current challenges in managing CRC.
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Affiliation(s)
- Siew-Wai Pang
- Department of Medical Sciences, School of Healthcare and Medical Sciences, Sunway University, Jalan Universiti, Bandar Sunway, Subang Jaya 47500, Malaysia
| | - Noel Jacques Awi
- Department of Medical Sciences, School of Healthcare and Medical Sciences, Sunway University, Jalan Universiti, Bandar Sunway, Subang Jaya 47500, Malaysia
| | - Subasri Armon
- Pathology Department, Hospital Kuala Lumpur, Jalan Pahang, Kuala Lumpur 50588, Malaysia
| | - Wendy Wan-Dee Lim
- Sunway Medical Centre, Jalan Lagoon Selatan, Bandar Sunway, Subang Jaya 47500, Malaysia
| | - John Seng-Hooi Low
- Sunway Medical Centre, Jalan Lagoon Selatan, Bandar Sunway, Subang Jaya 47500, Malaysia
| | - Kaik-Boo Peh
- Mahkota Medical Centre, Mahkota Melaka, Jalan Merdeka, Melaka 75000, Malaysia
| | - Suat-Cheng Peh
- Department of Medical Sciences, School of Healthcare and Medical Sciences, Sunway University, Jalan Universiti, Bandar Sunway, Subang Jaya 47500, Malaysia
- Sunway Medical Centre, Jalan Lagoon Selatan, Bandar Sunway, Subang Jaya 47500, Malaysia
| | - Sin-Yeang Teow
- Department of Medical Sciences, School of Healthcare and Medical Sciences, Sunway University, Jalan Universiti, Bandar Sunway, Subang Jaya 47500, Malaysia
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González-Llorente L, Santacatterina F, García-Aguilar A, Nuevo-Tapioles C, González-García S, Tirpakova Z, Toribio ML, Cuezva JM. Overexpression of Mitochondrial IF1 Prevents Metastatic Disease of Colorectal Cancer by Enhancing Anoikis and Tumor Infiltration of NK Cells. Cancers (Basel) 2019; 12:cancers12010022. [PMID: 31861681 PMCID: PMC7017164 DOI: 10.3390/cancers12010022] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2019] [Revised: 11/19/2019] [Accepted: 12/13/2019] [Indexed: 02/06/2023] Open
Abstract
Increasing evidences show that the ATPase Inhibitory Factor 1 (IF1), the physiological inhibitor of the ATP synthase, is overexpressed in a large number of carcinomas contributing to metabolic reprogramming and cancer progression. Herein, we show that in contrast to the findings in other carcinomas, the overexpression of IF1 in a cohort of colorectal carcinomas (CRC) predicts less chances of disease recurrence, IF1 being an independent predictor of survival. Bioinformatic and gene expression analyses of the transcriptome of colon cancer cells with differential expression of IF1 indicate that cells overexpressing IF1 display a less aggressive behavior than IF1 silenced (shIF1) cells. Proteomic and functional in vitro migration and invasion assays confirmed the higher tumorigenic potential of shIF1 cells. Moreover, shIF1 cells have increased in vivo metastatic potential. The higher metastatic potential of shIF1 cells relies on increased cFLIP-mediated resistance to undergo anoikis after cell detachment. Furthermore, tumor spheroids of shIF1 cells have an increased ability to escape from immune surveillance by NK cells. Altogether, the results reveal that the overexpression of IF1 acts as a tumor suppressor in CRC with an important anti-metastatic role, thus supporting IF1 as a potential therapeutic target in CRC.
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Affiliation(s)
- Lucía González-Llorente
- Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid (CSIC-UAM), 28049 Madrid, Spain; (L.G.-L.); (F.S.); (A.G.-A.); (C.N.-T.); (S.G.-G.); (Z.T.); (M.L.T.)
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), ISCIII, 28049 Madrid, Spain
- Instituto de Investigación Hospital 12 de Octubre, Universidad Autónoma de Madrid, 28049 Madrid, Spain
| | - Fulvio Santacatterina
- Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid (CSIC-UAM), 28049 Madrid, Spain; (L.G.-L.); (F.S.); (A.G.-A.); (C.N.-T.); (S.G.-G.); (Z.T.); (M.L.T.)
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), ISCIII, 28049 Madrid, Spain
- Instituto de Investigación Hospital 12 de Octubre, Universidad Autónoma de Madrid, 28049 Madrid, Spain
| | - Ana García-Aguilar
- Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid (CSIC-UAM), 28049 Madrid, Spain; (L.G.-L.); (F.S.); (A.G.-A.); (C.N.-T.); (S.G.-G.); (Z.T.); (M.L.T.)
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), ISCIII, 28049 Madrid, Spain
- Instituto de Investigación Hospital 12 de Octubre, Universidad Autónoma de Madrid, 28049 Madrid, Spain
| | - Cristina Nuevo-Tapioles
- Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid (CSIC-UAM), 28049 Madrid, Spain; (L.G.-L.); (F.S.); (A.G.-A.); (C.N.-T.); (S.G.-G.); (Z.T.); (M.L.T.)
