Browse
Submit Data
Databases
API
Help

Dataset Information

27 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Germline variants in POLE are associated with early onset mismatch repair deficient colorectal cancer.

ABSTRACT: Germline variants affecting the exonuclease domains of POLE and POLD1 predispose to multiple colorectal adenomas and/or colorectal cancer (CRC). The aim of this study was to estimate the prevalence of previously described heterozygous germline variants POLE c.1270C>G, p.(Leu424Val) and POLD1 c.1433G>A, p.(Ser478Asn) in a Dutch series of unexplained familial, early onset CRC and polyposis index cases. We examined 1188 familial CRC and polyposis index patients for POLE p.(Leu424Val) and POLD1 p.(Ser478Asn) variants using competitive allele-specific PCR. In addition, protein expression of the POLE and DNA mismatch repair genes was studied by immunohistochemistry in tumours from POLE carriers. Somatic mutations were screened using semiconductor sequencing. We detected three index patients (0.25%) with a POLE p.(Leu424Val) variant. In one patient, the variant was found to be de-novo. Tumours from three patients from two families were microsatellite instable, and immunohistochemistry showed MSH6/MSH2 deficiency suggestive of Lynch syndrome. Somatic mutations but no germline MSH6 and MSH2 variants were subsequently found, and one tumour displayed a hypermutator phenotype. None of the 1188 patients carried the POLD1 p.(Ser478Asn) variant. POLE germline variant carriers are also associated with a microsatellite instable CRC. POLE DNA analysis now seems warranted in microsatellite instable CRC, especially in the absence of a causative DNA mismatch repair gene germline variant.

SUBMITTER: Elsayed FA

PROVIDER: S-EPMC4351893 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

A novel germline POLE mutation causes an early onset cancer prone syndrome mimicking constitutional mismatch repair deficiency.

Project description:In a 14-year-old boy with polyposis and rectosigmoid carcinoma, we identified a novel POLE germline mutation, p.(Val411Leu), previously found as recurrent somatic mutation in 'ultramutated' sporadic cancers. This is the youngest reported cancer patient with polymerase proofreading-associated polyposis indicating that POLE mutation p.(Val411Leu) may confer a more severe phenotype than previously reported POLE and POLD1 germline mutations. The patient had multiple café-au-lait macules and a pilomatricoma mimicking the clinical phenotype of constitutional mismatch repair deficiency. We hypothesize that these skin features may be common to different types of constitutional DNA repair defects associated with polyposis and early-onset cancer.

| S-EPMC5243902 | biostudies-literature

Deficient DNA mismatch repair is common in Lynch syndrome-associated colorectal adenomas.

Project description:Lynch syndrome is caused by germline mutations in DNA mismatch repair (MMR) genes. Both microsatellite instability (MSI) testing and immunohistochemical analyses (IHC) of colon cancers are valuable diagnostic strategies for Lynch syndrome. We sought to determine whether these markers of MMR deficiency were also detectable in pre-cancerous colorectal adenomas. Fifteen subjects with a germline MMR gene mutation who had 44 adenomas removed during surveillance colonoscopy were identified. MSI testing and IHC for MLH1, MSH2, and MSH6 were performed. MSI was detected in 23 adenomas. There was a significant association between MSI and high-grade dysplasia (P = 0.006) and distal location (P = 0.0008). Loss of MMR protein by IHC was detected in 31 adenomas. A significant association was observed between loss of staining by IHC and high-grade dysplasia (P = 0.04). Among the 40 adenomas in which both MSI tests and IHC were performed, the presence of a germline mutation correlated with an abnormal MSI result in 58% of cases, an abnormal IHC result in 70% of cases, and either an abnormal MSI or IHC result in 73% of cases. The combination of MSI and IHC testing in colorectal adenomas is a sensitive screen for the detection of Lynch syndrome and may be particularly useful when Lynch syndrome is suspected and adenomatous polyps are the only tissues available for analysis.

| S-EPMC2671341 | biostudies-literature

Compound heterozygous MSH3 germline variants and associated tumor somatic DNA mismatch repair dysfunction.

