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    Role of Deficient DNA Mismatch Repair Status in Patients With Stage III Colon Cancer Treated With FOLFOX Adjuvant Chemotherapy: A Pooled Analysis From 2 Randomized Clinical Trials. Zaanan Aziz,Shi Qian,Taieb Julien,Alberts Steven R,Meyers Jeffrey P,Smyrk Thomas C,Julie Catherine,Zawadi Ayman,Tabernero Josep,Mini Enrico,Goldberg Richard M,Folprecht Gunnar,Van Laethem Jean Luc,Le Malicot Karine,Sargent Daniel J,Laurent-Puig Pierre,Sinicrope Frank A JAMA oncology Importance:The prognostic impact of DNA mismatch repair (MMR) status in stage III colon cancer patients receiving FOLFOX (folinic acid, fluorouracil, and oxaliplatin) adjuvant chemotherapy remains controversial. Objective:To determine the association of MMR status with disease-free survival (DFS) in patients with stage III colon cancer treated with FOLFOX. Design, Setting, and Participants:The evaluated biomarkers for MMR status were determined from prospectively collected tumor blocks from patients treated with FOLFOX in 2 open-label, phase 3 randomized clinical trials: NCCTG N0147 and PETACC8. The studies were conducted in general community practices, private practices, and institutional practices in the United States and Europe. All participants had stage III colon adenocarcinoma. They were enrolled in NCCTG N0147 from February 2004 to November 2009 and in PETACC8 from December 2005 to November 2009. Interventions:Patients in the clinical trials were randomly assigned to receive 6 months of chemotherapy with FOLFOX or FOLFOX plus cetuximab. Only those patients treated with FOLFOX alone were included in the present study. Main Outcomes and Measures:Association of MMR status with DFS was analyzed using a stratified Cox proportional hazards model. Multivariable models were adjusted for age, sex, tumor grade, pT/pN stage, tumor location, ECOG (Eastern Cooperative Oncology Group) performance status, and BRAF V600E mutational status. Results:Among 2636 patients with stage III colon cancer treated with FOLFOX, MMR status was available for 2501. Of these, 252 (10.1%) showed deficient MMR status (dMMR; 134 women, 118 men; median age, 59 years), while 2249 (89.9%) showed proficient MMR status (pMMR; 1020 women, 1229 men; median age, 59 years). The 3-year DFS rates in the dMMR and pMMR groups were 75.6% and 74.4%, respectively. By multivariate analysis, patients with dMMR phenotype had significantly longer DFS than those with pMMR (adjusted hazard ratio, 0.73; 95% CI, 0.54-0.97; P = .03). Conclusions and Relevance:The deficient MMR phenotype remains a favorable prognostic factor in patients with stage III colon cancer receiving FOLFOX adjuvant chemotherapy. Trial Registration:clinicaltrials.gov Identifier: NCT00079274 for the NCCTG N0147 trial and EudraCT identifier: 2005-003463-23 for the PETACC8 trial. 10.1001/jamaoncol.2017.2899
    SATB2 and CDX2 are prognostic biomarkers in DNA mismatch repair protein deficient colon cancer. Ma Changqing,Olevian Dane,Miller Caitlyn,Herbst Cameron,Jayachandran Priya,Kozak Margaret M,Chang Daniel T,Pai Reetesh K Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc DNA mismatch repair protein deficient colon cancer frequently displays reduced CDX2 expression, and recent literature has suggested that negative CDX2 expression is a poor prognostic biomarker in colon cancer. We have recently demonstrated that SATB2 is an immunohistochemical marker that is complementary to CDX2. Using a tissue microarray approach, we evaluated SATB2 and CDX2 immunohistochemical expression in 514 patients with colonic adenocarcinoma including 146 with mismatch repair protein deficient tumors and correlated expression with histopathologic variables, molecular alterations, and survival. Overall, SATB2-negative and/or CDX2-negative expression was identified in 33% of mismatch repair protein deficient tumors compared with only 15% of mismatch repair protein proficient tumors (p < 0.001) and in 36% of BRAF V600E mutated compared with only 13% of BRAF wild-type tumors (p < 0.001). Both SATB2-negative and CDX2-negative colonic adenocarcinomas more often displayed lymphatic invasion, venous invasion, and perineural invasion (all with p < 0.05). SATB2-negative expression was also more frequently identified in tumors with mucinous or signet ring cell differentiation (p < 0.01 for both). In a multivariable analysis of survival in patients with mismatch repair protein deficient tumors (n = 131), only tumor stage (p = 0.01) and SATB2-negative and/or CDX2-negative expression (p = 0.009) independently predicted disease-specific survival. Of the 99 patients with stage II or III mismatch repair protein deficient tumors, death from disease only occurred in patients with either SATB2-negative or CDX2-negative tumors, and no patients with SATB2-positive/CDX2-positive tumors developed recurrence or died of disease. SATB2 and CDX2 expression had no effect on patient survival in mismatch repair protein proficient, BRAF-mutated, or KRAS-mutated tumors. In summary, our results suggest that SATB2 and CDX2 are prognostic biomarkers in patients with mismatch repair protein deficient colon cancer and that inclusion of SATB2 and CDX2 immunohistochemistry may be helpful as part of a comprehensive pathologic risk assessment in mismatch repair protein deficient colon cancer. 10.1038/s41379-019-0265-1
    PD-L1 is a double-edged sword in colorectal cancer: the prognostic value of PD-L1 depends on the cell type expressing PD-L1. Ho Hsiang-Ling,Chou Teh-Ying,Yang Shung-Haur,Jiang Jeng-Kai,Chen Wei-Shone,Chao Yee,Teng Hao-Wei Journal of cancer research and clinical oncology PURPOSE:To investigate the associations between programmed cell death ligand-1 (PD-L1) on tumor cells (TCs) or PD-L1 on tumor-infiltrating immune cells (TIICs) and the microsatellite instability (MSI) status in colorectal cancer (CRC). METHODS:In total, 238 CRC patients were enrolled. PD-L1 expression and MSI status were studied by immunohistochemical staining and polymerase chain reaction. The χ test was used to compare characteristics. The Kaplan-Meier method was used for survival analysis. Cox proportional hazards models were used to determine the prognostic influence of clinicopathological factors. RESULTS:Eighteen patients (7.6%) were had MSI-high (MSI-H) CRC. The number of patients with PD-L1 expression on TCs, stromal TIICs and intraepithelial TIICs was 13 (5.5%), 64 (26.9%) and 45 (18.9%), respectively. The MSI-H phenotype was significantly associated with younger age, right sidedness, mucinous component, high grade, stromal TIICs expressing PD-L1 (P = 0.042) and intraepithelial TIICs expressing PD-L1 (P < 0.001), but not TCs expressing PD-L1. PD-L1-expressing TCs were an independent marker of poor prognosis [hazard ratio (HR) = 3.387, P = 0.003], and PD-L1-expressing stromal TIICs were an independent marker of good prognosis (HR = 0.551, P < 0.001). CONCLUSIONS:PD-L1-expressing TCs were a marker of poor prognosis; in contrast, PD-L1-expressing TIICs were a marker of good prognosis. The MSI-H phenotype was associated with the presence of PD-L1-expressing TIICs, but not of PD-L1-expressing TCs. 10.1007/s00432-019-02942-y
