Non-Lynch Familial and Early-Onset Colorectal Cancer Explained by Accumulation of Low-Risk Genetic Variants.
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SUBMITTER: Mur P
PROVIDER: S-EPMC8345397 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Background & aimsColorectal cancer (CRC) is uncommon in individuals <50 years old. Lynch syndrome is caused by germline mutations in DNA mismatch repair (MMR) genes and associated with early-onset CRC, but little is known about the proportion of young patients with apparently sporadic CRC who actually have Lynch syndrome. We examined patterns of microsatellite instability (MSI) and MMR genes among patients <50 years old with non-familial CRC (patients with not more than 1 family member with CRC).MethodsTissue specimens were collected from 75 CRC patients <50 years old (mean age, 34.5 years) and analyzed using immunohistochemical analyses of MLH1, MSH2, MSH6, and PMS2. MSI and mutations in BRAF and KRAS were also analyzed.ResultsMost cancers (72%) arose in the distal colon. MSI was detected in 21% of the samples, and loss of 1 or more MMR proteins was observed in 21%. Interestingly, only 38% of the MMR-deficient CRCs lost either MLH1 or MSH2, whereas 63% of the MMR-deficient CRC samples lost either PMS2 or MSH6. All 11 CRC samples that had lost MSH2, MLH1, or PMS2 had MSI, but only 2 of the 5 tumors that lost only MSH6 had MSI. There were no BRAF mutations in any tumor.ConclusionsIn young patients with apparently sporadic CRC, most tumors arise in the distal colon; only 21% have features of Lynch syndrome. Loss of MSH6 or PMS2 occurred in 13.3% of these tumors. Most tumors that lose MSH6 will not be detected in screens for MSI; CRC screening might be modified to identify more patients with Lynch syndrome.
| S-EPMC2964436 | biostudies-literature
Project description:BackgroundFamilial Colorectal Cancer Type X (FCCTX) is defined as individuals with colorectal cancer (CRC) who families meet Amsterdam Criteria-1 (AC1), but whose tumours are DNA-mismatch-repair-proficient, unlike Lynch syndrome (LS). FCCTX does not have an increased risk of extra-colonic cancers. This analysis compares epidemiologic and clinicopathologic features among FCCTX, LS, and 'non-familial' (non-AC1) CRC cases.MethodsFrom the Colon Cancer Family Registry, FCCTX (n=173), LS (n=303), and non-AC1 (n=9603) CRC cases were identified. Questionnaire-based epidemiologic information and CRC pathologic features were compared across case groups using polytomous logistic regression.ResultsCompared with LS, FCCTX cases were less likely to be current (vs never) smokers; have a proximal subsite (vs rectal) tumour; or have mucinous histology, poor differentiation, or tumour-infiltrating lymphocytes. There were no observed differences in co-morbidities or medication usage.ConclusionsFCCTX were less likely to be current tobacco users; other exposures were similar between these groups. Histopathologic differences highly suggestive of LS CRCs do not appear to be shared by FCCTX.
| S-EPMC4119982 | biostudies-literature
Project description:To investigate whether whole-exome sequencing may serve as an efficient method to identify known or novel colorectal cancer (CRC) predisposing genes in early-onset or familial CRC cases.We performed whole-exome sequencing in 23 Chinese patients from 21 families with non-polyposis CRC diagnosed at ? 40 years of age, or from multiple affected CRC families with at least 1 first-degree relative diagnosed with CRC at ? 55 years of age. Genomic DNA from blood was enriched for exome sequences using the SureSelect Human All Exon Kit, version 2 (Agilent Technologies) and sequencing was performed on an Illumina HiSeq 2000 platform. Data were processed through an analytical pipeline to search for rare germline variants in known or novel CRC predisposing genes.In total, 32 germline variants in 23 genes were identified and confirmed by Sanger sequencing. In 6 of the 21 families (29%), we identified 7 mutations in 3 known CRC predisposing genes including MLH1 (5 patients), MSH2 (1 patient), and MUTYH (biallelic, 1 patient), five of which were reported as pathogenic. In the remaining 15 families, we identified 20 rare and novel potentially deleterious variants in 19 genes, six of which were truncating mutations. One previously unreported variant identified in a conserved region of EIF2AK4 (p.Glu738_Asp739insArgArg) was found to represent a local Chinese variant, which was significantly enriched in our early-onset CRC patient cohort compared to a control cohort of 100 healthy Chinese individuals scored negative by colonoscopy (33.3% vs 7%, P < 0.001).Whole-exome sequencing of early-onset or familial CRC cases serves as an efficient method to identify known and potential pathogenic variants in established and novel candidate CRC predisposing genes.
