TY - JOUR
T1 - A germline homozygous mutation in the base-excision repair gene NTHL1 causes adenomatous polyposis and colorectal cancer
AU - Weren, Robbert D A
AU - Ligtenberg, Marjolijn J L
AU - Kets, C. Marleen
AU - De Voer, Richarda M.
AU - Verwiel, Eugène T P
AU - Spruijt, Liesbeth
AU - Van Zelst-Stams, Wendy A G
AU - Jongmans, Marjolijn C.
AU - Gilissen, Christian
AU - Hehir-Kwa, Jayne Y.
AU - Hoischen, Alexander
AU - Shendure, Jay
AU - Boyle, Evan A.
AU - Kamping, Eveline J.
AU - Nagtegaal, Iris D.
AU - Tops, Bastiaan B J
AU - Nagengast, Fokko M.
AU - Geurts Van Kessel, Ad
AU - Van Krieken, J. Han J M
AU - Kuiper, Roland P.
AU - Hoogerbrugge, Nicoline
PY - 2015/5/27
Y1 - 2015/5/27
N2 - The genetic cause underlying the development of multiple colonic adenomas, the premalignant precursors of colorectal cancer (CRC), frequently remains unresolved in patients with adenomatous polyposis. Here we applied whole-exome sequencing to 51 individuals with multiple colonic adenomas from 48 families. In seven affected individuals from three unrelated families, we identified a homozygous germline nonsense mutation in the base-excision repair (BER) gene NTHL1. This mutation was exclusively found in a heterozygous state in controls (minor allele frequency of 0.0036; n = 2,329). All three families showed recessive inheritance of the adenomatous polyposis phenotype and progression to CRC in at least one member. All three affected women developed an endometrial malignancy or premalignancy. Genetic analysis of three carcinomas and five adenomas from different affected individuals showed a non-hypermutated profile enriched for cytosine-to-thymine transitions. We conclude that a homozygous loss-of-function germline mutation in the NTHL1 gene predisposes to a new subtype of BER-associated adenomatous polyposis and CRC.
AB - The genetic cause underlying the development of multiple colonic adenomas, the premalignant precursors of colorectal cancer (CRC), frequently remains unresolved in patients with adenomatous polyposis. Here we applied whole-exome sequencing to 51 individuals with multiple colonic adenomas from 48 families. In seven affected individuals from three unrelated families, we identified a homozygous germline nonsense mutation in the base-excision repair (BER) gene NTHL1. This mutation was exclusively found in a heterozygous state in controls (minor allele frequency of 0.0036; n = 2,329). All three families showed recessive inheritance of the adenomatous polyposis phenotype and progression to CRC in at least one member. All three affected women developed an endometrial malignancy or premalignancy. Genetic analysis of three carcinomas and five adenomas from different affected individuals showed a non-hypermutated profile enriched for cytosine-to-thymine transitions. We conclude that a homozygous loss-of-function germline mutation in the NTHL1 gene predisposes to a new subtype of BER-associated adenomatous polyposis and CRC.
UR - http://www.scopus.com/inward/record.url?scp=84930084903&partnerID=8YFLogxK
U2 - 10.1038/ng.3287
DO - 10.1038/ng.3287
M3 - Letter
C2 - 25938944
AN - SCOPUS:84930084903
SN - 1061-4036
VL - 47
SP - 668
EP - 671
JO - Nature Genetics
JF - Nature Genetics
IS - 6
ER -