    The Association Between Mutations in BRAF and Colorectal Cancer-Specific Survival Depends on Microsatellite Status and Tumor Stage. Bläker Hendrik,Alwers Elizabeth,Arnold Alexander,Herpel Esther,Tagscherer Katrin E,Roth Wilfried,Jansen Lina,Walter Viola,Kloor Matthias,Chang-Claude Jenny,Brenner Hermann,Hoffmeister Michael Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association BACKGROUND & AIMS:Colorectal tumors with mutations in BRAF and microsatellite stability (MSS) have been associated with adverse outcomes of patients. Combined tests for microsatellite instability-high (MSI-H) and BRAF mutations might therefore be used in risk assessment, particularly for patients with stage II tumors. We investigate the stage-specific prognostic value of combined testing for MSI-H and BRAF for patients with colorectal cancer. METHODS:We performed a retrospective analysis of colorectal tumor samples collected from 1995 patients at 22 hospitals in Germany, between 2003 and 2010. Samples were analyzed for MSI-H using an established mononucleotide marker panel; BRAF mutations (BRAFV600E) were detected by Sanger sequencing or in tissue microarray blocks using immunohistochemistry. Cancers were assigned to categories of having MSS without mutations in BRAF, MSS with mutant BRAF, MSI-H without mutations in BRAF, and MSI-H with mutant BRAF. We investigated the association between tumor categories with clinical and pathologic features and patient's overall, disease-specific, and recurrence-free survival (median follow-up time, 5.1 y). RESULTS:Tumors were stage I in 364 (18%), stage II in 678 (34%), stage III in 673 (34%), and stage IV (14%) in 280 patients. Sixty-three percent of tumors were located in the colon and 37% in the rectum. Most tumors (85%) had MSS without mutations in BRAF, 3% had MSS with mutant BRAF, 7% had MSI-H without mutations in BRAF, and 5% had MSI-H with mutant BRAF. In patients whose tumors were MSI-H, mutation of BRAF did not significantly affect survival time. Patients whose tumors had MSS with mutant BRAF had significantly reduced overall survival (hazard ratio [HR], 2.16; 95% CI, 1.54-3.04; P < .001), disease-specific survival (HR, 2.59; 95% CI, 1.77-3.79; P < .001), and recurrence-free survival (HR, 2.45; 95% CI, 1.70-3.52; P < .001) than patients whose tumors had MSS without BRAF mutation. Although BRAF mutations in tumors with MSS were associated with disease-specific survival of patients with stage III or IV tumors (P < .001), these features did not affect survival of patients with stage II tumors (P = .639). CONCLUSIONS:In an analysis of almost 2000 patients with colorectal cancer, we found BRAF mutations to reduce survival of patients in stage III or IV (but not stage II) tumors with MSS. These findings do not support testing stage I or II colorectal tumors for BRAF mutations, although additional large studies are needed. 10.1016/j.cgh.2018.04.015
    A gene expression assay for simultaneous measurement of microsatellite instability and anti-tumor immune activity. Danaher Patrick,Warren Sarah,Ong SuFey,Elliott Nathan,Cesano Alessandra,Ferree Sean Journal for immunotherapy of cancer BACKGROUND:Clinical benefit from checkpoint inhibitors has been associated in a tumor-agnostic manner with two main tumor traits. The first is tumor antigenicity, which is typically measured by tumor mutation burden, microsatellite instability (MSI), or Mismatch Repair Deficiency using gene sequence platforms and/or immunohistochemistry. The second is the presence of a pre-existing adaptive immune response, typically measured by immunohistochemistry (e.g. single analyte PD-L1 expression) and/or gene expression signatures (e.g. tumor "inflamed" phenotype). These two traits have been shown to provide independent predictive information. Here we investigated the potential of using gene expression to predict tumor MSI, thus enabling the measurement of both tumor antigenicity and the level of tumor inflammation in a single assay, possibly reducing sample requirement, turn-around time, and overall cost. METHODS:Using The Cancer Genome Atlas RNA-seq datasets with the greatest MSI-H incidence, i.e. those from colon (n = 208), stomach (n = 269), and endometrial (n = 241) cancers, we trained an algorithm to predict tumor MSI from under-expression of the mismatch repair genes MLH1, PMS2, MSH2, and MSH6 and from 10 additional genes with strong pan-cancer associations with tumor hypermutation. The algorithms were validated on the NanoString nCounter™ platform in independent cohorts of colorectal (n = 52), endometrial (n = 11), and neuroendocrine (n = 4) tumors pre-characterized using the MMR immunohistochemistry assay. RESULTS:In the validation cohorts, the algorithm showed high prediction accuracy of tumor MSI status, with sensitivity of at least 88% attained at thresholds chosen to achieve 100% specificity. Furthermore, MSI status was compared to the Tumor Inflammation Signature (TIS), an analytically validated diagnostic assay which measures a suppressed adaptive immune response in the tumor and enriches for response to immune checkpoint blockade. TIS score was largely independent of MSI status, suggesting that measuring both parameters may identify more patients that would respond to immune checkpoint blockade than either assay alone. CONCLUSIONS:Development of a gene expression signature of MSI status raises the possibility of a combined diagnostic assay on a single platform which measures both tumor antigenicity and presence of a suppressed adaptive immune response. Such an assay would have significant advantages over multi-platform assays for both ease of use and turnaround time and could lead to a diagnostic test with improved clinical performance. 10.1186/s40425-018-0472-1
    Low microsatellite instability is associated with poor prognosis in stage C colon cancer. Kohonen-Corish Maija R J,Daniel Joseph J,Chan Charles,Lin Betty P C,Kwun Sun Young,Dent Owen F,Dhillon Varinderpal S,Trent Ronald J A,Chapuis Pierre H,Bokey E Leslie Journal of clinical oncology : official journal of the American Society of Clinical Oncology PURPOSE:The significance of low microsatellite instability (MSI-L) in colorectal cancer is poorly understood. No clear biologic distinction has been found between MSI-L and microsatellite stable (MSS) colorectal cancer, and these two phenotypes are usually combined when analyzed against the well-defined high MSI (MSI-H) phenotype. Evidence is emerging that an O(6)-methylguanine DNA methyltransferase (MGMT) gene defect is associated with MSI-L. Therefore, to further define this phenotype, we undertook a detailed analysis of the prognostic significance of MSI-L and loss of MGMT expression in colon cancer. PATIENTS AND METHODS:The study cohort was 183 patients with clinicopathologic stage C colon cancer who had not received adjuvant therapy. We analyzed MSI status, MGMT, and mismatch repair protein expression, as well as MGMT and p16 promoter hypermethylation. RESULTS:We showed that MSI-L defines a group of patients with poorer survival (P = .026) than MSS patients, and that MSI-L was an independent prognostic indicator (P = .005) in stage C colon cancer. Loss of MGMT protein expression was associated with the MSI-L phenotype but was not a prognostic factor for overall survival in colon cancer. p16 methylation was significantly less frequent in MSI-L than in MSI-H and MSS tumors and was not associated with survival. CONCLUSION:MSI-L characterizes a distinct subgroup of stage C colon cancer patients, including the MSI-L subset of proximal colon cancer, who have a poorer outcome. Neither the MGMT defect nor p16 methylation are likely to contribute to the worse prognosis of the MSI-L phenotype. 10.1200/JCO.2005.00.109
    Defective mismatch repair as a predictive marker for lack of efficacy of fluorouracil-based adjuvant therapy in colon cancer. Sargent Daniel J,Marsoni Silvia,Monges Genevieve,Thibodeau Stephen N,Labianca Roberto,Hamilton Stanley R,French Amy J,Kabat Brian,Foster Nathan R,Torri Valter,Ribic Christine,Grothey Axel,Moore Malcolm,Zaniboni Alberto,Seitz Jean-Francois,Sinicrope Frank,Gallinger Steven Journal of clinical oncology : official journal of the American Society of Clinical Oncology PURPOSE:Prior reports have indicated that patients with colon cancer who demonstrate high-level microsatellite instability (MSI-H) or defective DNA mismatch repair (dMMR) have improved survival and receive no benefit from fluorouracil (FU) -based adjuvant therapy compared with patients who have microsatellite-stable or proficient mismatch repair (pMMR) tumors. We examined MMR status as a predictor of adjuvant therapy benefit in patients with stages II and III colon cancer. METHODS:MSI assay or immunohistochemistry for MMR proteins were performed on 457 patients who were previously randomly assigned to FU-based therapy (either FU + levamisole or FU + leucovorin; n = 229) versus no postsurgical treatment (n = 228). Data were subsequently pooled with data from a previous analysis. The primary end point was disease-free survival (DFS). RESULTS:Overall, 70 (15%) of 457 patients exhibited dMMR. Adjuvant therapy significantly improved DFS (hazard ratio [HR], 0.67; 95% CI, 0.48 to 0.93; P = .02) in patients with pMMR tumors. Patients with dMMR tumors receiving FU had no improvement in DFS (HR, 1.10; 95% CI, 0.42 to 2.91; P = .85) compared with those randomly assigned to surgery alone. In the pooled data set of 1,027 patients (n = 165 with dMMR), these findings were maintained; in patients with stage II disease and with dMMR tumors, treatment was associated with reduced overall survival (HR, 2.95; 95% CI, 1.02 to 8.54; P = .04). CONCLUSION:Patient stratification by MMR status may provide a more tailored approach to colon cancer adjuvant therapy. These data support MMR status assessment for patients being considered for FU therapy alone and consideration of MMR status in treatment decision making. 10.1200/JCO.2009.27.1825