| S-EPMC4394074 | biostudies-literature
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
Project description:INTRODUCTION: Several studies evaluated the prevalence of Lynch Syndrome (LS) in young onset colorectal cancer (CRC) patients and the results were extremely variable (5%-20%). Immunohistochemistry (IHC) for MMR proteins and/or MSI analysis are screening tests that are done, either by themselves or in conjunction, on colon cancer tissue to identify individuals at risk for LS. The primary aim of our study was to evaluate the prevalence of LS in a large series of early-onset CRC without family history compared with those with family history. The secondary aim was to assess the diagnostic accuracy of IHC and MSI analysis as pre-screening tools for LS. METHODS: Early-onset CRC patients (? 50 years) were prospectively recruited in the study. IHC and MSI analysis were performed in all the patients. Germ-line mutation analysis (GMA) was carried out in all MMR deficient tumors. A logistic regression model was performed to identify clinical features predictive of MSI-H. RESULTS: 117 early onset CRC cases were categorized in three groups (A, B, C) according with family history of CRC. IHC and MSI analysis showed MMR deficiency in 6/70 patients (8.6%) of group A, 24/40 patients (60%) of group B and none of group C. GMA showed a deleterious mutation in 19 (47.5%) patients of group B. MSI analysis had a diagnostic accuracy of 95.7% (CI 92.1-99.4) and IHC of 83.8% (CI 77.1-90.4). The logistic regression model revealed that by using a combination of the two features "No Amsterdam Criteria" and "left sided CRC" to exclude MSI-H, accuracy was 89.7% (84.2-95.2). CONCLUSIONS: Early-onset CRC patients, with left sided CRC and without family history are "at very low risk" for Lynch syndrome. The two simple criteria of family history and CRC site could be used as a pre-screening tool to evaluate whether or not patients should undergo tissue molecular screening. In the few cases of suspected LS (right sided CRC and/or Amsterdam Criteria), a reasonable approach could be to perform MSI analysis first and IHC afterwards only in MSI-H patients.
| S-EPMC3892010 | biostudies-literature
Project description:In the majority of colorectal cancers (CRC) under clinical suspicion for a hereditary cause, the disease-causing genetic factors are still to be discovered. In order to identify such genetic factors we stringently selected a discovery cohort of 41 CRC index patients with microsatellite-stable tumors. All patients were below 40 years of age at diagnosis and/or exhibited an overt family history. We employed genome-wide copy number profiling using high-resolution SNP-based array CGH on germline DNA, which resulted in the identification of novel copy number variants (CNVs) in 6 patients (15%) encompassing, among others, the cadherin gene CDH18, the bone morphogenetic protein antagonist family gene GREM1, and the breakpoint cluster region gene BCR. In addition, two genomic deletions were encountered encompassing two microRNA genes, hsa-mir-491/KIAA1797 and hsa-mir-646/AK309218. None of these CNVs has previously been reported in relation to CRC predisposition in humans, nor were they encountered in large control cohorts (>1,600 unaffected individuals). Since several of these newly identified candidate genes may be functionally linked to CRC development, our results illustrate the potential of this approach for the identification of novel candidate genes involved in CRC predisposition. Copy number detection was performed using CNAG2.0 software for 250k SNP arrays and using the Affymetrix Genotyping Console v2.1 software for SNP 6.0 arrays, Reference genomes are included in this data set. Germline genomic DNA from 41 patients with early-onset microsatellite stable colorectal cancer was hybridized on Affymetrix Nsp/6.0 SNP-based arrays according to manufacturer's procedures.
2010-11-01 | E-GEOD-13429 | biostudies-arrayexpress
Project description:Lynch syndrome is an autosomal dominant syndrome of familial malignancies resulting from germ line mutations in DNA mismatch repair (MMR) genes. Our goal was to take a pathway-based approach to investigate the influence of polymorphisms in cell cycle-related genes on age of onset for Lynch syndrome using a tree model.We evaluated polymorphisms in a panel of cell cycle-related genes (AURKA, CDKN2A, TP53, E2F2, CCND1, TP73, MDM2, IGF1, and CDKN2B) in 220 MMR gene mutation carriers from 129 families. We applied a novel statistical approach, tree modeling (Classification and Regression Tree), to the analysis of data on patients with Lynch syndrome to identify individuals with a higher probability of developing colorectal cancer at an early age and explore the gene-gene interactions between polymorphisms in cell cycle genes.We found that the subgroup with CDKN2A C580T wild-type genotype, IGF1 CA-repeats >or=19, E2F2 variant genotype, AURKA wild-type genotype, and CCND1 variant genotype had the youngest age of onset, with a 45-year median onset age, while the subgroup with CDKN2A C580T wild-type genotype, IGF1 CA-repeats >or=19, E2F2 wild-type genotype, and AURKA variant genotype had the latest median age of onset, which was 70 years. Furthermore, we found evidence of a possible gene-gene interaction between E2F2 and AURKA genes related to CRC age of onset.Polymorphisms in these cell cycle-related genes work together to modify the age at the onset of CRC in patients with Lynch syndrome. These studies provide an important part of the foundation for development of a model for stratifying age of onset risk among those with Lynch syndrome.
