Monoallelic NTHL1 Loss of Function Not Associated With Colorectal Cancer

Monoallelic NTHL1 Loss of Function Not Associated With Colorectal Cancer

Douglas K. Rex, MD, MASGE, reviewing Elsayed FA, et al. Gastroenterology 2020 Aug 26.

NTHL1 encodes endonuclease III-like protein 1, an enzyme involved in base-excision repair that identifies and removes oxidized pyrimidines. Biallelic loss-of-function mutations of base-excision repair genes, such as MUTYH and NTHL1, are known to predispose to colorectal polyps and colorectal cancer (CRC). Monoallelic MUTYH mutations are also known to confer a small increased risk of colorectal cancer; however, the significance of monoallelic NTHL1 loss-of-function mutations (which represent 0.28% of the general population) is not currently known.

In a study of 5492 individuals with unexplained polyposis, familial CRC, sporadic CRC at a young age, or suspected Lynch syndrome with CRC or multiple adenomas, the authors found no association between monoallelic NTHL1 carriers and risk of polyposis and/or CRC. Further, colorectal tumors from monoallelic NTHL1 loss-of-function carriers did not show evidence of a second hit in NTHL1. However, the authors were unable to rule out a small risk of CRC similar to what has been observed for MUTYH carriers.

Douglas K. Rex, MD, FASGE

COMMENT

MUTYH carriers are considered to have a small increased risk of CRC, but these data suggest that monoallelic NTHL1 is not associated with increased risk and may not warrant increased screening or surveillance when detected. 

Note to readers: At the time we reviewed this paper, its publisher noted that it was not in final form and that subsequent changes might be made.

CITATION(S)

Elsayed FA, Grolleman JE, Ragunathan A, et al. Monoallelic NTHL1 loss of function variants and risk of polyposis and colorectal cancer. Gastroenterology 2020 Aug 26. (Epub ahead of print) (https://doi.org/10.1053/j.gastro.2020.08.042)

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