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), ISCIII, 28049 Madrid, Spain
- Instituto de Investigación Hospital 12 de Octubre, Universidad Autónoma de Madrid, 28049 Madrid, Spain
| | - Sara González-García
- Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid (CSIC-UAM), 28049 Madrid, Spain; (L.G.-L.); (F.S.); (A.G.-A.); (C.N.-T.); (S.G.-G.); (Z.T.); (M.L.T.)
| | - Zuzana Tirpakova
- Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid (CSIC-UAM), 28049 Madrid, Spain; (L.G.-L.); (F.S.); (A.G.-A.); (C.N.-T.); (S.G.-G.); (Z.T.); (M.L.T.)
| | - María Luisa Toribio
- Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid (CSIC-UAM), 28049 Madrid, Spain; (L.G.-L.); (F.S.); (A.G.-A.); (C.N.-T.); (S.G.-G.); (Z.T.); (M.L.T.)
| | - José M. Cuezva
- Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid (CSIC-UAM), 28049 Madrid, Spain; (L.G.-L.); (F.S.); (A.G.-A.); (C.N.-T.); (S.G.-G.); (Z.T.); (M.L.T.)
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), ISCIII, 28049 Madrid, Spain
- Instituto de Investigación Hospital 12 de Octubre, Universidad Autónoma de Madrid, 28049 Madrid, Spain
- Correspondence: ; Tel.: +34-91-196-4618; Fax: +34-91-196-4420
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Treatment with checkpoint inhibitors in a metastatic colorectal cancer patient with molecular and immunohistochemical heterogeneity in MSI/dMMR status. J Immunother Cancer 2019; 7:297. [PMID: 31703605 PMCID: PMC6842181 DOI: 10.1186/s40425-019-0788-5] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2019] [Accepted: 10/23/2019] [Indexed: 01/25/2023] Open
Abstract
Background Analysis of deficiency in DNA mismatch repair (dMMR) is currently considered a standard molecular test in all patients with colorectal cancer (CRC) for its implications in screening, prognosis and prediction of benefit from immune checkpoint inhibitors. While the molecular heterogeneity of CRC has been extensively studied in recent years, specific data on dMMR status are lacking, and its clinical consequences are unknown. Case presentation We report the case of a metastatic CRC (mCRC) patient with immunohistochemical and molecular heterogeneity in dMMR/microsatellite instability status in the primary tumour. The patient was treated with nivolumab plus ipilimumab and achieved a deep and lasting response with clear clinical benefit. Whole-exome sequencing and RNA-seq data are reported to support the evidence for molecular heterogeneity. Re-biopsy at the time of progression ruled out the selection of MMR proficient clones as an escape mechanism. A large single-institution retrospective dataset was interrogated to further explore the real incidence of heterogeneity in its different presentations. Conclusions The present case supports the efficacy of immune checkpoint inhibition in mCRC with heterogeneity in MMR/microsatellite instability status. Clinical issues that may arise in these rare patients are discussed in detail.
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Rao S, Peri S, Hoffmann J, Cai KQ, Harris B, Rhodes M, Connolly DC, Testa JR, Wiest DL. RPL22L1 induction in colorectal cancer is associated with poor prognosis and 5-FU resistance. PLoS One 2019; 14:e0222392. [PMID: 31581233 PMCID: PMC6776433 DOI: 10.1371/journal.pone.0222392] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2019] [Accepted: 08/19/2019] [Indexed: 12/22/2022] Open
Abstract
We have previously demonstrated that loss of the tumor suppressive activity of ribosomal protein (RP) RPL22 predisposes to development of leukemia in mouse models and aggressive disease in human patients; however, the role of RPL22 in solid tumors, specifically colorectal cancer (CRC), had not been explored. We report here that RPL22 is either deleted or mutated in 36% of CRC and provide new insights into its mechanism of action. Indeed, Rpl22 inactivation causes the induction of its highly homologous paralog, RPL22L1, which serves as a driver of cell proliferation and anchorage-independent growth in CRC cells. Moreover, RPL22L1 protein is highly expressed in patient CRC samples and correlates with poor survival. Interestingly, the association of high RPL22L1 expression with poor prognosis appears to be linked to resistance to 5-Fluorouracil, which is a core component of most CRC therapeutic regimens. Indeed, in an avatar trial, we found that human CRC samples that were unresponsive to 5-Fluorouracil in patient-derived xenografts exhibited elevated expression levels of RPL22L1. This link between RPL22L1 induction and 5-Fluorouracil resistance appears to be causal, because ectopic expression or knockdown of RPL22L1 in cell lines increases and decreases 5-Fluorouracil resistance, respectively, and this is associated with changes in expression of the DNA-repair genes, MGMT and MLH1. In summary, our data suggest that RPL22L1 might be a prognostic marker in CRC and predict 5-FU responsiveness.