    A novel histological examination with dynamic three-dimensional reconstruction from multiple immunohistochemically stained sections of a PD-L1-positive colon cancer. Korehisa Shotaro,Ikeda Tetsuo,Okano Shinji,Saeki Hiroshi,Oki Eiji,Oda Yoshinao,Hashizume Makoto,Maehara Yoshihiko Histopathology AIMS:Programmed cell death-ligand 1 (PD-L1) expression is observed in patients with microsatellite instability-high (MSI-H) colon cancer, which is susceptible to immune checkpoint blockade. The aim of this study was to investigate the interrelationship between PD-L1-positive cells and cytotoxic T cells, lymphatic vessels and vascular endothelium by using histological examination with the three-dimensional (3D) reconstruction of a PD-L1-positive colon cancer. METHODS AND RESULTS:Serial sections of MSI-H colon cancer tissue were stained with haematoxylin and eosin (H&E) and Masson trichrome stains; immunohistochemical analysis of PD-L1, CD8, D2-40 and CD31 was performed. Several 3D models of MSI-H colon cancer were reconstructed with a 3D data visualisation system. Moreover, 18 serial sections were stained with PD-L1, cytokeratin AE1/AE3, CD45, CD31, CD68 and H&E in the same case to confirm that PD-L1 was expressed on tumour cells, CD31-positive cells and macrophages in the invasive frontal region. Notably, there was a peak in the expression of PD-L1 and CD31 in the invasive frontal region. D2-40-positive cells were abundant in the overall tumour stroma, and CD8-positive cells infiltrated the tumour parenchyma. PD-L1 was expressed on tumour cells in the parenchyma and other cells in the stroma. Additional staining of 18 consecutive sections revealed that the other cells were CD68-positive and CD45-positive macrophages and CD31-positive proliferating vascular endothelial cells. CONCLUSIONS:We confirmed that PD-L1 was highly expressed in the invasive frontal region in 3D models of MSI-H colon cancer tissue. This method can be useful for accurately evaluating the localisation of immune checkpoint molecules. 10.1111/his.13400
    Clinical Implications of Mismatch Repair Status in Patients With High-risk Stage II Colon Cancer. Baek Dong Won,Kang Byung Woog,Lee Soo Jung,Kim Hye Jin,Park Su Yeon,Park Jun Seok,Choi Gyu Seog,Baek Jin Ho,Kim Jong Gwang In vivo (Athens, Greece) BACKGROUND/AIM:This study evaluated the clinical significance of the mismatch repair (MMR) status and prognostic factors in patients with high-risk stage II colon cancer (CC). MATERIALS AND METHODS:This was a retrospective analysis of 237 patients diagnosed with high-risk stage II CC who had test results for MMR status. RESULTS:Among the 237 patients, 76 (32.1%) were identified as having a microsatellite instability-high (MSI-H) status. No significant differences were identified in disease-free or overall survival according to the MMR status. Moreover, no association was found between the use of adjuvant chemotherapy and survival outcomes of the MSI-H group. In a multivariate survival analysis, the primary tumor location (right-sided versus left-sided, hazard ratio(HR)=0.172, p=0.003) and T-stage (HR=4.764, p=0.005) were identified as independent prognostic factors for disease-free survival. CONCLUSION:The present study found that the MMR status was neither prognostic nor predictive in patients with high-risk stage II CC. 10.21873/invivo.11523
    Is Adjuvant Chemotherapy Efficient in Colon Cancer with High Microsatellite Instability? A Look Towards the Future. Schiappacasse Cocio Guido V,Schiappacasse Enrico D Cancer research The high microsatellite instability (MSI-H) is frequently observed in localized colorectal adenocarcinoma. MSI-H is a good prognostic factor in nonmetastatic colon adenocarcinoma. However, MSI-H is not a predictive factor because it is not related with better survival in patients with colon cancer with adjuvant chemotherapy. MSI-H should be a predictive factor because it is associated with a higher expression of enzymes, which are inhibited by cytotoxic agents. Here, we analyze this controversy. We conclude MSI-H is not a predictive factor because the adjuvant therapy based on traditional cytotoxic agents does not act on either immune signaling pathways or BRAF mutation. 10.1158/0008-5472.CAN-18-2991
    Proteogenomic Analysis of Human Colon Cancer Reveals New Therapeutic Opportunities. Vasaikar Suhas,Huang Chen,Wang Xiaojing,Petyuk Vladislav A,Savage Sara R,Wen Bo,Dou Yongchao,Zhang Yun,Shi Zhiao,Arshad Osama A,Gritsenko Marina A,Zimmerman Lisa J,McDermott Jason E,Clauss Therese R,Moore Ronald J,Zhao Rui,Monroe Matthew E,Wang Yi-Ting,Chambers Matthew C,Slebos Robbert J C,Lau Ken S,Mo Qianxing,Ding Li,Ellis Matthew,Thiagarajan Mathangi,Kinsinger Christopher R,Rodriguez Henry,Smith Richard D,Rodland Karin D,Liebler Daniel C,Liu Tao,Zhang Bing, Cell We performed the first proteogenomic study on a prospectively collected colon cancer cohort. Comparative proteomic and phosphoproteomic analysis of paired tumor and normal adjacent tissues produced a catalog of colon cancer-associated proteins and phosphosites, including known and putative new biomarkers, drug targets, and cancer/testis antigens. Proteogenomic integration not only prioritized genomically inferred targets, such as copy-number drivers and mutation-derived neoantigens, but also yielded novel findings. Phosphoproteomics data associated Rb phosphorylation with increased proliferation and decreased apoptosis in colon cancer, which explains why this classical tumor suppressor is amplified in colon tumors and suggests a rationale for targeting Rb phosphorylation in colon cancer. Proteomics identified an association between decreased CD8 T cell infiltration and increased glycolysis in microsatellite instability-high (MSI-H) tumors, suggesting glycolysis as a potential target to overcome the resistance of MSI-H tumors to immune checkpoint blockade. Proteogenomics presents new avenues for biological discoveries and therapeutic development. 10.1016/j.cell.2019.03.030
    Review of PD-1/PD-L1 Inhibitors in Metastatic dMMR/MSI-H Colorectal Cancer. Oliveira André F,Bretes Luís,Furtado Irene Frontiers in oncology There are a wide range of therapies for metastatic colorectal cancer (CRC) available, but outcomes remain suboptimal. Learning the role of the immune system in cancer development and progression led to advances in the treatment over the last decade. While the field is rapidly evolving, PD-1, and PD-L1 inhibitors have a leading role amongst immunomodulatory agents. They act against pathways involved in adaptive immune suppression resulting in immune checkpoint blockade. Immunotherapy has been slow to impact the management of this patient population due to disappointing results, mainly when used broadly. Nevertheless, some patients with microsatellite-instability-high (MSI-H) or mismatch repair-deficient (dMMR) CRC appear to be susceptible to checkpoint inhibitors with objective and sustained clinical responses, providing a new therapeutic option for patients with advanced disease. This article provides a comprehensive review of the early and late phase trials with the updated data of PD-1/PD-L1 inhibitors alone or in combination with other therapies (immunotherapy, targeted therapy and chemotherapy). While data is still limited, many ongoing trials are underway, testing the efficacy of these agents in CRC. Current and future challenges of PD-1 and PD-L1 inhibitors are also discussed. 10.3389/fonc.2019.00396