Project description:We describe here an individual from a fourth family with germline compound heterozygous MSH3 germline variants and its observed biological consequences. The patient was initially diagnosed with invasive moderately-differentiated adenocarcinoma of the colon at the age of 43. Germline multigene panel testing revealed a pathogenic variant MSH3 c.2436-1 G > A and a variant of (initial) uncertain significance MSH3 c.3265 A > T (p.Lys1089*). Germline genetic testing of family members confirm the variants are in trans with the c.2436-1 G > A variant of paternal and the c.3265 A > T variant of maternal origin. Tumor DNA exhibits low levels of microsatellite instability and elevated microsatellite alterations at selected tetranucleotide repeats (EMAST). Tissue immunohistochemical staining for MSH3 demonstrated variant MSH3 protein is present in the cytoplasm and cell membrane but not in the nucleus of normal and tumor epithelial cells. Furthermore, variant MSH3 is accompanied by loss of nuclear MSH6 and a reduced level of nuclear MSH2 in some tumor cells, suggesting that the variant MSH3 protein may inhibit binding of MSH6 to MSH2.

| S-EPMC10798947 | biostudies-literature

Mismatch Repair-Deficient Colorectal Cancer: Building on Checkpoint Blockade.

Project description:Colorectal cancer (CRC) with deficient DNA mismatch repair (dMMR) is characterized by hypermutation leading to abundant neoantigens that activate an antitumor immune response in the tumor microenvironment. Immune checkpoint inhibitors (ICIs) have transformed the treatment of this subset of CRC and other solid tumors with dMMR, by producing frequent and durable responses that extend patient survival. Recently, the anti-programmed death-1 (PD-1) antibody pembrolizumab was shown to produce significantly longer progression-free survival with fewer adverse events compared with chemotherapy as first-line treatment of metastatic CRC (mCRC) with dMMR. Accordingly, single-agent pembrolizumab represents a new standard of care for dMMR mCRCs including patients with Lynch syndrome and the more common sporadic cases. Furthermore, data indicate that the combination of PD-1 and cytotoxic T-cell lymphocyte-4 inhibitors was more effective than single-agent PD-1 inhibition in patients with dMMR mCRCs, suggesting nonredundant mechanisms of action. Although the benefit of ICIs is currently limited to metastatic disease, studies evaluating ICIs as neoadjuvant and adjuvant therapy in earlier-stage dMMR CRC are ongoing. Despite success of ICIs in the treatment of metastatic dMMR cancers, an appreciable proportion of these tumors demonstrate intrinsic or acquired resistance, and biomarkers to identify these patients are needed. Advances in the understanding of immunotherapy resistance mechanisms hold promise for both biomarker identification and development of novel strategies to circumvent treatment resistance. In this review, we present a comprehensive overview of the evidence for the role of immunotherapy in the treatment of dMMR CRC, discuss resistance mechanisms, and outline potential strategies to circumvent primary and secondary resistance with the goal of broadening the benefit of ICIs.

| S-EPMC9390830 | biostudies-literature

New Pathogenic Germline Variants in Very Early Onset and Familial Colorectal Cancer Patients.

Project description:A genetic diagnosis facilitates personalized cancer treatment and clinical care of relatives at risk, however, although 25% of colorectal cancer cases are familial, around 95% of the families are genetically unresolved. In this study, we performed gene panel analysis on germline DNA of 32 established or candidate colorectal cancer predisposing genes in 149 individuals from either families with an accumulation of colorectal cancers or families with only one sporadic case of very early onset colorectal cancer (≤40 years at diagnosis). We identified pathogenic or likely pathogenic genetic variants in 10.1% of the participants in genes such as APC, POLE, MSH2 or PMS2. The MSH2 variant, c.2168C>T, p.(Ser723Phe) was previously described as a variant of unknown significance, but we have now reclassified it to be likely pathogenic. The POLE variant, c.1089C>A, p.(Asn363Lys) was identified in a patient with three metachronous colorectal cancers from age 28 and turned out to be de novo. One pathogenic PMS2 variant was novel. We also identified a number of highly interesting variants of unknown significance in APC, BUB1, TP53 and RPS20. The RPS20 variant is novel and was found in a large Amsterdam I positive family with a multi tumor phenotype including 12 cases of CRC from as early as age 24. This variant was found to segregate with cancer in the family and multiple in silico tools predict it to be pathogenic. Our data further support the shift from phenotypic-based cancer panels to large panels including all established genes involved in hereditary cancer syndromes or (targeted) whole genome sequencing. Additionally, identification of a likely disease-predisposing variant in RPS20 expands the phenotypic spectrum of RPS20-related cancers and emphasize that this gene is relevant to include in colorectal cancer gene panels.

| S-EPMC7541943 | biostudies-literature

Germline POLE mutation in a child with hypermutated medulloblastoma and features of constitutional mismatch repair deficiency.