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Affiliation(s)
- Shuyun Rao
- Center for Translational Medicine, Department of Surgery, George Washington University, Washington, DC, United States of America
- * E-mail: (DW); (SR)
| | - Suraj Peri
- Blood Cell Development and Function Program, Fox Chase Cancer Center, Philadelphia, PA, United States of America
| | - Jens Hoffmann
- Experimental Pharmacology & Oncology Berlin-Buch GMBH, Berlin-Buch, Germany
| | - Kathy Q. Cai
- Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA, United States of America
| | - Bryan Harris
- Blood Cell Development and Function Program, Fox Chase Cancer Center, Philadelphia, PA, United States of America
| | - Michele Rhodes
- Blood Cell Development and Function Program, Fox Chase Cancer Center, Philadelphia, PA, United States of America
| | - Denise C. Connolly
- Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA, United States of America
| | - Joseph R. Testa
- Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA, United States of America
| | - David L. Wiest
- Blood Cell Development and Function Program, Fox Chase Cancer Center, Philadelphia, PA, United States of America
- * E-mail: (DW); (SR)
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Deng Z, Qin Y, Wang J, Wang G, Lang X, Jiang J, Xie K, Zhang W, Xu H, Shu Y, Zhang Y. Prognostic and predictive role of DNA mismatch repair status in stage II‐III colorectal cancer: A systematic review and meta‐analysis. Clin Genet 2019; 97:25-38. [PMID: 31432497 DOI: 10.1111/cge.13628] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2019] [Revised: 08/15/2019] [Accepted: 08/20/2019] [Indexed: 12/21/2022]
Affiliation(s)
- Zhujun Deng
- Precision Medicine Center, State Key Laboratory of Biotherapy, and Precision Medicine Key Laboratory of Sichuan Province, West China HospitalSichuan University Chengdu Sichuan China
| | - Yun Qin
- Department of Radiology, West China HospitalSichuan University Chengdu Sichuan China
| | - Jing Wang
- Precision Medicine Center, State Key Laboratory of Biotherapy, and Precision Medicine Key Laboratory of Sichuan Province, West China HospitalSichuan University Chengdu Sichuan China
| | - Gang Wang
- Precision Medicine Center, State Key Laboratory of Biotherapy, and Precision Medicine Key Laboratory of Sichuan Province, West China HospitalSichuan University Chengdu Sichuan China
| | - Xiaoqiang Lang
- Precision Medicine Center, State Key Laboratory of Biotherapy, and Precision Medicine Key Laboratory of Sichuan Province, West China HospitalSichuan University Chengdu Sichuan China
| | - Juan Jiang
- Precision Medicine Center, State Key Laboratory of Biotherapy, and Precision Medicine Key Laboratory of Sichuan Province, West China HospitalSichuan University Chengdu Sichuan China
| | - Kang Xie
- Precision Medicine Center, State Key Laboratory of Biotherapy, and Precision Medicine Key Laboratory of Sichuan Province, West China HospitalSichuan University Chengdu Sichuan China
| | - Wengeng Zhang
- Precision Medicine Center, State Key Laboratory of Biotherapy, and Precision Medicine Key Laboratory of Sichuan Province, West China HospitalSichuan University Chengdu Sichuan China
| | - Heng Xu
- Precision Medicine Center, State Key Laboratory of Biotherapy, and Precision Medicine Key Laboratory of Sichuan Province, West China HospitalSichuan University Chengdu Sichuan China
- State Key Laboratory of Biotherapy and Cancer CenterWest China Hospital, Sichuan University Chengdu Sichuan China
| | - Yang Shu
- State Key Laboratory of Biotherapy and Cancer CenterWest China Hospital, Sichuan University Chengdu Sichuan China
| | - Yan Zhang
- Department of Thoracic Oncology, Cancer CenterWest China Hospital, Sichuan University Chengdu Sichuan China
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Evaluation of a Fully Automated Idylla Test System for Microsatellite Instability in Colorectal Cancer. Clin Colorectal Cancer 2019; 18:e316-e323. [PMID: 31375292 DOI: 10.1016/j.clcc.2019.05.006] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2019] [Revised: 04/05/2019] [Accepted: 05/28/2019] [Indexed: 12/17/2022]
Abstract
BACKGROUND Microsatellite instability (MSI) is a phenotype commonly observed in colorectal cancer, and is caused by a deficient mismatch repair system. Determining MSI status greatly aids tumor prognosis and treatment plans in colorectal cancer, and plays a critical role in recent United States Food and Drug Administration-approved immunotherapies. As recognition of its importance grows, MSI has been identified in more types of cancers, underscoring the importance of accurate assays for determining MSI status in tumor cells. Currently, tumor MSI status is detected via polymerase chain reaction-based methods or immunohistochemistry. MATERIALS AND METHODS In this study, we tested a new, fully automated MSI detection system (Idylla MSI detection kit) released by Biocartis. We evaluated 42 formalin-fixed paraffin-embedded tumor tissues, which were clinically tested for MSI status using the polymerase chain reaction or immunohistochemistry method, with the Idylla MSI detection system. RESULTS The Idylla MSI detection system showed an overall 97.62% concordance rate with previously used methods. Moreover, this fully automated system requires less than 5 minutes "hands on" preparation time and 150 minutes total run time per sample. CONCLUSION The Biocartis Idylla MSI kit proves a powerful tool to accurately detect MSI status in tumor cells in a rapid and almost labor-free manner.
