Monoallelic NTHL1 Loss of Function Not Associated With Colorectal Cancer

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.