Abstract
BACKGROUND AND AIM: To systematically describe the genotypes and phenotypes of NTHL1-associated tumour syndrome (NATS) cases reported in the literature. METHODS: A systematic review of literature across Medline, Embase and Web of Science was carried out by two independent reviewers. Studies reporting individuals with germline biallelic NTHL1 likely pathogenic/pathogenic variants (PVs) were identified and collected for statistical analysis. RESULTS: In total, 24 studies reported 77 individuals with germline biallelic NTHL1 PVs (51.9% female) from 54 families with 81.8% (63/77) of cases developing at least one cancer [median age at first cancer diagnosis 47 years; range 19–68 years]. The c.244 C > T, p.(Gln82*) PV occurred in 50/54 (92.6%) probands with 31 of these being homozygous and 19 having this PV in compound heterozygosity with another PV. Colorectal cancer occurred in 39/77; (50.6%), with the median age at diagnosis 50 years; range 31–73 years followed by breast cancer 25/77; (32.5%), with median age at diagnosis 47 years; range 36–68 years. Other phenotypes were central nervous system neoplasia, skin, gynecological, urothelial and hematological cancers. Colonic polyposis (≥ 10 polyps of any histology) was observed in 39/70 (55.7%) cases reported to have colonoscopy. In probands, colorectal cancer was the most common indication for genetic testing (38/54; 70.4%) followed by colorectal and breast cancer (8/54; 14.8%). The presence of COSMIC mutational signature SBS30 in a cancer genome may indicate the presence of biallelic NTHL1 deficiency. CONCLUSION: The prevalence of colorectal-, breast, endometrial cancers and meningiomas in this series highlights the importance of surveillance. Findings of this systematic review should inform guidelines for screening and diagnosis. COSMIC mutational signature 30 may assist in defining the tumour spectrum and assessing the pathogenicity of variants of unknown significance. Prospective studies on cancer development in NATS cases, with broader ascertainment, are recommended to further characterize of the cancer spectrum and penetrance. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13053-025-00323-w.