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De' Angelis GL, Bottarelli L, Azzoni C, De' Angelis N, Leandro G, Di Mario F, Gaiani F, Negri F. Microsatellite instability in colorectal cancer. ACTA BIO-MEDICA : ATENEI PARMENSIS 2018; 89:97-101. [PMID: 30561401 PMCID: PMC6502181 DOI: 10.23750/abm.v89i9-s.7960] [Citation(s) in RCA: 89] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Download PDF] [Subscribe] [Scholar Register] [Received: 12/06/2018] [Indexed: 12/12/2022]
Abstract
Microsatellites are short tandem repeat DNA sequences of one to tetra base pairs distributed throughout the human genome, both in coding and non-coding regions. Owing to their repeated structure, microsatellites are particularly prone to replication errors that are normally repaired by the Mismatch Repair (MMR) system. MMR is a very highly conserved cellular process, involving many proteins, resulting in the identification, and subsequent repair of mismatched bases, likely to have arisen during DNA replication, genetic recombination or chemical or physical damage. Proteins within the MMR system include MLH1, PMS2, MSH2, MSH6, MLH3, MSH3, PMS1, and Exo1. Deficient MMR (dMMR) results in a strong mutator phenotype known as microsatellite instability (MSI), characterized by widespread length polymorphisms of microsatellite sequences due to DNA polymerase slippage. MSI is recognized as one of the major carcinogenetic pathways of colorectal cancer (CRC): it represents a molecular hallmark of hereditary nonpolyposis colorectal cancer (HNPCC), also known as Lynch syndrome (LS); moreover it is detected in 15% of sporadic colorectal cancers, more often due to an epigenetic inactivation of MLH1. Identification of MSI CRC is important, as MSI may serve as a screening tool for detecting LS, a prognostic marker for patient outcome, and a predictive marker for response to chemotherapy and to immunotherapy. (www.actabiomedica.it)
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Affiliation(s)
- Gian Luigi De' Angelis
- Gastroenterology and Endoscopy Unit, Department of Medicine and Surgery, University of Parma, Parma, Italy.
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MSH2 Expression and Resistance to Cisplatin in Muscle-invasive Bladder Cancer: A Mix of Progress and Challenges. Eur Urol 2018; 75:251-252. [PMID: 30470617 DOI: 10.1016/j.eururo.2018.11.014] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2018] [Accepted: 11/06/2018] [Indexed: 12/24/2022]
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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: 86] [Impact Index Per Article: 12.3] [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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Matevska-Geshkovska N, Staninova-Stojovska M, Kapedanovska-Nestorovska A, Petrushevska-Angelovska N, Panovski M, Grozdanovska B, Mitreski N, Dimovski A. Influence of MSI and 18q LOH markers on capecitabine adjuvant monotherapy in colon cancer patients. Pharmgenomics Pers Med 2018; 11:193-203. [PMID: 30464574 PMCID: PMC6219100 DOI: 10.2147/pgpm.s172467] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
PURPOSE The aim of this study was to evaluate whether pretreatment analysis of selected molecular markers can be used for the prediction of disease-free survival (DFS)/overall survival (OS) of capecitabine adjuvant monotherapy in colon cancer patients. PATIENTS AND METHODS A total of 126 patients enrolled in a capecitabine Phase IV clinical trial were analyzed for microsatellite instability (MSI), 18q loss of heterozygosity (LOH), thymidylate synthase (TYMS) 5' variable number of tandem repeat (VNTR), and methylene tetrahydrofolate reductase (MTHFR) C677T variants. The significance in predicting 5-year DFS/OS was assessed by Kaplan-Meier and Cox regression analyses. RESULTS The MSI-high (MSI-H) genotype was significantly associated with DFS (HR 0.205, 95% CI 0.05-0.88, P=0.033) and OS (HR 0.208, 95% CI 0.05-0.89, P=0.035) compared to the microsatellite stable genotype. In models stratified according to clinicopathologic characteristics, the MSI-H genotype remained a positive predictive factor for DFS/OS only in patients with stage III (P=0.023) and patients with tumors localized proximally to the splenic flexure (P=0.004). Distal colon cancers with 18q LOH have a greater survival rate when treated with capecitabine than patients with stable tumors (81.3% vs 50.0%, HR for relapse 0.348, 95% CI 0.13-0.97, P=0.043). TYMS 5'VNTR and MTHFR C677T variants were not associated with DFS or OS. CONCLUSION MSI and 18q LOH markers have the potential to be utilized in the selection of colon cancer patients eligible for capecitabine adjuvant monotherapy.
