NTHL1
Overview
NTHL1 (Nth-like DNA glycosylase 1) encodes a base excision repair (BER) enzyme that removes oxidized pyrimidine bases from DNA. Germline biallelic loss-of-function in NTHL1 causes NTHL1-associated polyposis (NAP), a recessive hereditary cancer predisposition syndrome. NTHL1-deficient tumors exhibit a distinct mutational signature (primarily C>T transitions at CpCpX contexts) and defective mismatch repair (dMMR), predisposing carriers to colorectal cancer and other malignancies.
Alterations observed in the corpus
- Germline biallelic loss-of-function in PanNET patient PN2 in a WGTA study of rare metastatic neuroendocrine neoplasms; drove a strong dMMR mutational signature (previously published by the same group) PMID:24326773
Cancer types (linked)
- Pancreatic neuroendocrine tumor (PanNET) — germline NTHL1 biallelic loss as a predisposing event with dMMR signature PMID:24326773
Co-occurrence and mutual exclusivity
- Associated with dMMR mutational signature in PN2; the germline origin suggests a hereditary predisposition context PMID:24326773
Therapeutic relevance
- dMMR tumors driven by NTHL1 loss may be candidates for immune-checkpoint inhibitor therapy; specific evaluation was not reported for PN2 in this study PMID:24326773
Open questions
- Frequency of germline NTHL1 mutations among PanNET patients is unknown; whether the dMMR phenotype in NTHL1-deficient NENs predicts checkpoint-inhibitor response requires prospective study.
Sources
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