welcome to oneFAPvoice- a positively charged Familial Adenomatous Polyposis community.
- join today!
Exome Sequencing Identifies Biallelic MSH3 Germline Mutations as a Recessive Subtype of Colorectal Adenomatous Polyposis
source: American Journal of Human Genetics
authors: Adam R, Spier I, Zhao B, Kloth M, Marquez J, Hinrichsen I, Kirfel J, Tafazzoli A, Horpaopan S, Uhlhaas S, Stienen D, Friedrichs N, Altmüller J, Laner A, Holzapfel S, Peters S, Kayser K, Thiele H, Holinski-Feder E, Marra G, Kristiansen G, Nöthen MM, Büttner R, Möslein G, Betz RC, Brieger A, Lifton RP, Aretz Ssummary/abstract:
In ∼30% of families affected by colorectal adenomatous polyposis, no germline mutations have been identified in the previously implicated genes APC, MUTYH, POLE, POLD1, and NTHL1, although a hereditary etiology is likely. To uncover further genes with high-penetrance causative mutations, we performed exome sequencing of leukocyte DNA from 102 unrelated individuals with unexplained adenomatous polyposis. We identified two unrelated individuals with differing compound-heterozygous loss-of-function (LoF) germline mutations in the mismatch-repair gene MSH3. The impact of the MSH3 mutations (c.1148delA, c.2319-1G>A, c.2760delC, and c.3001-2A>C) was indicated at the RNA and protein levels. Analysis of the diseased individuals’ tumor tissue demonstrated high microsatellite instability of di- and tetranucleotides (EMAST), and immunohistochemical staining illustrated a complete loss of nuclear MSH3 in normal and tumor tissue, confirming the LoF effect and causal relevance of the mutations. The pedigrees, genotypes, and frequency of MSH3 mutations in the general population are consistent with an autosomal-recessive mode of inheritance. Both index persons have an affected sibling carrying the same mutations. The tumor spectrum in these four persons comprised colorectal and duodenal adenomas, colorectal cancer, gastric cancer, and an early-onset astrocytoma. Additionally, we detected one unrelated individual with biallelic PMS2 germline mutations, representing constitutional mismatch-repair deficiency. Potentially causative variants in 14 more candidate genes identified in 26 other individuals require further workup. In the present study, we identified biallelic germline MSH3 mutations in individuals with a suspected hereditary tumor syndrome. Our data suggest that MSH3 mutations represent an additional recessive subtype of colorectal adenomatous polyposis.organization: Center for Hereditary Tumor Syndromes University of Bonn, Yale University School of Medicine, Goethe-University Frankfurt, University of Cologne, HELIOS Klinikum Wuppertal University of Witten/Herdecke
read more full text source
expertly curated content related to this topic
Education and Management of Patients with Familial Adenomatous Polyposis. Are We Making Progress? A Case ReportAbstract: A 25-year-old male patient was...
Genotype and Phenotype of Patients with Both Familial Adenomatous Polyposis and Thyroid CarcinomaThe incidence of thyroid carcinoma in fa...
Familial Investigations of Childhood Cancer PredispositionWhile it is well recognized that heredit...
Familial Adenomatous Polyposis and Other Polyposis SyndromesThis book discusses Familial Adenomatou...
Rare Case of Intraintestinal Stromal Tumors in the Patient with Familial Adenomatous PolyposisAIM : To describe the case of metachrono...
Different Phenotype Manifestation of Familial Adenomatous Polyposis in Families with APC Mutation at Codon 1309Germline mutation in APC gene induced de...
Three Novel Mutations of the APC Gene in Korean Patients with Familial Adenomatous PolyposisGermline mutations within the adenomatou...