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Affiliation(s)
- Nadica Matevska-Geshkovska
- Center for Biomolecular Pharmaceutical Analyses, Faculty of Pharmacy, Ss. Cyril and Methodius University in Skopje, Skopje, Macedonia,
| | - Marija Staninova-Stojovska
- Center for Biomolecular Pharmaceutical Analyses, Faculty of Pharmacy, Ss. Cyril and Methodius University in Skopje, Skopje, Macedonia,
| | | | | | - Milco Panovski
- University Clinic for Abdominal Surgery, Ss. Cyril and Methodius University in Skopje, Skopje, Macedonia
| | - Biljana Grozdanovska
- University Clinic for Oncology and Radiotherapy, Ss. Cyril and Methodius University in Skopje, Skopje, Macedonia
| | - Nenad Mitreski
- University Clinic for Oncology and Radiotherapy, Ss. Cyril and Methodius University in Skopje, Skopje, Macedonia
| | - Aleksandar Dimovski
- Center for Biomolecular Pharmaceutical Analyses, Faculty of Pharmacy, Ss. Cyril and Methodius University in Skopje, Skopje, Macedonia,
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Murcia O, Juárez M, Rodríguez-Soler M, Hernández-Illán E, Giner-Calabuig M, Alustiza M, Egoavil C, Castillejo A, Alenda C, Barberá V, Mangas-Sanjuan C, Yuste A, Bujanda L, Clofent J, Andreu M, Castells A, Llor X, Zapater P, Jover R. Colorectal cancer molecular classification using BRAF, KRAS, microsatellite instability and CIMP status: Prognostic implications and response to chemotherapy. PLoS One 2018; 13:e0203051. [PMID: 30188916 PMCID: PMC6126803 DOI: 10.1371/journal.pone.0203051] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2018] [Accepted: 08/14/2018] [Indexed: 01/14/2023] Open
Abstract
Objective The aim of this study was to validate a molecular classification of colorectal cancer (CRC) based on microsatellite instability (MSI), CpG island methylator phenotype (CIMP) status, BRAF, and KRAS and investigate each subtype’s response to chemotherapy. Design This retrospective observational study included a population-based cohort of 878 CRC patients. We classified tumours into five different subtypes based on BRAF and KRAS mutation, CIMP status, and MSI. Patients with advanced stage II (T4N0M0) and stage III tumours received 5-fluoruracil (5-FU)-based chemotherapy or no adjuvant treatment based on clinical criteria. The main outcome was disease-free survival (DFS). Results Patients with the combination of microsatellite stable (MSS) tumours, BRAF mutation and CIMP positive exhibited the worst prognosis in univariate (log rank P<0.0001) and multivariate analyses (hazard ratio 1.75, 95% CI 1.05–2.93, P = 0.03) after adjusting for age, sex, chemotherapy, and TNM stage. Treatment with 5-FU-based regimens improved prognosis in patients with the combination of MSS tumours, KRAS mutation and CIMP negative (log rank P = 0.003) as well as in patients with MSS tumours plus BRAF and KRAS wild-type and CIMP negative (log-rank P<0.001). After adjusting for age, sex, and TNM stage in the multivariate analysis, only patients with the latter molecular combination had independently improved prognosis after adjuvant chemotherapy (hazard ratio 2.06, 95% CI 1.24–3.44, P = 0.005). Conclusion We confirmed the prognostic value of stratifying CRC according to molecular subtypes using MSI, CIMP status, and somatic KRAS and BRAF mutation. Patients with traditional chromosomally unstable tumours obtained the best benefit from adjuvant 5-FU-based chemotherapy.
