TY  - JOUR
A1  - Adam, Ronja
A1  - Spier, Isabel
A1  - Zhao, Bixiao
A1  - Kloth, Michael
A1  - Marquez, Jonathan
A1  - Hinrichsen, Inga
A1  - Kirfel, Jutta
A1  - Tafazzoli, Aylar
A1  - Horpaopan, Sukanya
A1  - Uhlhaas, Siegfried
A1  - Stienen, Dietlinde
A1  - Friedrichs, Nicolaus
A1  - Altmüller, Janine
A1  - Laner, Andreas
A1  - Holzapfel, Stefanie
A1  - Peters, Sophia
A1  - Kayser, Katrin
A1  - Thiele, Holger
A1  - Holinski-Feder, Elke
A1  - Marra, Giancarlo
A1  - Kristiansen, Glen
A1  - Nöthen, Markus Maria
A1  - Büttner, Reinhard
A1  - Möslein, Gabriela
A1  - Betz, Regina Christine
A1  - Brieger, Angela
A1  - Lifton, Richard P.
A1  - Aretz, Stefan
T1  - Exome sequencing identifies biallelic MSH3 germline mutations as a recessive subtype of colorectal adenomatous polyposis
T2  - American journal of human genetics
N2  - 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.
KW  - familial colorectal cancer
KW  - adenomatous polyposis
KW  - candidate genes
KW  - mismatch repair
KW  - exome sequencing
KW  - massive parallel sequencing
KW  - hereditary tumor syndromes
Y1  - 2017
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/44031
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-440315
SN  - 0002-9297
SN  - 1537-6605
N1  - © 2016 American Society of Human Genetics.
VL  - 99
IS  - 2
SP  - 337
EP  - 351
PB  - Elsevier ; Cell Press
CY  - New York, NY [u. a.]
ER  -