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Project description:Approximately 15% of colorectal cancer (CRC) patients present with high levels of microsatellite instability (MSI-H), which is driven by defective mismatch repair (dMMR). While about 20% of MSI-H tumors are associated with the hereditary condition, Lynch syndrome (LS), the majority develop through non-hereditary mechanisms. In recent years, the molecular processes underpinning tumor development in LS patients has been debated, with the longstanding view that dMMR is a secondary process in CRC development of LS patients being questioned. Here, we performed the first multi-omic analysis of normal colon organoids developed from LS and healthy patients to address questions regarding the development of dMMR in LS colon epithelial cells from cancer-free individuals.
2023-06-01 | GSE211221 | GEO
Project description:Approximately 15% of colorectal cancer (CRC) patients present with high levels of microsatellite instability (MSI-H), which is driven by defective mismatch repair (dMMR). While about 20% of MSI-H tumors are associated with the hereditary condition, Lynch syndrome (LS), the majority develop through non-hereditary mechanisms. In recent years, the molecular processes underpinning tumor development in LS patients has been debated, with the longstanding view that dMMR is a secondary process in CRC development of LS patients being questioned. Here, we performed the first multi-omic analysis of normal colon organoids developed from LS and healthy patients to address questions regarding the development of dMMR in LS colon epithelial cells from cancer-free individuals.
2023-06-01 | GSE210018 | GEO
Project description:PurposeMicrosatellite instability (MSI) and/or mismatch repair deficiency (MMR-D) testing has traditionally been performed in patients with colorectal (CRC) and endometrial cancer (EC) to screen for Lynch syndrome (LS)-associated cancer predisposition. The recent success of immunotherapy in high-frequency MSI (MSI-H) and/or MMR-D tumors now supports testing for MSI in all advanced solid tumors. The extent to which LS accounts for MSI-H across heterogeneous tumor types is unknown. Here, we establish the prevalence of LS across solid tumors according to MSI status.MethodsMSI status was determined using targeted next-generation sequencing, with tumors classified as MSI-H, MSI-indeterminate, or microsatellite-stable. Matched germline DNA was analyzed for mutations in LS-associated mismatch repair genes ( MLH1, MSH2, MSH6, PMS2, EPCAM). In patients with LS with MSI-H/I tumors, immunohistochemical staining for MMR-D was assessed.ResultsAmong 15,045 unique patients (more than 50 cancer types), LS was identified in 16.3% (53 of 326), 1.9% (13 of 699), and 0.3% (37 of 14,020) of patients with MSI-H, MSI-indeterminate, and microsatellite-stable tumors, respectively ( P < .001). Among patients with LS with MSI-H/I tumors, 50% (33 of 66) had tumors other than CRC/EC, including urothelial, prostate, pancreas, adrenocortical, small bowel, sarcoma, mesothelioma, melanoma, gastric, and germ cell tumors. In these patients with non-CRC/EC tumors, 45% (15 of 33) did not meet LS genetic testing criteria on the basis of personal/family history. Immunohistochemical staining of LS-positive MSI-H/I tumors demonstrated MMR-D in 98.2% (56 of 57) of available cases.ConclusionMSI-H/MMR-D is predictive of LS across a much broader tumor spectrum than currently appreciated. Given implications for cancer surveillance and prevention measures in affected families, these data support germline genetic assessment for LS for patients with an MSI-H/MMR-D tumor, regardless of cancer type or family cancer history.
| S-EPMC6553803 | biostudies-literature
Project description:High levels of microsatellite instability (MSI-high) are a cardinal feature of colorectal tumors from patients with Lynch Syndrome. Other key characteristics of Lynch Syndrome are that these patients experience fewer metastases and have enhanced survival when compared to patients diagnosed with microsatellite stable (MSS) colorectal cancer. Many of the characteristics associated with Lynch Syndrome including enhanced survival are also observed in patients with sporadic MSI-high colorectal cancer. In this review we will present the current state of knowledge regarding the mechanisms that are utilized by the host to control colorectal cancer in Lynch Syndrome and why these same mechanisms fail in MSS colorectal cancers.
| S-EPMC2901607 | biostudies-literature
Project description:OBJECTIVE:: Germline mutations in mismatch repair (MMR) genes cause Lynch syndrome (LS). LS is an inherited disease, and an important consequence of MMR deficiency is microsatellite instability (MSI) phenotype. MSI phenotype influences the efficacy of 5 fluorouracil (5-FU) chemotherapy. Reproducible, cost effective, and easy to perform laboratory tests are required to include MSI detection in routine laboratory practice. Evaluation of CAT25 as monomorphic short tandem repeat sequence enables CAT25 to be an efficient screening tool among hereditary nonpolyposis colorectal cancer (HNPCC) patients compared with other methods used currently. METHODS:: Based on Amsterdam II criteria, 31 patients in 31 families were shortlisted from a total number of 1,659 colorectal cancer patients. MSI status was examined in these patients using CAT25 and a commercially available Promega MSI five-marker-based detection system as well as immunohistochemical (IHC) staining of four important MMR proteins. Patients were scored as high microsatellite instable (MSI-H), low (MSI-L), or stable (MSS). MSI status determined by CAT25 single mononucleotide marker was compared with that of five mononucleotide markers, Promega commercial kit, and IHC method. RESULTS:: MMR protein deficiency was observed on 7/31 probands using IHC methodology and 6/31 categorized as MSI-H using commercial kit or CAT25 single marker. The sensitivity and specificity of the CAT25 single marker were the same as those detected by five-marker Promega commercial kit in our patients. CONCLUSIONS:: Based on our results, the performance of the CAT25 single mononucleotide marker for MSI status determination in our HNPCC patients is the same as that of the five-marker-based commercial kit.