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Affiliation(s)
- Oscar Murcia
- Servicio de Medicina Digestiva, Hospital General Universitario de Alicante, Instituto de Investigación Sanitaria ISABIAL, Alicante, Spain
| | - Míriam Juárez
- Unidad de Investigación, Hospital General Universitario de Alicante, Instituto de Investigación Sanitaria ISABIAL, Alicante, Spain
| | - María Rodríguez-Soler
- Servicio de Medicina Digestiva, Hospital General Universitario de Alicante, Instituto de Investigación Sanitaria ISABIAL, Alicante, Spain
| | - Eva Hernández-Illán
- Unidad de Investigación, Hospital General Universitario de Alicante, Instituto de Investigación Sanitaria ISABIAL, Alicante, Spain
| | - Mar Giner-Calabuig
- Unidad de Investigación, Hospital General Universitario de Alicante, Instituto de Investigación Sanitaria ISABIAL, Alicante, Spain
| | - Miren Alustiza
- Unidad de Investigación, Hospital General Universitario de Alicante, Instituto de Investigación Sanitaria ISABIAL, Alicante, Spain
| | - Cecilia Egoavil
- Unidad de Investigación, Hospital General Universitario de Alicante, Instituto de Investigación Sanitaria ISABIAL, Alicante, Spain
| | - Adela Castillejo
- Molecular Genetics Laboratory, Hospital General Universitario de Elche, Instituto de Investigación Sanitaria ISABIAL, Alicante, Spain
| | - Cristina Alenda
- Department of Pathology, Hospital General Universitario de Alicante, Instituto de Investigación Sanitaria ISABIAL, Alicante, Spain
| | - Víctor Barberá
- Molecular Genetics Laboratory, Hospital General Universitario de Elche, Instituto de Investigación Sanitaria ISABIAL, Alicante, Spain
| | - Carolina Mangas-Sanjuan
- Servicio de Medicina Digestiva, Hospital General Universitario de Alicante, Instituto de Investigación Sanitaria ISABIAL, Alicante, Spain
| | - Ana Yuste
- Oncology Department, Hospital General Universitario de Alicante, Instituto de Investigación Sanitaria ISABIAL, Alicante, Spain
| | - Luís Bujanda
- Gastroenterology Unity, Hospital Donostia/Instituto Biodonostia, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Universidad del País Vasco (UPV/EHU), San Sebastián, Spain
| | - Joan Clofent
- Gastroentyerology Unit, Hospital de Sagunto, Sagunto, Spain
| | - Montserrat Andreu
- Gastroenterology Unit, IMIM: Institut Hospital del Mar d'Investigacions Mèdiques, Hospital del Mar, Barcelona, Spain
| | - Antoni Castells
- Gastroenterology Unit, Hospital Clínic, IDIBAPS, CIBERehd, University of Barcelona, Barcelona, Spain
| | - Xavier Llor
- Section of Digestive Diseases, Yale University, Yale New Haven Hospital, New Haven, Connecticut, United States of America
| | - Pedro Zapater
- Clinical Pharmacology Department, Hospital General Universitario de Alicante, Instituto de Investigación Sanitaria ISABIAL, Alicante, Spain
| | - Rodrigo Jover
- Servicio de Medicina Digestiva, Hospital General Universitario de Alicante, Instituto de Investigación Sanitaria ISABIAL, Alicante, Spain
- * E-mail:
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Pellino G, Gallo G, Pallante P, Capasso R, De Stefano A, Maretto I, Malapelle U, Qiu S, Nikolaou S, Barina A, Clerico G, Reginelli A, Giuliani A, Sciaudone G, Kontovounisios C, Brunese L, Trompetto M, Selvaggi F. Noninvasive Biomarkers of Colorectal Cancer: Role in Diagnosis and Personalised Treatment Perspectives. Gastroenterol Res Pract 2018; 2018:2397863. [PMID: 30008744 PMCID: PMC6020538 DOI: 10.1155/2018/2397863] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2017] [Revised: 04/03/2018] [Accepted: 04/15/2018] [Indexed: 02/08/2023] Open
Abstract
Colorectal cancer (CRC) is the third leading cause of cancer-related deaths worldwide. It has been estimated that more than one-third of patients are diagnosed when CRC has already spread to the lymph nodes. One out of five patients is diagnosed with metastatic CRC. The stage of diagnosis influences treatment outcome and survival. Notwithstanding the recent advances in multidisciplinary management and treatment of CRC, patients are still reluctant to undergo screening tests because of the associated invasiveness and discomfort (e.g., colonoscopy with biopsies). Moreover, the serological markers currently used for diagnosis are not reliable and, even if they were useful to detect disease recurrence after treatment, they are not always detected in patients with CRC (e.g., CEA). Recently, translational research in CRC has produced a wide spectrum of potential biomarkers that could be useful for diagnosis, treatment, and follow-up of these patients. The aim of this review is to provide an overview of the newer noninvasive or minimally invasive biomarkers of CRC. Here, we discuss imaging and biomolecular diagnostics ranging from their potential usefulness to obtain early and less-invasive diagnosis to their potential implementation in the development of a bespoke treatment of CRC.
