Tumor spectrum in lynch syndrome, DNA mismatch repair system and endogenous carcinogens

Medina-Arana, Vicente; Delgado, L.; Bravo, Alberto; Martín, J. I.; Fernández-Peralta, Antonia M.; González-Aguilera, Juan J.

doi:10.1002/jso.23054

Cited by 8 publications

(5 citation statements)

References 85 publications

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“…At least eight extra-colonic malignancies are associated with LS, including cancers of the endometrium, ovary, stomach, ureter/renal pelvis, brain, small bowel, and hepatobiliary tract as well as sebaceous tumors. In our analysis, endometrial cancer was the most frequent extra-colonic manifestation in carriers of MMR mutations, which is the same as reported in other populations [ 31 , 32 ]. The apparent high incidence of renal pelvic tumors was attributable to a single family that carried an exon 7 deletion of the MSH2 gene.…”

Section: Discussionsupporting

confidence: 90%

Clinical and Molecular Characterization of Brazilian Patients Suspected to Have Lynch Syndrome

et al. 2015

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Lynch syndrome (LS) accounts for 3–5% of all colorectal cancers (CRC) and is inherited in an autosomal dominant fashion. This syndrome is characterized by early CRC onset, high incidence of tumors in the ascending colon, excess of synchronous/metachronous tumors and extra-colonic tumors. Nowadays, LS is regarded of patients who carry deleterious germline mutations in one of the five mismatch repair genes (MMR), mostly in MLH1 and MSH2, but also in MSH6, PMS1 and PMS2. To comprehensively characterize 116 Brazilian patients suspected for LS, we assessed the frequency of germline mutations in the three minor genes MSH6, PMS1 and PMS2 in 82 patients negative for point mutations in MLH1 and MSH2. We also assessed large genomic rearrangements by MLPA for detecting copy number variations (CNVs) in MLH1, MSH2 and MSH6 generating a broad characterization of MMR genes. The complete analysis of the five MMR genes revealed 45 carriers of pathogenic mutations, including 25 in MSH2, 15 in MLH1, four in MSH6 and one in PMS2. Eleven novel pathogenic mutations (6 in MSH2, 4 in MSH6 and one in PMS2), and 11 variants of unknown significance (VUS) were found. Mutations in the MLH1 and MSH2 genes represented 89% of all mutations (40/45), whereas the three MMR genes (MSH6, PMS1 and PMS2) accounted for 11% (5/45). We also investigated the MLH1 p.Leu676Pro VUS located in the PMS2 interaction domain and our results revealed that this variant displayed no defective function in terms of cellular location and heterodimer interaction. Additionally, we assessed the tumor phenotype of a subset of patients and also the frequency of CRC and extra-colonic tumors in 2,365 individuals of the 116 families, generating the first comprehensive portrait of the genetic and clinical aspects of patients suspected of LS in a Brazilian cohort.

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Section: Discussionsupporting

confidence: 90%

Clinical and Molecular Characterization of Brazilian Patients Suspected to Have Lynch Syndrome

et al. 2015

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“…Carriers have a greatly increased lifetime risk of CRC of up to 70%; this CRC is highly preventable by biennial colonoscopy from age 25 onwards but not by iFOBT screening . In addition, carriers are at increased risk for endometrial cancer (13–54%) and various other Lynch syndrome‐associated tumours (LSATs) such as ovarian, stomach, small bowel, biliary or urinary tract and central nervous system cancers (1–15%) .…”

Section: Introductionmentioning

confidence: 99%

An online self‐test added to colorectal cancer screening can increase the effectiveness of familial cancer risk assessment without increasing distress

et al. 2018

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“…The MMR pathway genes, MLH1, MSH2, MSH6 or PMS2 , produce fundamental proteins that are responsible for maintaining DNA integrity, correcting nucleotide mismatches that have been overlooked by the usual editing function of DNA polymerase [13]. Loss of MMR function results in an increased mutation rate through the accumulation of polymerase errors, thus increasing genomic microsatellite instability [14]. Strategies for identifying MMR gene mutation carriers include the evaluation of personal and family cancer history using family pedigrees, molecular diagnostic testing of tumors, clinical prediction models, and germline DNA mutational analysis.…”

Section: Introductionmentioning

confidence: 99%

Clinical characterization and mutation spectrum in Caribbean Hispanic families with Lynch syndrome

et al. 2015

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Lynch Syndrome (LS) is an inherited form of colorectal cancer caused by germline mutations in the Mismatch Repair (MMR) genes. It accounts for approximately 5% of all colorectal cancers. The prevalence of Lynch Syndrome among US Hispanics is unknown. The objective of this study was to describe the germline mutations of Lynch Syndrome in Caribbean Hispanics from Puerto Rico and Dominican Republic. A total of 89 subjects were recruited through the Puerto Rico Familial Colorectal Cancer Registry and were classified according to Amsterdam and Bethesda clinical guidelines. For those tumors with lack of expression of MMR protein, gene sequencing was ordered. A total of 35 individuals with deficient MMR system were identified: 22 had MMR mutations and 13 had tumors with absent MMR protein expression. Our results show that the mutation spectrum of Caribbean Hispanic LS patients was composed mostly of MSH2 (66.7 %) mutations, followed by MLH1 (25.0 %). One mutation was identified in MSH6 (8.3 %). A previously unidentified mutation in MLH1 gene c.2044_2045del was found in one Caribbean Hispanic family. MMR mutation-positive individuals were found to be more likely to have a prominent family history of CRC and tumors located at the proximal colon. Compared to MSH2 mutation carriers, MLH1 mutation-positive individuals were more likely to have a strong family history of CRC and LS associated cancers. Furthermore, insurance coverage for genetic testing was found to be limited in the study population with 65.1% of the individuals recruited were denied coverage. This report presents the first description of the mutation spectrum and clinicopathologic characteristics of LS Caribbean Hispanics patients.

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Tumor spectrum in lynch syndrome, DNA mismatch repair system and endogenous carcinogens

Cited by 8 publications

References 85 publications

Clinical and Molecular Characterization of Brazilian Patients Suspected to Have Lynch Syndrome

Clinical and Molecular Characterization of Brazilian Patients Suspected to Have Lynch Syndrome

An online self‐test added to colorectal cancer screening can increase the effectiveness of familial cancer risk assessment without increasing distress

Clinical characterization and mutation spectrum in Caribbean Hispanic families with Lynch syndrome

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