Exome Sequencing Identifies Biallelic MSH3 Germline Mutations as a Recessive Subtype of Colorectal Adenomatous Polyposis.

TitleExome Sequencing Identifies Biallelic MSH3 Germline Mutations as a Recessive Subtype of Colorectal Adenomatous Polyposis.
Publication TypeJournal Article
Year of Publication2016
AuthorsAdam, 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, S
JournalAm J Hum Genet
Date Published2016 Aug 04
KeywordsAdenomatous Polyposis Coli, Adolescent, Adult, Alleles, Child, Preschool, Colorectal Neoplasms, DNA Mutational Analysis, DNA-Binding Proteins, Exome, Female, Genes, Recessive, Germ-Line Mutation, Humans, Male, Middle Aged, Mismatch Repair Endonuclease PMS2, MutS Homolog 3 Protein, Pedigree

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.

Alternate JournalAm. J. Hum. Genet.
PubMed ID27476653
PubMed Central IDPMC4974087
Grant ListT32 GM007205 / GM / NIGMS NIH HHS / United States
U54 HG006504 / HG / NHGRI NIH HHS / United States
UL1 TR001863 / TR / NCATS NIH HHS / United States
UM1 HG006504 / HG / NHGRI NIH HHS / United States