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Affiliation(s)
- Gianluca Pellino
- Unit of General Surgery, Department of Medical, Surgical, Neurological, Metabolic and Ageing Sciences, Università degli Studi della Campania “Luigi Vanvitelli”, Piazza Miraglia 2, 80138 Naples, Italy
- Colorectal Surgery Unit, Hospital Universitario y Politécnico La Fe, Valencia, Spain
| | - Gaetano Gallo
- Department of Medical and Surgical Sciences, OU of General Surgery, University of Catanzaro, Catanzaro, Italy
- Department of Colorectal Surgery, Clinic S. Rita, Vercelli, Italy
| | - Pierlorenzo Pallante
- Institute of Experimental Endocrinology and Oncology (IEOS), National Research Council (CNR), Via S. Pansini 5, Naples, Italy
| | - Raffaella Capasso
- Department of Medicine and Health Sciences, University of Molise, Via Francesco de Sanctis 1, 86100 Campobasso, Italy
| | - Alfonso De Stefano
- Department of Abdominal Oncology, Division of Abdominal Medical Oncology, Istituto Nazionale per lo Studio e la Cura dei Tumori, “Fondazione G. Pascale, ” IRCCS, Naples, Italy
| | - Isacco Maretto
- 1st Surgical Clinic, Department of Surgical, Oncological, and Gastroenterological Sciences, University of Padua, Padua, Italy
| | - Umberto Malapelle
- Dipartimento di Sanità Pubblica, Università degli Studi di Napoli Federico II, Naples, Italy
| | - Shengyang Qiu
- Department of Colorectal Surgery, Royal Marsden Hospital, London, UK
| | - Stella Nikolaou
- Department of Colorectal Surgery, Royal Marsden Hospital, London, UK
| | - Andrea Barina
- 1st Surgical Clinic, Department of Surgical, Oncological, and Gastroenterological Sciences, University of Padua, Padua, Italy
| | - Giuseppe Clerico
- Department of Colorectal Surgery, Clinic S. Rita, Vercelli, Italy
| | - Alfonso Reginelli
- Department of Internal and Experimental Medicine, Magrassi-Lanzara, Institute of Radiology, Università degli Studi della Campania “Luigi Vanvitelli”, Piazza Miraglia 2, 80138 Naples, Italy
| | - Antonio Giuliani
- Department of Medicine and Health Sciences “V. Tiberio”, University of Molise, Campobasso, Italy
| | - Guido Sciaudone
- Unit of General Surgery, Department of Medical, Surgical, Neurological, Metabolic and Ageing Sciences, Università degli Studi della Campania “Luigi Vanvitelli”, Piazza Miraglia 2, 80138 Naples, Italy
| | - Christos Kontovounisios
- Department of Colorectal Surgery, Royal Marsden Hospital, London, UK
- Department of Surgery and Cancer, Chelsea and Westminster Hospital Campus, Imperial College London, London, UK
| | - Luca Brunese
- Department of Medicine and Health Sciences, University of Molise, Via Francesco de Sanctis 1, 86100 Campobasso, Italy
| | - Mario Trompetto
- Department of Colorectal Surgery, Clinic S. Rita, Vercelli, Italy
| | - Francesco Selvaggi
- Unit of General Surgery, Department of Medical, Surgical, Neurological, Metabolic and Ageing Sciences, Università degli Studi della Campania “Luigi Vanvitelli”, Piazza Miraglia 2, 80138 Naples, Italy
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Abstract
Background Colorectal carcinomas with high-frequency microsatellite instability (MSI-H) account for 15% of all colorectal cancers, including 12% of sporadic cases and 3% of cancers associated with Lynch syndrome (also known as hereditary nonpolyposis colorectal cancer syndrome, HNPCC). Lynch syndrome is an autosomal dominant hereditary cancer syndrome, caused by germline mutations in mismatch repair genes, including MLH1, MSH2, MSH6 and PMS2. Methods Published articles from peer-reviewed journals were obtained from PubMed, Google Scholar and Clinicaltrials.gov. Based on the recent research data, we provide an update on the MSI testing, along with the evolving role of MSI in diagnosis, prognosis and treatment of colorectal cancers. Results Studies have led to significant advances in the molecular pathogenesis and clinicopathological characteristics of MSI-H colorectal cancers. Emerging evidence suggests that colorectal cancers with MSI-H show different outcome and treatment response from those with microsatellite stable (MSS) tumors. Therefore, MSI testing is essential not only in the genetic context, but it may also have important prognostic and predictive value of response to chemotherapy and immunotherapy. Conclusions Many experts and professional authorities have recommended a universal MSI testing in all individuals newly diagnosed with colorectal cancers.
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Nikolouzakis TK, Vassilopoulou L, Fragkiadaki P, Sapsakos TM, Papadakis GZ, Spandidos DA, Tsatsakis AM, Tsiaoussis J. Improving diagnosis, prognosis and prediction by using biomarkers in CRC patients (Review). Oncol Rep 2018; 39:2455-2472. [PMID: 29565457 PMCID: PMC5983921 DOI: 10.3892/or.2018.6330] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2018] [Accepted: 03/21/2018] [Indexed: 12/17/2022] Open
Abstract
Colorectal cancer (CRC) is among the most common cancers. In fact, it is placed in the third place among the most diagnosed cancer in men, after lung and prostate cancer, and in the second one for the most diagnosed cancer in women, following breast cancer. Moreover, its high mortality rates classifies it among the leading causes of cancer‑related death worldwide. Thus, in order to help clinicians to optimize their practice, it is crucial to introduce more effective tools that will improve not only early diagnosis, but also prediction of the most likely progression of the disease and response to chemotherapy. In that way, they will be able to decrease both morbidity and mortality of their patients. In accordance with that, colon cancer research has described numerous biomarkers for diagnostic, prognostic and predictive purposes that either alone or as part of a panel would help improve patient's clinical management. This review aims to describe the most accepted biomarkers among those proposed for use in CRC divided based on the clinical specimen that is examined (tissue, faeces or blood) along with their restrictions. Lastly, new insight in CRC monitoring will be discussed presenting promising emerging biomarkers (telomerase activity, telomere length and micronuclei frequency).