    Mutational signatures of DNA mismatch repair deficiency in and human cancers. Meier Bettina,Volkova Nadezda V,Hong Ye,Schofield Pieta,Campbell Peter J,Gerstung Moritz,Gartner Anton Genome research Throughout their lifetime, cells are subject to extrinsic and intrinsic mutational processes leaving behind characteristic signatures in the genome. DNA mismatch repair (MMR) deficiency leads to hypermutation and is found in different cancer types. Although it is possible to associate mutational signatures extracted from human cancers with possible mutational processes, the exact causation is often unknown. Here, we use genome sequencing of and knockouts to reveal the mutational patterns linked to MMR deficiency and their dependency on endogenous replication errors and errors caused by deletion of the polymerase ε subunit Signature extraction from 215 human colorectal and 289 gastric adenocarcinomas revealed three MMR-associated signatures, one of which closely resembles the MMR spectrum and strongly discriminates microsatellite stable and unstable tumors (AUC = 98%). A characteristic difference between human and MMR deficiency is the lack of elevated levels of NG > NTG mutations in likely caused by the absence of cytosine (CpG) methylation in worms The other two human MMR signatures may reflect the interaction between MMR deficiency and other mutagenic processes, but their exact cause remains unknown. In summary, combining information from genetically defined models and cancer samples allows for better aligning mutational signatures to causal mutagenic processes. 10.1101/gr.226845.117
    Dynamic control of strand excision during human DNA mismatch repair. Jeon Yongmoon,Kim Daehyung,Martín-López Juana V,Lee Ryanggeun,Oh Jungsic,Hanne Jeungphill,Fishel Richard,Lee Jong-Bong Proceedings of the National Academy of Sciences of the United States of America Mismatch repair (MMR) is activated by evolutionarily conserved MutS homologs (MSH) and MutL homologs (MLH/PMS). MSH recognizes mismatched nucleotides and form extremely stable sliding clamps that may be bound by MLH/PMS to ultimately authorize strand-specific excision starting at a distant 3'- or 5'-DNA scission. The mechanical processes associated with a complete MMR reaction remain enigmatic. The purified human (Homo sapien or Hs) 5'-MMR excision reaction requires the HsMSH2-HsMSH6 heterodimer, the 5' → 3' exonuclease HsEXOI, and the single-stranded binding heterotrimer HsRPA. The HsMLH1-HsPMS2 heterodimer substantially influences 5'-MMR excision in cell extracts but is not required in the purified system. Using real-time single-molecule imaging, we show that HsRPA or Escherichia coli EcSSB restricts HsEXOI excision activity on nicked or gapped DNA. HsMSH2-HsMSH6 activates HsEXOI by overcoming HsRPA/EcSSB inhibition and exploits multiple dynamic sliding clamps to increase tract length. Conversely, HsMLH1-HsPMS2 regulates tract length by controlling the number of excision complexes, providing a link to 5' MMR. 10.1073/pnas.1523748113
    Stochastic Processes and Component Plasticity Governing DNA Mismatch Repair. Liu Jiaquan,Lee Jong-Bong,Fishel Richard Journal of molecular biology DNA mismatch repair (MMR) is a DNA excision-resynthesis process that principally enhances replication fidelity. Highly conserved MutS (MSH) and MutL (MLH/PMS) homologs initiate MMR and in higher eukaryotes act as DNA damage sensors that can trigger apoptosis. MSH proteins recognize mismatched nucleotides, whereas the MLH/PMS proteins mediate multiple interactions associated with downstream MMR events including strand discrimination and strand-specific excision that are initiated at a significant distance from the mismatch. Remarkably, the biophysical functions of the MLH/PMS proteins have been elusive for decades. Here we consider recent observations that have helped to define the mechanics of MLH/PMS proteins and their role in choreographing MMR. We highlight the stochastic nature of DNA interactions that have been visualized by single-molecule analysis and the plasticity of protein complexes that employ thermal diffusion to complete the progressions of MMR. 10.1016/j.jmb.2018.05.039
    The interaction between BRAF mutation and microsatellite instability (MSI) status in determining survival outcomes after adjuvant 5FU based chemotherapy in stage III colon cancer. Chouhan Hanumant,Sammour Tarik,Thomas Michelle L,Moore James W Journal of surgical oncology PURPOSE:The predictive role of biomarkers in colon cancer is still being defined. The aim of this study is to determine the interaction between BRAF mutation and microsatellite instability (MSI) status in determining survival benefit after adjuvant 5-FU based chemotherapy in stage III colon cancer. METHODS:We performed a retrospective cohort study including all curatively resected stage III colon cancer cases over a 33-year period. A clinicopathological database was collated (adjuvant chemotherapy, age, gender, obstruction, perforation, tumor location, grade, mucin, nodal stage, extramural vascular, and perineural invasion). BRAF (V600E) mutation testing was performed and MSI status established by immunohistochemistry for mismatch repair proteins and molecular testing for National Cancer Institute panel markers. Patients were categorized into four groups for comparison: MSS and BRAF-ve (termed " traditional"), MSI and BRAF-ve (termed " presumed Lynch"), MSI and BRAF+ve (termed " sporadic MSI"), and MSS and BRAF+ve (termed " other BRAF"). The primary endpoint was cancer specific survival. Interaction testing was conducted to determine whether there were different responses to chemotherapy between groups. RESULTS:A total of 686 unselected cases met inclusion criteria and had tissue available, of which 15.7% had BRAF mutation (BRAF+ve) and 13.8% had MSI. Thirty-nine percent received chemotherapy. Overall, adjuvant chemotherapy produced a cancer specific survival benefit (HR 0.66, 95% CI, 0.49-0.88, P < 0.01). On adjusted analysis, neither BRAF nor MSI status were individually predictive of survival benefit. On adjusted analysis specifically of the chemotherapy effect in each subgroup, only patients in the presumed Lynch (HR 0.260, 95% CI, 0.09-0.80, P < 0.01) and other BRAF groups (HR 0.45, 95% CI, 0.23-0.87, P < 0.01) had a significant survival benefit from chemotherapy. On interaction testing of subgroups, adjusting for all the clinicopathological parameters, only patients in the presumed Lynch group (HR 0.277, 95% CI, 0.10-0.75, P < 0.01) gained a differentially greater benefit from chemotherapy than other groups. CONCLUSIONS:In this historical cohort, MSI testing is predictive of response to adjuvant chemotherapy in stage III colon cancer, but only when results are interpreted in combination with BRAF. This supports the role of routine testing for these biomarkers. 10.1002/jso.25275
