Mismatch repair genes status in sporadic Saudi colorectal cancer patients
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ABSTRACT:
SUBMITTER: Ata M
PROVIDER: S-EPMC4075644 | biostudies-literature | 2014 Jan
REPOSITORIES: biostudies-literature
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Project description:A deficient mismatch repair system (dMMR) is present in 10-20% of patients with sporadic colorectal cancer (CRC) and is associated with a favourable prognosis in early stage disease. Data on patients with advanced disease are scarce. Our aim was to investigate the incidence and outcome of sporadic dMMR in advanced CRC. Data were collected from a phase III study in 820 advanced CRC patients. Expression of mismatch repair proteins was examined by immunohistochemistry. In addition microsatellite instability analysis was performed and the methylation status of the MLH1 promoter was assessed. We then correlated MMR status to clinical outcome. Deficient mismatch repair was found in only 18 (3.5%) out of 515 evaluable patients, of which 13 were caused by hypermethylation of the MLH1 promoter. The median overall survival in proficient MMR (pMMR), dMMR caused by hypermethylation of the MLH1 promoter and total dMMR was 17.9 months (95% confidence interval 16.2-18.8), 7.4 months (95% CI 3.7-16.9) and 10.2 months (95% CI 5.9-19.8), respectively. The disease control rate in pMMR and dMMR patients was 83% (95% CI 79-86%) and 56% (30-80%), respectively. We conclude that dMMR is rare in patients with sporadic advanced CRC. This supports the hypothesis that dMMR tumours have a reduced metastatic potential, as is observed in dMMR patients with early stage disease. The low incidence of dMMR does not allow drawing meaningful conclusions about the outcome of treatment in these patients.
| S-EPMC2634718 | biostudies-literature
Project description:BackgroundMismatch repair (MMR) genes are known to be frequently altered in colorectal cancer (CRC). Both genetics and epigenetics modifications seems to be relevant in this phenomenon, however it is still not clear how these two aspects are interconnected. The present study aimed at characterizing of epigenetic and gene expression profiles of MMR genes in sporadic CRC patients from the Czech Republic, a country with one of the highest incidences of this cancer all over Europe.MethodsExpression levels and CpG promoter methylation status of all MMR genes were evaluated in DNA from tumor and adjacent mucosal samples of 53 incident CRC patients.ResultsWe have found significantly increased transcription levels in EXO1 gene in tumor tissues (P = 0.05) and significant over-expression of MSH3 gene in colon tumors when compared to adjacent mucosal tissues (P = 0.02). Interestingly, almost all MMR genes were differently expressed when localization of tumors was compared. In particular, colon tumors showed an up-regulation of EXO1, MSH2, MSH3, MSH6, and PMS2 genes in comparison to rectal tumors (P = 0.02). Expression levels of all MMR genes positively correlated between each other. The promoter methylation of MLH1 gene was observed in 9% of CRC tissues only.ConclusionsIn our study, we have observed different pattern of MMR genes expression according to tumor localization. However, a lack of association between methylation in MMR genes and their corresponding expressions was noticed in this study, the relationship between these two aspects is worthy to be analyzed in larger population studies and in pre-malignant stages.