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Affiliation(s)
| | - Loukia Vassilopoulou
- Laboratory of Forensic Sciences and Toxicology, Medical School, University of Crete, 71409 Heraklion, Crete, Greece
| | - Persefoni Fragkiadaki
- Laboratory of Forensic Sciences and Toxicology, Medical School, University of Crete, 71409 Heraklion, Crete, Greece
| | - Theodoros Mariolis Sapsakos
- Laboratory of Anatomy and Histology, Nursing School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Georgios Z. Papadakis
- Foundation for Research and Technology Hellas (FORTH), Institute of Computer Sciences (ICS), Computational Biomedicine Laboratory (CBML), 71003 Heraklion, Crete, Greece
| | - Demetrios A. Spandidos
- Laboratory of Clinical Virology, Medical School, University of Crete, 71003 Heraklion, Crete, Greece
| | - Aristides M. Tsatsakis
- Laboratory of Forensic Sciences and Toxicology, Medical School, University of Crete, 71409 Heraklion, Crete, Greece
| | - John Tsiaoussis
- Laboratory of Anatomy-Histology-Embryology, Medical School, University of Crete, 71110 Heraklion, Greece
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Leicher LW, Lammertink MHA, Offerman SR, Morreau H, de Jong MM, de Groot JWB, van Westreenen HL, Vasen HFA, de Vos Tot Nederveen Cappel WH. Consequences of testing for mismatch repair deficiency of colorectal cancer in clinical practice. Scand J Gastroenterol 2018; 53:632-636. [PMID: 29161904 DOI: 10.1080/00365521.2017.1406534] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
INTRODUCTION Mismatch repair deficiency (dMMR) can be found in Lynch syndrome (LS)-associated colorectal carcinoma and in 15% of sporadic colorectal cancer (CRC). Outcome of MMR-deficiency testing is important for surgical decisions as extended colectomy is recommended in young LS-patients with CRC. Moreover, the finding of a dMMR tumour has consequences for the choices of adjuvant chemotherapy as MMR-deficient CRC is resistant to 5-fluorouracil (5-FU) monotherapy. Aims of our study are to evaluate whether MMR-deficiency testing leads to (1) identification of LS, (2) change in surgical treatment and (3) adjustment of systemic therapy in patients with dMMR CRC. METHODS We performed a multicentre, retrospective study, in a community hospital and a University Medical Centre. We included all CRC-patients between 2012 and 2016 who were tested for microsatellite instability. We collected clinical data such as gender, age, referral to clinical geneticist, surgical procedure and choice of chemotherapy. RESULTS We analysed 225 CRCs. Twenty-four (10.7%) of 225 CRC were MMR-deficient. Of the 24 patients with dMMR CRC, 18 (75%) were referred to the clinical geneticist and in nine (37%) patients a MMR mutation was identified. In one (4%) of the 24 patients, a subtotal colectomy was performed. In seven (35%) out of 20 MMR deficient patients, the chemotherapy regimen was adjusted. CONCLUSIONS The finding of a dMMR CRC had consequences for decisions on chemotherapy in a relative high proportion of patients. We recommend testing in all patients with CRC independent of age at diagnosis, as proper treatment decisions and genetic counselling are very important.
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Affiliation(s)
- L W Leicher
- a Department of Gastroenterology and Hepatology , Isala , Zwolle , The Netherlands
| | - M H A Lammertink
- a Department of Gastroenterology and Hepatology , Isala , Zwolle , The Netherlands
| | - S R Offerman
- b Department of Pathology , Isala , Zwolle , The Netherlands
| | - H Morreau
- c Department of Pathology , Leiden University Medical Centre , Leiden , The Netherlands
| | - M M de Jong
- d Department of Genetics , University Medical Centre Groningen , Groningen , The Netherlands
| | - J W B de Groot
- e Department of Oncology , Isala , Zwolle , The Netherlands
| | | | - H F A Vasen
- g Department of Gastroenterology , Leiden University Medical Centre , Leiden , The Netherlands.,h The Netherlands Foundation for the Detection of Hereditary Tumors , Leiden , The Netherlands
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Feng C, Zhang L, Sun Y, Li X, Zhan L, Lou Y, Wang Y, Liu L, Zhang Y. GDPD5, a target of miR-195-5p, is associated with metastasis and chemoresistance in colorectal cancer. Biomed Pharmacother 2018; 101:945-952. [DOI: 10.1016/j.biopha.2018.03.028] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2017] [Revised: 03/06/2018] [Accepted: 03/06/2018] [Indexed: 12/12/2022] Open
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