    Prognosis of stage II and III colon cancer treated with adjuvant 5-fluorouracil or FOLFIRI in relation to microsatellite status: results of the PETACC-3 trial. Klingbiel D,Saridaki Z,Roth A D,Bosman F T,Delorenzi M,Tejpar S Annals of oncology : official journal of the European Society for Medical Oncology BACKGROUND:Although colon cancer (CC) with microsatellite instability (MSI) has a more favorable prognosis than microsatellite stable (MSS) CC, the impact varies according to clinicopathological parameters. We studied how MSI status affects prognosis in a trial-based cohort of stage II and III CC patients treated with 5-fluorouracil (5-FU)/leucovorin or FOLFIRI. MATERIALS AND METHODS:Tissue specimens of 1254 patients were tested for 10 different loci and were classified as MSI-high (MSI-H) when three or more loci were unstable and MSS otherwise. Study end points were overall survival (OS) and relapse-free survival (RFS). RESULTS:In stage II, RFS and OS were better for patients with MSI-H than with MSS CC [hazard ratio (HR) 0.26, 95% CI 0.10-0.65, P = 0.004 and 0.16, 95% CI 0.04-0.64, P = 0.01). In stage III, RFS was slightly better for patients with MSI-H CC (HR 0.67, 95% CI 0.46-0.99, P = 0.04), but the difference was not statistically significant for OS (HR 0.70, 95% CI 0.44-1.09, P = 0.11). Outcomes for patients with MSI-H CC were not different between the two treatment arms. RFS was better for patients with MSI-H than with MSS CC in the right and left colon, whereas for OS this was significant only in the right colon. For patients with KRAS- and BRAF-mutated CC, but not for double wild-type patients, RFS and OS were significantly better when the tumors were also MSI-H. An interaction test was statistically significant for KRAS and MSI status (P = 0.005), but not for BRAF status (P = 0.14). CONCLUSIONS:Our results confirm that for patients with stage II CC but less so for those with stage III MSI-H is strongly prognostic for RFS and OS. In the presence of 5-FU treatment, stage II patients with MSI-H tumors maintain their survival advantage in comparison with MSS patients and adding irinotecan has no added benefit. CLINICALTRIALS.GOV IDENTIFIER: NCT00026273. 10.1093/annonc/mdu499
    The vigorous immune microenvironment of microsatellite instable colon cancer is balanced by multiple counter-inhibitory checkpoints. Llosa Nicolas J,Cruise Michael,Tam Ada,Wicks Elizabeth C,Hechenbleikner Elizabeth M,Taube Janis M,Blosser Richard L,Fan Hongni,Wang Hao,Luber Brandon S,Zhang Ming,Papadopoulos Nickolas,Kinzler Kenneth W,Vogelstein Bert,Sears Cynthia L,Anders Robert A,Pardoll Drew M,Housseau Franck Cancer discovery UNLABELLED:We examined the immune microenvironment of primary colorectal cancer using immunohistochemistry, laser capture microdissection/qRT-PCR, flow cytometry, and functional analysis of tumor-infiltrating lymphocytes. A subset of colorectal cancer displayed high infiltration with activated CD8(+) cytotoxic T lymphocyte (CTL) as well as activated Th1 cells characterized by IFNγ production and the Th1 transcription factor TBET. Parallel analysis of tumor genotypes revealed that virtually all of the tumors with this active Th1/CTL microenvironment had defects in mismatch repair, as evidenced by microsatellite instability (MSI). Counterbalancing this active Th1/CTL microenvironment, MSI tumors selectively demonstrated highly upregulated expression of multiple immune checkpoints, including five-PD-1, PD-L1, CTLA-4, LAG-3, and IDO-currently being targeted clinically with inhibitors. These findings link tumor genotype with the immune microenvironment, and explain why MSI tumors are not naturally eliminated despite a hostile Th1/CTL microenvironment. They further suggest that blockade of specific checkpoints may be selectively efficacious in the MSI subset of colorectal cancer. SIGNIFICANCE:The findings reported in this article are the first to demonstrate a link between a genetically defined subtype of cancer and its corresponding expression of immune checkpoints in the tumor microenvironment. The mismatch repair-defective subset of colorectal cancer selectively upregulates at least five checkpoint molecules that are targets of inhibitors currently being clinically tested. 10.1158/2159-8290.CD-14-0863
    Microsatellite Instability as a Biomarker for PD-1 Blockade. Dudley Jonathan C,Lin Ming-Tseh,Le Dung T,Eshleman James R Clinical cancer research : an official journal of the American Association for Cancer Research Initial results by Le and colleagues, which were published in the June 25, 2015 issue of the New England Journal of Medicine, report significant responses of cancers with microsatellite instability (MSI) to anti-PD-1 inhibitors in patients who failed conventional therapy. This finding fits into a broader body of research associating somatic hypermutation and neoepitope formation with response to immunotherapy, with the added benefit of relying on a simple, widely used diagnostic test. This review surveys the pathogenesis and prognostic value of MSI, diagnostic guidelines for detecting it, and the frequency of MSI across tumors, with the goal of providing a reference for its use as a biomarker for PD-1 blockade. MSI usually arises from either germline mutations in components of the mismatch repair (MMR) machinery (MSH2, MSH6, MLH1, PMS2) in patients with Lynch syndrome or somatic hypermethylation of the MLH1 promoter. The result is a cancer with a 10- to 100-fold increase in mutations, associated in the colon with poor differentiation, an intense lymphocytic infiltrate, and a superior prognosis. Diagnostic approaches have evolved since the early 1990s, from relying exclusively on clinical criteria to incorporating pathologic features, PCR-based MSI testing, and immunohistochemistry for loss of MMR component expression. Tumor types can be grouped into categories based on the frequency of MSI, from colorectal (20%) and endometrial (22%-33%) to cervical (8%) and esophageal (7%) to skin and breast cancers (0%-2%). If initial results are validated, MSI testing could have an expanded role as a tool in the armamentarium of precision medicine. 10.1158/1078-0432.CCR-15-1678
    Heterogeneity of KRAS, NRAS, BRAF and PIK3CA mutations in metastatic colorectal cancer and potential effects on therapy in the CAPRI GOIM trial. Normanno N,Rachiglio A M,Lambiase M,Martinelli E,Fenizia F,Esposito C,Roma C,Troiani T,Rizzi D,Tatangelo F,Botti G,Maiello E,Colucci G,Ciardiello F, Annals of oncology : official journal of the European Society for Medical Oncology BACKGROUND:Evidence suggests that metastatic colorectal carcinoma (mCRC) has a high level of intratumor heterogeneity. We carried out a quantitative assessment of tumor heterogeneity for KRAS, NRAS, BRAF and PIK3CA mutations, in order to assess potential clinical implications. PATIENTS AND METHODS:Tumor samples (n = 182) from the CAPRI-GOIM trial of first-line cetuximab + FOLFIRI in KRAS exon-2 wild-type mCRC patients were assessed by next-generation sequencing that allows quantitative assessment of mutant genes. Mutant allelic frequency was normalized for the neoplastic cell content and, assuming that somatic mutations usually affect one allele, the Heterogeneity Score (HS) was calculated by multiplying by 2 the frequency of mutant alleles in neoplastic cells. Therefore, HS virtually corresponds to the fraction of neoplastic cells carrying a specific mutation. RESULTS:The KRAS HS ranged between 12 and 260 with mean value of 87.1 and median value of 84.4, suggesting that in most CRC, the majority of neoplastic cells carry mutant KRAS. Similar findings were observed for NRAS (HS range 35.5-146.7; mean 102.8; median 117.1). In contrast, in BRAF (HS range 17.1-120; mean 54.8; median 54.3) and PIK3CA (HS range 14.3-120; mean 59.5; median 47.3) mutant cases, only a fraction of neoplastic cells seem to carry the mutant allele. The response rate was 70% in KRAS mutant patients with an HS <33 (low KRAS; n = 10) and 45.7% in KRAS HS >33 patients (high KRAS; n = 35); median progression-free survival were 7.97 and 8.37 months, respectively. Low-KRAS tumors had a higher frequency of additional mutations in PIK3CA when compared with high-KRAS (6/10 versus 8/35). CONCLUSIONS:KRAS and NRAS mutations are usually present in the majority of neoplastic cells, whereas BRAF and PIK3CA mutations often affect a limited fraction of transformed cells. Resistance to cetuximab in low-KRAS patients might be driven by the complex mutational profile rather than KRAS mutation load. 10.1093/annonc/mdv176