| S-EPMC3913626 | biostudies-literature
Project description:BackgroundThere is evidence that colorectal cancers (CRC) with DNA mismatch repair deficiency (MMR-D) are associated with a better prognosis than the generality of large bowel malignancies. Since an active immune surveillance process has been demonstrated to influence CRC outcome, we investigated whether MMR-D can enhance the immune response in CRC.Patients and methodsA group of 113 consecutive patients operated for CRC (42 stage I or II and 71 with stage III or IV) was retrospectively analyzed. The expression of MMR genes (MSH2, MLH1, MSH6 and PSM2) and co-stimulatory molecule CD80 was assessed by tissue microarray immunohistochemistry. In addition, tumor infiltrating mononuclear cells (TIMC) and T cell subpopulations (CD4, CD8, T-bet and FoxP-3) were quantified. The effect of specific siRNA (siMSH2, siMLH1, siMSH6 and siPSM2) transfection in HT29 on CD80 expression was quantified by flow cytometry. Non parametric statistics and survival analysis were used.ResultsPatients with MMR-D showed a higher T-bet/CD4 ratio (p = 0.02), a higher rate of CD80 expression and CD8 lymphocyte infiltration compared to those with no MMR-D. Moreover, in the MMR-D group, the Treg marker FoxP-3 was not expressed (p = 0.05). MMR-D patients with stage I or II and T-bet expression had a significant better survival (p = 0.009). Silencing of MSH2, MLH1 and MSH6, but not PSM2, significantly increased the rate of CD80+ HT29 cells (p = 0.007, p = 0.023 and p = 0.015, respectively).ConclusionsCRC with MMR-D showed a higher CD80 expression, and CD8+ and Th1 T-cell infiltration. In vitro silencing of MSH2, MLH1 and MSH6 significantly increased CD80+ cell rate. These results suggest an enhanced immune surveillance mechanism in presence of MMR-D.
| S-EPMC4791244 | biostudies-literature
Project description: Not available
| S-EPMC11760291 | biostudies-literature
Project description:Immunohistochemistry has recently been validated for the detection of the BRAFV600E mutation across a range of tumor types. In colorectal carcinoma, the presence of the BRAFV600E mutation can be used to virtually exclude Lynch syndrome in mismatch repair-deficient tumors. In mismatch repair-proficient tumors, BRAFV600E mutation assessed by molecular methods has been proposed as a poor prognostic factor. We investigated whether combined BRAFV600E and mismatch repair status assessment by immunohistochemistry alone can be used as a prognostic marker in the routine clinical setting. We performed immunohistochemistry for BRAFV600E, MLH1, PMS2, MSH2, and MSH6 on 1426 consecutive unselected colorectal carcinomas. Ninety-one (6.4%) carcinomas were mismatch repair-proficient and BRAFV600E mutant, and these tumors demonstrated a significantly worse 5-year survival of 49.7% compared with mismatch repair-proficient BRAF wild type (74.1% of tumors, 65.4% survival), mismatch repair-deficient BRAFV600E mutant (12.9% of tumors, 70.1% survival), and mismatch repair-deficient BRAF wild type (6.6% of tumors, 73.6% survival). The poor survival was confirmed by univariate analysis (P<0.01) but fell away in multivariate analysis (P=0.68) because of the strong effect of tumor stage and age on overall survival. We conclude that in addition to its utility in screening for Lynch syndrome, reflex BRAFV600E and mismatch repair assessment by immunohistochemistry can be used as a powerful predictor of all-cause survival.
| S-EPMC4021849 | biostudies-other
Project description:Purpose: Mismatch repair-deficient (dMMR) colorectal cancer (CRC) is associated with increased local immune response as compared with mismatch repair-proficient (pMMR) CRC. We evaluated the relationship between MMR status and systemic inflammatory factors, including neutrophil lymphocyte ratio (NLR) and C-reactive protein (CRP). We also assessed the prognostic value of these parameters. Methods and materials: We analysed the relationship between MMR status (obtained by histochemical analysis), neutrophil and lymphocyte counts, NLR, and CRP level. The impact of systemic inflammatory factors on survival was also evaluated in dMMR and pMMR CRC patients. Results: A total of 1353 male and 892 female patients were eligible for analysis, of which, 253 patients (11.3%) were found to have dMMR status. Patients with dMMR status presented with increased neutrophil counts, and higher NLR and CRP levels in early stage CRC. In stage IV CRC patients, no correlation between MMR status and systemic inflammatory factors was found. Lymphocyte counts did not correlate with MMR status. High NLR was a prognostic factor for poor survival in pMMR CRC. However, NLR was not a prognostic factor in dMMR CRC. Conclusions: Our results suggest that dMMR CRC correlates with higher neutrophil count, NLR and CRP levels only in non-metastatic patients, and NLR has prognostic value only in pMMR CRC.