| S-EPMC5444926 | biostudies-literature
Project description:The colorectal cancer spectrum has changed due to population screening programs, with a shift toward adenomas and early cancers. Whether it would be a feasible option to test these adenomas for detection of Lynch syndrome (LS) patients is unclear. Through meta-analysis and systematic review, risk factors for DNA mismatch repair deficiency (dMMR) and microsatellite instability (MSI) in adenomas were identified in LS and unselected patient cohorts. Data were extracted for patient age and MMR variant together with adenoma type, grade, size, and location. A total of 41 studies were included, and contained more than 519 LS patients and 1698 unselected patients with 1142 and 2213 adenomas respectively. dMMR/MSI was present in 69.5% of conventional adenomas in LS patients, compared with 2.8% in unselected patients. In the LS cohort, dMMR/MSI was more frequently present in patients older than 60 years (82% versus 54%). dMMR/MSI was also more common in villous adenomas (84%), adenomas over 1?cm (81%), and adenomas with high grade dysplasia (88%). No significant differences were observed for dMMR/MSI in relation to MMR variants and location of adenomas. In the context of screening, we conclude that detection of dMMR/MSI in conventional adenomas of unselected patients is uncommon and might be considered as indication for LS testing. Within the LS cohort, 69.5% of LS patients could have been detected through dMMR/MSI screening of their conventional adenomas.
| S-EPMC7028913 | biostudies-literature
Project description:Microsatellite Instability (MSI) is a hallmark of colorectal cancer (CRC) and occurs in 15-16% of CRC. Molecular biological information of CRC in South Africa (SA) is largely unrecorded. This study was undertaken to determine the frequency of MSI, with particular reference to Lynch syndrome (LS) with a view to improve surveillance and prevention strategies. This was a retrospective study on CRC samples diagnosed between 2011-2015 at Charlotte Maxeke Johannesburg Academic Hospital (CMJAH). Samples diagnosed between 2011-2012 were screened for MSI by PCR and mismatch repair (MMR) immunohistochemistry (IHC), and additional BRAFV600E mutational analysis performed. T-tests, Fischer's exact and Chi square statistical tests were applied. Twelve percent of patients displayed MSI, with increased frequency in black (15%) versus other ethnic group (OEG) (8%) patients. MSI patients were significantly younger than microsatellite stable (MSS) patients, however when stratified by ethnicity, black patients were predominantly younger (median age: 47), with increased MSH2/6 loss, and no BRAF mutations. These findings suggest a large proportion of young black SA CRC patients develop via the LS pathway due to earlier age onset and predominant MSH2/6 protein loss. SA patients of other ethnicities appear to follow the more well established sporadic MSI pathway.
| S-EPMC6803663 | biostudies-literature
Project description:Immune checkpoint blockade (ICB) has changed the landscape of cancer therapy in multiple tumor types since the first agent, Ipilimumab, was first FDA approved for the treatment of metastatic melanoma in 2011. Its role in GI Cancers, particularly in colon cancers, has not been as robust as in other tumor types but select patients with DNA mismatch repair defects, even those who has progressed on multiple standard chemotherapeutic regimens have demonstrated significant, almost unprecedented, responses in this multidrug refractory population. Unfortunately, these cases represent only a small percentage of colon cancer patients with little efficacy in the 95% of metastatic colon cancers who have proficient DNA mismatch repair. Multiple strategies have been, and are currently being, evaluated to determine the potential benefits of this drug class to microsatellite stable (MSS) patients.
| S-EPMC7724178 | biostudies-literature
Project description:Non-alcoholic fatty liver disease (NAFLD) is a consequence of sedentary life style and high fat diets with an estimated prevalence of about 30% in western countries. It is associated with insulin resistance, obesity, glucose intolerance and drug toxicity. Additionally, polymorphisms within, e.g., APOC3, PNPLA3, NCAN, TM6SF2 and PPP1R3B, correlate with NAFLD. Several studies have already investigated later stages of the disease. This study explores the early steatosis stage of NAFLD with the aim of identifying molecular mechanisms underlying the etiology of NAFLD. We analyzed liver biopsies and serum samples from patients with high- and low-grade steatosis (also pre-disease states) employing transcriptomics, ELISA-based serum protein analyses and metabolomics. Here, we provide a detailed description of the various related datasets produced in the course of this study. These datasets may help other researchers find new clues for the etiology of NAFLD and the mechanisms underlying its progression to more severe disease states.
| S-EPMC4672680 | biostudies-literature
Project description: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-? 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-? and IFN-? associated genes are highly expressed. And all those genes are favorable effects in colon cancer progress. In addition, we find that Wnt-?-catenin and TGF? 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.
| S-EPMC6585086 | biostudies-literature