In a recent paper published in Nature Genetics, Robbert Weren, Dept. of Human Genetics and colleagues describe the identification of a novel autosomal recessive colorectal cancer syndrome caused by a homozygous nonsense mutation in the base excision repair gene NTHL1.
The syndrome is associated with increased numbers of colonic adenomas, referred to as adenomatous polyposis. NTHL1 encodes one of the DNA glycosylases of the base excision repair pathway. Three families were identified with, in total, 7 affected individuals with adenomatous polyps, colorectal cancer or endometrial malignancies and pre-malignancies. The causal relationship between the base excision repair defect and the polyposis phenotype was further established by revealing the presence of a mutation spectrum strongly biased towards C:G>T:A transitions, which correlates with a defect in NTHL1 function. NTHL1-associated polyposis is, next to MUTYH-associated polyposis, the second colorectal cancer syndrome caused by a base excision repair defect. Both syndromes show an autosomal recessive inheritance pattern. In contrast to other colorectal cancer syndromes, children of affected individuals will not be at increased risk, which is of high relevance for the families involved.
Robbert D.A. Weren, Marjolijn J.L. Ligtenberg, C. Marleen Kets, Richarda M. de Voer, Eugène T. P. Verwiel, Liesbeth Spruijt, Wendy A.G. van Zelst‐Stams, Marjolijn C. Jongmans, Christian Gilissen, Jayne Y. Hehir‐Kwa, Alexander Hoischen, Jay Shendure, Evan A. Boyle, Eveline J. Kamping, Iris D. Nagtegaal, Bastiaan B.J. Tops, Fokko M. Nagengast, Ad Geurts van Kessel, J. Han J.M. van Krieken, Roland P. Kuiper, Nicoline Hoogerbrugge. A germline homozygous mutation in the base excision repair gene NTHL1 causes adenomatous polyposis and colorectal cancer. Nat Genet. 2015
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