    Microsatellite instability in gastric cancer: molecular bases, clinical perspectives, and new treatment approaches. Ratti Margherita,Lampis Andrea,Hahne Jens C,Passalacqua Rodolfo,Valeri Nicola Cellular and molecular life sciences : CMLS Gastric cancer is one of the most aggressive malignancies, with limited treatment options in both locally advanced and metastatic setting, resulting in poor prognosis. Based on genomic characterization, stomach tumour has recently been described as a heterogeneous disease composed by different subtypes, each of them with peculiar molecular aspects and specific clinical behaviour. With an incidence of 22% among all western gastric tumour cases, stomach cancer with microsatellite instability was identified as one of these subgroups. Retrospective studies and limited prospective trials reported differences between gastric cancers with microsatellite stability and those with instability, mainly concerning clinical and pathological features, but also in regard to immunological microenvironment, correlation with prognostic value, and responses to treatment. In particular, gastric cancer with microsatellite instability constitutes a small but relevant subgroup associated with older age, female sex, distal stomach location, and lower number of lymph-node metastases. Emerging data attribute to microsatellite instability status a favourable prognostic meaning, whereas the poor outcomes reported after perioperative chemotherapy administration suggest a detrimental role of cytotoxic drugs in this gastric cancer subgroup. The strong immunogenicity and the widespread expression of immune-checkpoint ligands make microsatellite instability subtype more vulnerable to immunotherapeutic approach, e.g., with anti-PD-L1 and anti-CTLA4 antibodies. Since gastric cancer with microsatellite instability shows specific features and clinical behaviour not overlapping with microsatellite stable disease, microsatellite instability test might be suitable for inclusion in a diagnostic setting for all tumour stages to guarantee the most targeted and effective treatment to every patient. 10.1007/s00018-018-2906-9
    Correlations between microsatellite instability and the biological behaviour of tumours. Yang Guang,Zheng Ru-Yi,Jin Zai-Shun Journal of cancer research and clinical oncology PURPOSE:Microsatellites are widely distributed repetitive DNA motifs, accounting for approximately 3% of the genome. Due to mismatch repair system deficiency, insertion or deletion of repetitive units often occurs, leading to microsatellite instability. In this review, we aimed to explore the relationship between MSI and biological behaviour of colorectal carcinoma, gastric carcinoma, lymphoma/leukaemia and endometrial carcinoma, as well as the application of frameshift peptide vaccines in cancer therapy. METHODS:The relevant literature from PubMed and Baidu Xueshu were reviewed in this article. The ClinicalTrials.gov database was searched for clinical trials related to the specific topic. RESULTS:Microsatellite instability is divided into three subtypes: high-level, low-level microsatellite instability, and stable microsatellites. The majority of tumour patients with high-level microsatellite instability often show a better efficacy and prognosis than those with low-level microsatellite instability or stable microsatellites. In coding regions, especially for genes involved in tumourigenesis, microsatellite instability often results in inactivation of proteins and contributes to tumourigenesis. Moreover, the occurrence of microsatellite instability in coding regions can also cause the generation of frameshift peptides that are thought to be unknown and novel to the individual immune system. Thus, these frameshift peptides have the potential to be biomarkers to raise tumour-specific immune responses. CONCLUSION:MSI has the potential to become a key predictor for evaluating the degree of malignancy, efficacy and prognosis of tumours. Clinically, MSI patterns will provide more valuable information for clinicians to create optimal individualized treatment strategies based on frameshift peptides vaccines. 10.1007/s00432-019-03053-4
    Subgroups and prognostication in stage III colon cancer: future perspectives for adjuvant therapy. Auclin E,Zaanan A,Vernerey D,Douard R,Gallois C,Laurent-Puig P,Bonnetain F,Taieb J Annals of oncology : official journal of the European Society for Medical Oncology Since the MOSAIC study, oxaliplatin-based adjuvant chemotherapy has been the standard treatment of stage III colon cancer. Combination therapy with fluoropyrimidines and oxaliplatin has improved overall survival (OS) and reduced the risk of recurrence in patients with resected stage III colon cancer. However, only 20% of patients really benefit from adjuvant chemotherapy, exposing 80% of patients to unnecessary toxicity. Recent analyses of large multicenter adjuvant studies have focused on the prognostication of OS and disease-free survival in stage III colon cancer in order to reduce over-treatment and to find more accurate prognostic tools than those used for adjuvant treatment decision-making in stage II disease. Indeed, clinical and pathological prognostic factors, although important, are not sufficient to decide which stage III patients will benefit from adjuvant therapy, and biomarkers will help select patient that need adjuvant treatment. Molecular markers such as microsatellite status and BRAF and KRAS mutations have recently been explored, and molecular signatures have been identified as promising prognostic factor for OS. Furthermore, recent studies have highlighted the prognostic value of immune infiltration. This review focuses on pathologic, immunologic and molecular prognostic markers for stage III colon cancer that could help clinicians tailor adjuvant treatment in a comprehensive transversal approach. 10.1093/annonc/mdx030
    Mismatch repair polymorphisms and risk of colon cancer, tumour microsatellite instability and interactions with lifestyle factors. Campbell P T,Curtin K,Ulrich C M,Samowitz W S,Bigler J,Velicer C M,Caan B,Potter J D,Slattery M L Gut BACKGROUND:Germline mutations in DNA mismatch repair (MMR) genes cause Lynch syndrome colon cancers. Less understood is the risk of colon cancer associated with common polymorphisms in MMR genes and the potential interacting role of lifestyle factors known to damage DNA. METHODS:A study was conducted to examine whether MLH1 (-93G>A and Ile219Val) and MSH6 (Gly39Glu) polymorphisms were associated with risk of colon cancer in data from 1609 colon cancer cases and 1972 controls. Genotype data were further stratified by microsatellite instability status, smoking, alcohol, Western diet, alcohol and obesity, to investigate potential heterogeneity. RESULTS:The MSH6 39Glu allele was associated with increased risk of colon cancer among men (Gly/Glu or Glu/Glu vs Gly/Gly, OR 1.27; 95% CI 1.04 to 1.54). Neither MLH1 polymorphism was associated with colon cancer risk overall. When stratified by microsatellite stability status, however, the MLH1 -93A allele was associated with a more than doubling in microsatellite instability (MSI)-positive colon cancer risk (AA vs GG, OR 2.47; 95% CI 1.48 to 4.11); no associations were observed between the MMR polymorphisms examined and MSI-negative colon cancer. Statistically significant interactions were observed between: MLH1 -93G>A and smoking (MSI-negative colon cancer only, p value interaction: 0.005); and MLH1 Ile219Val and Western diet (p value interaction: 0.03). CONCLUSIONS:The MSH6 Gly39Glu and MLH1 -93G>A polymorphisms were associated with risk of overall colon and MSI-positive colon cancers, respectively. Risk for colon cancer, stratified by MMR genotype, was further modified by smoking and Western diet. 10.1136/gut.2007.144220
