source: European Journal of Human Genetics
R.D.A. Weren, M.J.L Ligtenberg, C.M. Kets, R.M. de Voer, E.T.P. Verwiel, L. Spruijt, W.A.G. van Zelst-Stams, M.C. Jongmans, C. Gilissen, J.Y. Hehir-Kwa, A. Hoischen, J. Shendure, E.A. Boyle, E.J. Kamping, I.D. Nagtegaal, B.B.J. Tops, F.M. Nagengast, A. Geurts van Kessel, J.H.J.M. van Krieken, R.P. Kuiper, N. Hoogerbrugge
Introduction: Patients diagnosed with adenomatous polyposis, i.e., the constitutive development of multiple colorectal adenomatous polyps, are at an increased risk to develop colorectal cancer (CRC). Currently, two adenomatous polyposis-associated syndromes are known: familial adenomatous polyposis (FAP) and MUTYH-associated polyposis (MAP). Whereas monoallelic APC germline mutations underlie FAP, MAP is caused by biallelic germline mutations in the base excision repair (BER) gene MUTYH. No other causative genes have been identified and, therefore, a considerable fraction of adenomatous polyposis patients remains unexplained.
Materials and Methods: Whole-exome sequencing was applied to germline DNA derived from 51 individuals (from 48 families) with multiple colonic adenomas. After candidate gene selection, co-segregation analyses were performed. The somatic mutation spectrum of carcinomas and adenomas was determined by sequencing of 409 cancer-related genes and by targeted deep-sequencing of the APC gene, respectively.
Results: We identified a homozygous germline nonsense mutation in the BER gene NTHL1 in seven affected individuals from three unrelated families. All three families showed recessive inheritance of the adenomatous polyposis phenotype, which was consistently and exclusively encountered in homozygous carriers, indicating a high-penetrant predisposing effect. In controls, this germline mutation was only found in a heterozygous state (MAF 0.0036, n=2,329). Sequence analysis of carcinomas and adenomas from different affected homozygous carriers revealed a non-hypermutated profile enriched for C-to-T transitions, in line with a germline BER defect.
Conclusions: We show for the first time that a homozygous loss-of-function germline mutation in the NTHL1 gene predisposes to a novel subtype of BER-associated adenomatous polyposis and CRC.
Radboud university medical center, University of Washington