| S-EPMC6134814 | biostudies-literature
Project description:Background & aimsDirect germline analysis could be used to screen high-risk patients for mutations in DNA mismatch repair genes associated with Lynch Syndrome. We examined the prevalence of mutations in MLH1, MSH2, and MSH6 in a population-based sample of patients with young-onset (age <50 years) colorectal cancer (CRC).MethodsYoung-onset CRC cases were randomly selected from 3 Colon Cancer Family Registry sites. DNA was extracted from peripheral blood leukocytes; MLH1, MSH2, and MSH6 were sequenced, and duplication and deletion analyses was performed for MLH1 and MSH2. Results were reported as deleterious or suspected deleterious, likely neutral, variant of uncertain significance, or no alteration detected. Germline data were compared to Amsterdam II criteria (ACII) and immunohistochemistry results in secondary analyses.ResultsAmong 195 subjects, 11 had deleterious/suspected deleterious mutations (5.6%; 95% confidence interval [CI], 2.8%-9.9%), 12 had likely neutral alterations (6.2%; 95% CI, 3.2%-10.5%), 14 had variants of uncertain significance (7.2%; 95% CI, 4.0%-11.8%), 2 had a likely neutral alteration and a variant of uncertain significance (1.0%; 95% CI, 0.1%-3.7%), and 156 had no alteration detected (80.0%; 95% CI, 73.7%-85.4%). Sensitivity, specificity, and positive and negative predictive values for detecting deleterious/suspected deleterious mutations, based on ACII, were 36.4% (4/11), 96.7% (178/184), 40.0% (4/10), and 96.2% (178/185), respectively; based on immunohistochemistry these values were 85.7% (6/7), 91.9% (136/148), 33.3% (6/18), and 99.3% (136/137), respectively.ConclusionsIn a population-based sample of young-onset CRC cases, germline mutations in MLH1, MSH, and/or MSH6 were more prevalent than reported for CRC patients overall. Because only about 5% of young-onset CRC cases had confirmed deleterious or suspected deleterious mutations, further comparative effectiveness research is needed to determine the most appropriate screening strategy for Lynch Syndrome in this high-risk group.
| S-EPMC3058119 | biostudies-literature
Project description:BackgroundYoung adults with metastatic colorectal cancer (mCRC) may have higher rates of deficient mismatch repair (dMMR) than older patients. This study sought to assess patterns of MMR-testing and survival among young adult mCRC patients in the National Cancer Database (NCDB), hypothesizing that dMMR correlates with worse survival than in MMR-proficient (pMMR) patients.MethodsStage-IV colorectal cancers were identified in NCDB (2010-2016). Demographic and clinical features were compared between younger (age ≤ 30) and older mCRC patients and tested for association with overall survival. Stage-IV disease without other recorded metastatic sites defined peritoneal metastasis (PM). Fisher-exact tests compared proportions and Cox models tested association with overall survival.ResultsOf 124,587 stage-IV colorectal cancers, 1,123 (0.9%) were in young patients. Young patients were more likely to have mucinous histology, high-grade, rectal primaries, and isolated peritoneal metastases (P < 0.001). Younger patients more often had MMR-testing (29.1 versus 16.6%), with dMMR found at similar rates in young and older patients (21.7 versus 17.1% of those tested, P= 0.4). Despite higher rates of adverse prognostic features, younger patients had better survival (median 20.7 versus 14.8 months, P < 0.001). In MMR-tested patients, dMMR correlated with higher mortality risk compared to pMMR (median 16.6 months versus 25.5 months, P = 0.01). On multivariable analysis, grade and MMR-status remained independently associated with survival.ConclusionsMedian survival was worse with dMMR by 8.9 months compared to pMMR in young adults with mCRC. Despite higher rates of familial syndromes in young patients and recommendations for universal MMR-testing, over 70% of young mCRC patients had no MMR-status recorded.