    DNA Mismatch Repair Deficiency in Rectal Cancer: Benchmarking Its Impact on Prognosis, Neoadjuvant Response Prediction, and Clinical Cancer Genetics. de Rosa Nicole,Rodriguez-Bigas Miguel A,Chang George J,Veerapong Jula,Borras Ester,Krishnan Sunil,Bednarski Brian,Messick Craig A,Skibber John M,Feig Barry W,Lynch Patrick M,Vilar Eduardo,You Y Nancy Journal of clinical oncology : official journal of the American Society of Clinical Oncology PURPOSE:DNA mismatch repair deficiency (dMMR) hallmarks consensus molecular subtype 1 of colorectal cancer. It is being routinely tested, but little is known about dMMR rectal cancers. The efficacy of novel treatment strategies cannot be established without benchmarking the outcomes of dMMR rectal cancer with current therapy. We aimed to delineate the impact of dMMR on prognosis, the predicted response to fluoropyrimidine-based neoadjuvant therapy, and implications of germline alterations in the MMR genes in rectal cancer. METHODS:Between 1992 and 2012, 62 patients with dMMR rectal cancers underwent multimodality therapy. Oncologic treatment and outcomes as well as clinical genetics work-up were examined. Overall and rectal cancer-specific survival were calculated by the Kaplan-Meier method. RESULTS:The median age at diagnosis was 41 years. MMR deficiency was most commonly due to alterations in MSH2 (53%) or MSH6 (23%). After a median follow-up of 6.8 years, the 5-year rectal cancer-specific survival was 100% for stage I and II, 85.1% for stage III, and 60.0% for stage IV disease. Fluoropyrimidine-based neoadjuvant chemoradiation was associated with a complete pathologic response rate of 27.6%. The extent of surgical resection was influenced by synchronous colonic disease at presentation, tumor height, clinical stage, and pelvic radiation. An informed decision for a limited resection focusing on proctectomy did not compromise overall survival. Five of the 11 (45.5%) deaths during follow-up were due to extracolorectal malignancies. CONCLUSION:dMMR rectal cancer had excellent prognosis and pathologic response with current multimodality therapy including an individualized surgical treatment plan. Identification of a dMMR rectal cancer should trigger germline testing, followed by lifelong surveillance for both colorectal and extracolorectal malignancies. We herein provide genotype-specific outcome benchmarks for comparison with novel interventions. 10.1200/JCO.2016.66.6826
    Identification and survival of carriers of mutations in DNA mismatch-repair genes in colon cancer. Barnetson Rebecca A,Tenesa Albert,Farrington Susan M,Nicholl Iain D,Cetnarskyj Roseanne,Porteous Mary E,Campbell Harry,Dunlop Malcolm G The New England journal of medicine BACKGROUND:The identification of mutations in germ-line DNA mismatch-repair genes at the time of diagnosis of colorectal cancer is important in the management of the disease. METHODS:Without preselection and regardless of family history, we recruited 870 patients under the age of 55 years soon after they received a diagnosis of colorectal cancer. We studied these patients for germ-line mutations in the DNA mismatch-repair genes MLH1, MSH2, and MSH6 and developed a two-stage model by multivariate logistic regression for the prediction of the presence of mutations in these genes. Stage 1 of the model incorporated only clinical variables; stage 2 comprised analysis of the tumor by immunohistochemical staining and tests for microsatellite instability. The model was validated in an independent population of patients. We analyzed 2938 patient-years of follow-up to determine whether genotype influenced survival. RESULTS:There were 38 mutations among the 870 participants (4 percent): 15 mutations in MLH1, 16 in MSH2, and 7 in MSH6. Carrier frequencies in men (6 percent) and women (3 percent) differed significantly (P<0.04). The addition of immunohistochemical analysis in stage 2 of the model had a sensitivity of 62 percent and a positive predictive value of 80 percent. There were 35 mutations in the validation series of 155 patients (23 percent): 19 mutations in MLH1, 13 in MSH2, and 3 in MSH6. The performance of the model was robust among a wide range of cutoff probabilities and was superior to that of the Bethesda and Amsterdam criteria for hereditary nonpolyposis colorectal cancer. Survival among carriers was not significantly different from that among noncarriers. CONCLUSIONS:We devised and validated a method of identifying patients with colorectal cancer who are carriers of mutations in DNA repair genes. Survival was similar among carriers and noncarriers. 10.1056/NEJMoa053493
    Molecular markers identify subtypes of stage III colon cancer associated with patient outcomes. Sinicrope Frank A,Shi Qian,Smyrk Thomas C,Thibodeau Stephen N,Dienstmann Rodrigo,Guinney Justin,Bot Brian M,Tejpar Sabine,Delorenzi Mauro,Goldberg Richard M,Mahoney Michelle,Sargent Daniel J,Alberts Steven R Gastroenterology BACKGROUND & AIMS:Categorization of colon cancers into distinct subtypes using a combination of pathway-based biomarkers could provide insight into stage-independent variability in outcomes. METHODS:We used a polymerase chain reaction-based assay to detect mutations in BRAF (V600E) and in KRAS in 2720 stage III cancer samples, collected prospectively from patients participating in an adjuvant chemotherapy trial (NCCTG N0147). Tumors deficient or proficient in DNA mismatch repair (MMR) were identified based on detection of MLH1, MSH2, and MSH6 proteins and methylation of the MLH1 promoter. Findings were validated using tumor samples from a separate set of patients with stage III cancer (n = 783). Association with 5-year disease-free survival was evaluated using Cox proportional hazards models. RESULTS:Tumors were categorized into 5 subtypes based on MMR status and detection of BRAF or KRAS mutations which were mutually exclusive. Three subtypes were MMR proficient: those with mutations in BRAF (6.9% of samples), mutations in KRAS (35%), or tumors lacking either BRAF or KRAS mutations (49%). Two subtypes were MMR deficient: the sporadic type (6.8%) with BRAF mutation and/or or hypermethylation of MLH1 and the familial type (2.6%), which lacked BRAF(V600E) or hypermethylation of MLH1. A higher percentage of MMR-proficient tumors with BRAF(V600E) were proximal (76%), high-grade (44%), N2 stage (59%), and detected in women (59%), compared with MMR-proficient tumors without BRAF(V600E) or KRAS mutations (33%, 19%, 41%, and 42%, respectively; all P < .0001). A significantly lower proportion of patients with MMR-proficient tumors with mutant BRAF (hazard ratio = 1.43; 95% confidence interval: 1.11-1.85; Padjusted = .0065) or mutant KRAS (hazard ratio = 1.48; 95% confidence interval: 1.27-1.74; Padjusted < .0001) survived disease-free for 5 years compared with patients whose MMR-proficient tumors lacked mutations in either gene. Disease-free survival rates of patients with MMR-deficient sporadic or familial subtypes was similar to those of patients with MMR-proficient tumors without BRAF or KRAS mutations. The observed differences in survival rates of patients with different tumor subtypes were validated in an independent cohort. CONCLUSIONS:We identified subtypes of stage III colon cancer, based on detection of mutations in BRAF (V600E) or KRAS, and MMR status that show differences in clinical and pathologic features and disease-free survival. Patients with MMR-proficient tumors and BRAF or KRAS mutations had statistically shorter survival times than patients whose tumors lacked these mutations. The tumor subtype found in nearly half of the study cohort (MMR-proficient without BRAF(V600E) or KRAS mutations) had similar outcomes to those of patients with MMR-deficient cancers. 10.1053/j.gastro.2014.09.041