| S-EPMC3917505 | biostudies-literature
Project description:In the majority of colorectal cancers (CRC) under clinical suspicion for a hereditary cause, the disease-causing genetic factors are still to be discovered. In order to identify such genetic factors we stringently selected a discovery cohort of 41 CRC index patients with microsatellite-stable tumors. All patients were below 40 years of age at diagnosis and/or exhibited an overt family history. We employed genome-wide copy number profiling using high-resolution SNP-based array CGH on germline DNA, which resulted in the identification of novel copy number variants (CNVs) in 6 patients (15%) encompassing, among others, the cadherin gene CDH18, the bone morphogenetic protein antagonist family gene GREM1, and the breakpoint cluster region gene BCR. In addition, two genomic deletions were encountered encompassing two microRNA genes, hsa-mir-491/KIAA1797 and hsa-mir-646/AK309218. None of these CNVs has previously been reported in relation to CRC predisposition in humans, nor were they encountered in large control cohorts (>1,600 unaffected individuals). Since several of these newly identified candidate genes may be functionally linked to CRC development, our results illustrate the potential of this approach for the identification of novel candidate genes involved in CRC predisposition. Copy number detection was performed using CNAG2.0 software for 250k SNP arrays and using the Affymetrix Genotyping Console v2.1 software for SNP 6.0 arrays, Reference genomes are included in this data set.
2010-11-01 | GSE13429 | GEO
Project description:In 20-30% of patients suspected of a familial colorectal cancer (CRC) syndrome, no underlying genetic cause is detected. Recent advances in whole exome sequencing have generated evidence for new CRC-susceptibility genes including POLE, POLD1 and NTHL1¸ but many patients remain unexplained. Whole exome sequencing was performed on DNA from nine patients from five different families with familial clusters of CRC in which traditional genetic testing failed to yield a diagnosis. Variants were filtered by minor allele frequencies, followed by prioritization based on in silico prediction tools, and the presence in cancer susceptibility genes or genes in cancer-associated pathways. Effects of frameshift variants on protein structure were modeled using I-Tasser. One known pathogenic variant in POLD1 was detected (p.S478N), together with variants in 17 candidate genes not previously associated with CRC. Additional in silico analysis using SIFT, PROVEAN and PolyPhen on the 14 missense variants indicated a possible damaging effect in nine of 14 variants. Modeling of the insertions/deletions showed a damaging effect of two variants in NOTCH2 and CYP1B1. One family was explained by a mutation in a known familial CRC gene. In the remaining four families, the most promising candidates found are a frameshift NOTCH2 and a missense RAB25 variant. This study provides potential novel candidate variants in unexplained familial CRC patients, however, functional validation is imperative to confirm the role of these variants in CRC tumorigenesis. Additionally, while whole exome sequencing enables detection of variants throughout the exome, other causes explaining the familial phenotype such as multiple single nucleotide polymorphisms accumulating to a polygenic risk or epigenetic events, might be missed with this approach.
| S-EPMC7241873 | biostudies-literature
Project description:Family history is a major risk factor for colorectal cancer and many families segregate the disease as a seemingly monogenic trait. A minority of familial colorectal cancer could be explained by known monogenic genes and genetic loci. Familial polyposis and Lynch syndrome are two syndromes where the predisposing genes are known but numerous families have been tested without finding the predisposing gene. We performed a genome wide linkage analysis in 121 colorectal families with an increased risk of colorectal cancer. The families were ascertained from the department of clinical genetics at the Karolinska University Hospital in Stockholm, Sweden and were considered negative for Familial Polyposis and Lynch syndrome. In total 600 subjects were genotyped using single nucleotide polymorphism array chips. Parametric- and non-parametric linkage analyses were computed using MERLIN in all and subsets of families. No statistically significant result was seen, however, there were suggestive positive HLODs above two in parametric linkage analysis. This was observed in a recessive model for high-risk families, at locus 9q31.1 (HLOD=2.2, rs1338121) and for moderate-risk families, at locus Xp22.33 (LOD=2.2 and HLOD=2.5, rs2306737). Using families with early-onset, recessive analysis suggested one locus on 4p16.3 (LOD=2.2, rs920683) and one on 17p13.2 (LOD/HLOD=2.0, rs884250). No NPL score above two was seen for any of the families. Our linkage study provided additional support for the previously suggested region on chromosome 9 and suggested additional loci to be involved in colorectal cancer risk. Sequencing of genes in the regions will be done in future studies.
| S-EPMC3859667 | biostudies-literature