Project description:Ultra-hypermutation (>100 mutations/Mb) is rare in childhood cancer genomes and has been primarily reported in patients with constitutional mismatch repair deficiency (CMMRD) caused by biallelic germline mismatch repair (MMR) gene mutations. We report a 5-yr-old child with classic clinical features of CMMRD and an ultra-hypermutated medulloblastoma with retained MMR protein expression and absence of germline MMR mutations. Mutational signature analysis of tumor panel sequencing data revealed a canonical DNA polymerase-deficiency-associated signature, prompting further genetic testing that uncovered a germline POLE p.A456P missense variant, which has previously been reported as a recurrent somatic driver mutation in cancers. This represents the earliest known onset of malignancy in a patient with a germline mutation in the POLE proofreading polymerase. The clinical features in this child, virtually indistinguishable from those of CMMRD, suggest that polymerase-proofreading deficiency should be considered in the differential diagnosis of CMMRD patients with retained MMR function.

| S-EPMC6824253 | biostudies-literature

Prevalence and clinicopathological characteristics of mismatch repair-deficient colorectal carcinoma in early onset cases as compared with late-onset cases: a retrospective cross-sectional study in Northeastern Iran.

Project description:ObjectivesLynch syndrome (LS), a genetically inherited autosomal disorder, increases the incidence of colorectal carcinoma (CRC). We aimed to perform a universal strategy to assess the prevalence and clinicopathological characteristics of early onset CRCs at high risk of LS versus late-onset ones in the Iranian population.SettingA local population-based study from Northeastern Iran.Participants321 consecutive CRCs and pathology specimen screened between 2013 and 2016.Primary and secondary outcome measuresRetrospectively, information regarding the clinical criteria was obtained by interviewing the patients with CRC or, their families. Pathologists tested tumours with immunohistochemistry (IHC) staining of four mismatch repair (MMR) proteins (MLH1, MSH2, MSH6 and PMS2). Tumours with absent IHC staining of MLH1 were tested for BRAF mutations to exclude sporadic CRCs. Prevalence of early onset CRCs at high risk of LS and familial CRC type X were assessed as primary and secondary outcome measures, respectively.ResultsOf 321 CRCs (13/123 (10.57%), early onset vs 21/198 (10.6%) late-onset) were detected to be MMR-deficient (dMMR). Nine early onset cases and 14 late-onset ones with a loss of MLH1 underwent testing for the BRAF mutation, none of the early onset and four (2.02%) late-onset were recognised as sporadic. The difference in the outcome of IHC-analysis between early and late-onset CRCs at high risk of LS was not statistically significant (p=0.34). Majority of the suspected LS tumours from early onset patients had arisen in distal part (8/11 (72.72%) vs 8/14 (57.14%)), all of which were occurred in the rectum or sigmoid.ConclusionClinically, these findings suggest that in case of limitation for BRAF testing, the practitioner in Iran may consider managing early onset dMMR cases like LS until access to BRAF testing becomes available to them, before germline testing to accurately diagnose LS.

| S-EPMC6119423 | biostudies-literature

Rhesus Macaque Model of Mismatch Repair-Deficient Colorectal Cancer

Project description:This SuperSeries is composed of the SubSeries listed below. NIH grant(s): Grant ID: 5 P30 CA016672-44 Grant title: Cancer Center Support Grant Affiliation: The University of Texas MD Anderson Cancer Center Grantor: NCI

2022-03-31 | GSE178383 | GEO

Germline biallelic Mcm8 variants are associated with early-onset Lynch-like syndrome.

Project description:Lynch syndrome is the most common cause of hereditary colorectal cancer (CRC), and it is characterized by DNA mismatch repair (MMR) deficiency. The term Lynch-like syndrome (LLS) is used for patients with MMR-deficient tumors and neither germline mutation in MLH1, MSH2, MSH6, PMS2, or EPCAM nor MLH1 somatic methylation. Biallelic somatic inactivation or cryptic germline MMR variants undetected during genetic testing have been proposed to be involved. Sixteen patients with early-onset LLS CRC were selected for germline and tumor whole-exome sequencing. Two potentially pathogenic germline MCM8 variants were detected in a male patient with LLS with fertility problems. A knockout cellular model for MCM8 was generated by CRISPR/Cas9 and detected genetic variants were produced by mutagenesis. DNA damage, microsatellite instability, and mutational signatures were monitored. DNA damage was evident for MCM8KO cells and the analyzed genetic variants. Microsatellite instability and mutational signatures in MCM8KO cells were compatible with the involvement of MCM8 in MMR. Replication in an independent familial cancer cohort detected additional carriers. Unexplained MMR-deficient CRC cases, even showing somatic biallelic MMR inactivation, may be caused by underlying germline defects in genes different than MMR genes. We suggest MCM8 as a gene involved in CRC germline predisposition with a recessive pattern of inheritance.

| S-EPMC7526538 | biostudies-literature

Deficient mismatch repair system in patients with sporadic advanced colorectal cancer.

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

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data