    Association of Clinicopathologic and Molecular Markers on Stage-specific Survival of Right Versus Left Colon Cancer. Narayanan Sumana,Gabriel Emmanuel,Attwood Kristopher,Boland Patrick,Nurkin Steven Clinical colorectal cancer BACKGROUND:Previous studies have shown that variability in molecular markers correlates with poorer survival outcomes in patients with right-sided colon cancer (RCC) compared with left-sided colon cancer (LCC). However, several studies have shown conflicting results when examined stage for stage. We examined RCC and LCC to assess for differences in histopathologic features and overall survival (OS). MATERIALS AND METHODS:The National Cancer Database was used to identify patients with RCC and LCC from 2004 to 2013. A propensity-adjusted analysis evaluating the association between the primary site and OS was performed. RESULTS:Of the 422,443 patients identified, 54.7% had RCC and 45.3% had LCC. For all stages, the patients with RCC were older, had more poorly differentiated tumors, and had a greater degree of microsatellite instability compared with those with LCC. Patients with RCC also had more KRAS mutations than did those with LCC. RCC patients had poorer 3- and 5-year OS at all stages, especially stage 3 (62% vs. 73% and 50% vs. 62%, respectively; P < .001). The median OS was 77.5 months for LCC and 62.3 months for RCC (P < .001). CONCLUSION:The present study is one of the largest studies demonstrating that RCC and LCC are different biologic entities. Patients with RCC had significantly greater rates of microsatellite instability for all stages, which has been previously shown to be prognostically advantageous. However, the results of the present study showed poorer OS at every disease stage for RCC compared with LCC. These factors have important implications for the further use of targeted therapies in the treatment of advanced colon cancer. 10.1016/j.clcc.2018.07.001
    Biomarkers for PD-1/PD-L1 Blockade Therapy in Non-Small-cell Lung Cancer: Is PD-L1 Expression a Good Marker for Patient Selection? Chae Young Kwang,Pan Alan,Davis Andrew A,Raparia Kirtee,Mohindra Nisha A,Matsangou Maria,Giles Francis J Clinical lung cancer Immunotherapy has emerged as a promising treatment modality in cancer therapy. With improved understanding of how to tip the balance of immune homeostasis, novel therapeutics targeting immune checkpoints have been developed, with durable responses observed in multiple solid tumors, including melanoma, renal cell carcinoma, and non-small-cell lung cancer. Clinical trials have reported favorable responses using programmed cell death-1 protein receptor (PD-1)/programmed cell death-1 protein ligand (PD-L1) blockade as monotherapy and most impressively in combinatorial trials with cytotoxic T-lymphocyte antigen-4 protein blockade. Nonetheless, a clinical benefit has not been observed in all patients. Therefore, identifying the ideal biomarkers for patient selection would be of great value in optimizing and personalizing immunotherapy. The utility of PD-L1 expression as a biomarker has varied in different clinical trials and immunohistochemistry assays. In addition, the response to immune checkpoint inhibition has been complicated by PD-L1 expression as a marker influenced by the dynamic tumor microenvironment. No consensus has yet been reached on whether PD-L1 expression is an ideal marker for patient selection. Recent research has shown promise for alternative markers, including T-cell immunohistochemistry, other immunologic markers, T-cell receptor clonality, and somatic mutational burden. However, additional studies are needed to assess the value of these as practical predictive biomarkers for patient selection and treatment response. 10.1016/j.cllc.2016.03.011
    Global burden of colorectal cancer: emerging trends, risk factors and prevention strategies. Keum NaNa,Giovannucci Edward Nature reviews. Gastroenterology & hepatology Globally, colorectal cancer (CRC) is the third most commonly diagnosed malignancy and the second leading cause of cancer death. Arising through three major pathways, including adenoma-carcinoma sequence, serrated pathway and inflammatory pathway, CRC represents an aetiologically heterogeneous disease according to subtyping by tumour anatomical location or global molecular alterations. Genetic factors such as germline MLH1 and APC mutations have an aetiologic role, predisposing individuals to CRC. Yet, the majority of CRC is sporadic and largely attributable to the constellation of modifiable environmental risk factors characterizing westernization (for example, obesity, physical inactivity, poor diets, alcohol drinking and smoking). As such, the burden of CRC is shifting towards low-income and middle-income countries as they become westernized. Furthermore, the rising incidence of CRC at younger ages (before age 50 years) is an emerging trend. This Review provides a comprehensive summary of CRC epidemiology, with emphasis on modifiable lifestyle and nutritional factors, chemoprevention and screening. Overall, the optimal reduction of CRC incidence and mortality will require concerted efforts to reduce modifiable risk factors, to leverage chemoprevention research and to promote population-wide and targeted screening. 10.1038/s41575-019-0189-8
    Analysis of the transcriptomic features of microsatellite instability subtype colon cancer. Wang Haiwei,Wang Xinrui,Xu Liangpu,Zhang Ji,Cao Hua BMC cancer BACKGROUND:Programmed cell death protein 1(PD-1) blocking antibodies have been used to enhance immunity in solid tumors and achieve durable clinical responses with an acceptable safety profile in multiple types of cancer. However, only a subset of patients could benefit from PD-1 blockade therapy. Prognostic information including PD-1 ligand (PD-L1) expression, IFN-γ expression signature, tumor mutational burden, and microsatellite instability (MSI) have been evaluated for patients who are selected to receive immune checkpoint therapeutic treatment. Yet the relationship of those biomarkers in determining immune checkpoint therapy is largely unknown. METHODS:Immune-profiles of MSI subtype colon cancer were identified from integrating published MSI associated gene expression data. The enriched pathways and transcription factors were analyzed by GSEA assay. The infiltrations of immune cell types into MSI subtype colon cancer tissues were determined by CIBESORT assay. RESULTS:In the MSI subtype colon cancer patients, PD-L1, IFN-γ and IFN-γ associated genes are highly expressed. And all those genes are favorable effects in colon cancer progress. In addition, we find that Wnt-β-catenin and TGFβ signaling pathways which are two important factors inhibiting PD-1 checkpoint blockade therapy are negatively related with MSI status. We also identify that the immune-profiles in MSI subtype colon cancer are contributed by M1 macrophage infiltration in the tumor environment. CONCLUSIONS:Our results provide the detailed underlying mechanisms of MSI subtype cancer patients are sensitive to PD-1 checkpoint blockade. 10.1186/s12885-019-5802-2
    Association between expression of DNA mismatch repair genes and clinical features and prognosis of patients with radical resection of colon cancer. Wang J B,Ma D L,Li J Y,Sun Q D,Liu Y E Genetics and molecular research : GMR The aim of this study was to investigate the clinical significance of the expression of DNA mismatch repair (MMR) genes in patients subjected to radical surgical removal of colon cancer, as well as their correlation with disease prognosis. Ninety stage II and III colon cancer patients who received laparoscopic radical resection of colon cancer at our hospital were recruited in this study. The expression of hMLH1, hMSH2, hMSH6, and hPMS2 in the resected tumor tissues was examined by SP immunohistochemistry, in order to analyze the relationship between defective DNA MMR (dMMR) and the clinico-pathological features and prognosis of colon cancer. Patients were followed up over a period of 5-35 months, and the Kaplan-Meier survival curve was plotted. dMMR was confirmed in 27 subjects (30.0%), among whom recurrence with metastasis and death was reported in 5 (18.5%) and 2 (7.4%) patients, respectively. The remaining 63 subjects displayed proficient DNA MMR (pMMR); among these, 19 (30.2%) and 7 (11.1%) recurrences with metastasis and death were reported, respectively. dMMR showed no significant correlation with gender, age, or therapeutic modality (P > 0.05), but was significantly correlated with the degree of differentiation, tumor location, number of resected lymph nodes, presence of ileus, and TNM stage (P < 0.05). The prognosis of patients with dMMR was better than that of patients with pMMR. dMMR serves as a biomarker for the prognosis of stage II/III colon cancers. 10.4238/gmr.15038388