| S-EPMC8338754 | biostudies-literature
Project description:Patients with pancreatic cancer (PC) showing mismatch repair (MMR) deficiency may benefit from immunotherapy. Microsatellite instability (MSI) is a hallmark of MMR deficiency (MMR-D). Here, we estimated the prevalence of MSI in PC, investigated germline and somatic mutations in the three MMR genes (MLH1, MSH2, and MSH6), and assessed the relationship between MMR genes mutations and MSI status in PC. Clinical specimens from PC patients were analyzed using targeted next-generation sequencing, including paired normal and tumor specimens from 155 patients, tumor-only specimens from 86 patients, and normal-only specimens from 379 patients. The MSI status of 235 PCs was assessed via PCR. Pathogenic/likely pathogenic (P/LP) germline variants in the MMR genes were identified in 1.1% of patients, while somatic variants were found in 2.6% of patients. No MSI-H tumors were detected. One patient carried two variants (P (VAF = 0.57) and LP (VAF = 0.25)) simultaneously; however, their germline/somatic status remains unknown due to the investigation focusing solely on the tumor and MSI analysis was not performed for this patient. MSI is rare in PC, even in tumors with MMR genes mutations. Our findings underscore the importance of assessing tumor MMR-D status in PC patients with confirmed Lynch syndrome when deciding whether to prescribe immunotherapy.
| S-EPMC11171205 | biostudies-literature
Project description:BackgroundNaturally occurring colorectal cancers (CRC) in rhesus macaques share many features with their human counterparts and are useful models for cancer immunotherapy; but mechanistic data are lacking regarding the comparative molecular pathogenesis of these cancers.MethodsWe conducted state-of-the-art imaging including CT and PET, clinical assessments, and pathological review of 24 rhesus macaques with naturally occurring CRC. Additionally, we molecularly characterized these tumors utilizing immunohistochemistry (IHC), microsatellite instability assays, DNAseq, transcriptomics, and developed a DNA methylation-specific qPCR assay for MLH1, CACNA1G, CDKN2A, CRABP1, and NEUROG1, human markers for CpG island methylator phenotype (CIMP). We furthermore employed Monte-Carlo simulations to in-silico model alterations in DNA topology in transcription-factor binding site-rich promoter regions upon experimentally demonstrated DNA methylation.ResultsSimilar cancer histology, progression patterns, and co-morbidities could be observed in rhesus as reported for human CRC patients. IHC identified loss of MLH1 and PMS2 in all cases, with functional microsatellite instability. DNA sequencing revealed the close genetic relatedness to human CRCs, including a similar mutational signature, chromosomal instability, and functionally-relevant mutations affecting KRAS (G12D), TP53 (R175H, R273*), APC, AMER1, ALK, and ARID1A. Interestingly, MLH1 mutations were rarely identified on a somatic or germline level. Transcriptomics not only corroborated the similarities of rhesus and human CRCs, but also demonstrated the significant downregulation of MLH1 but not MSH2, MSH6, or PMS2 in rhesus CRCs. Methylation-specific qPCR suggested CIMP-positivity in 9/16 rhesus CRCs, but all 16/16 exhibited significant MLH1 promoter hypermethylation. DNA hypermethylation was modelled to affect DNA topology, particularly propeller twist and roll profiles. Modelling the DNA topology of a transcription factor binding motif (TFAP2A) in the MLH1 promoter that overlapped with a methylation-specific probe, we observed significant differences in DNA topology upon experimentally shown DNA methylation. This suggests a role of transcription factor binding interference in epigenetic silencing of MLH1 in rhesus CRCs.ConclusionsThese data indicate that epigenetic silencing suppresses MLH1 transcription, induces the loss of MLH1 protein, abrogates mismatch repair, and drives genomic instability in naturally occurring CRC in rhesus macaques. We consider this spontaneous, uninduced CRC in immunocompetent, treatment-naïve rhesus macaques to be a uniquely informative model for human CRC.
| S-EPMC10953092 | biostudies-literature