NTHL1 – Breast Cancer

NTHL1 has been implicated in a recessive multi-tumor syndrome with high lifetime risks for colorectal and breast cancers, but its role in breast cancer predisposition among heterozygous carriers is less clear. ClinGen assigns a Limited clinical validity for the NTHL1–breast cancer association due to consistent reports of biallelic loss promoting tumorigenesis, contrasted by mixed population data for heterozygotes.

Inheritance of biallelic loss-of-function (LoF) NTHL1 variants follows an autosomal recessive pattern, giving rise to the NTHL1 tumor syndrome, which includes breast cancer as a core feature. However, segregation data in heterozygous families are lacking, and no additional affected relatives with segregating truncating alleles have been described.

Large case–control series have evaluated heterozygous carriers. In an international study of 27,421 breast cancer cases and 19,759 controls, 138 cases and 93 controls harbored a heterozygous LoF variant (OR 1.06, 95% CI 0.82–1.39) and 316 cases versus 179 controls carried missense variants (OR 1.31, 95% CI 1.09–1.57) (PMID:33980861). A Finnish cohort study of p.(Gln90Ter) carriers (n=1,333) showed no enrichment in cases versus population (5/234 hereditary, 11/1,099 unselected; overall 1.2% vs 1.4% controls; p=0.61) (PMID:32949222).

The variant spectrum includes rare truncating alleles and missense changes within the endonuclease III domain. One recurrent truncating variant, c.268C>T (p.Gln90Ter), represents the major allele in recessive families and is enriched in certain populations.

Functional studies support a haploinsufficiency mechanism: immunohistochemistry of tumors from heterozygous carriers demonstrates reduced NTHL1 expression without the biallelic SBS30 signature; cellular assays reveal that truncated NTHL1 variants impair 5-hydroxyuracil excision and elevate mutation frequency (PMID:30552997).

Conflicting evidence arises from population studies showing no significant risk for heterozygotes (OR 1.06, pNS) and from a case report of benign tumors in a heterozygote suggesting limited penetrance (PMID:34367820).

In summary, biallelic NTHL1 LoF confers a well-established recessive predisposition to breast cancer, whereas heterozygous variants exhibit low to moderate, and at times non-significant, risk. Clinical testing should prioritize detection of biallelic truncating alleles for syndrome diagnosis, with heterozygous findings interpreted cautiously in risk assessments.

Key take-home: NTHL1 biallelic LoF alleles are clinically actionable for recessive breast cancer risk; heterozygous variants carry limited predictive utility.

References

• Molecular Genetics & Genomic Medicine • 2020 • Evaluating the role of NTHL1 p.Q90 allele in inherited breast cancer predisposition.* PMID:32949222
• NPJ Breast Cancer • 2021 • Evaluation of the association of heterozygous germline variants in NTHL1 with breast cancer predisposition: an international multi-center study of 47,180 subjects. PMID:33980861
• NPJ Breast Cancer • 2021 • Investigation of monogenic causes of familial breast cancer: data from the BEACCON case-control study. PMID:34117267
• Scientific Reports • 2023 • NTHL1 is a recessive cancer susceptibility gene. PMID:38036545
• Free Radical Biology & Medicine • 2019 • Defective repair capacity of variant proteins of the DNA glycosylase NTHL1 for 5-hydroxyuracil, an oxidation product of cytosine. PMID:30552997
• Cureus • 2021 • Benign Tumors Associated With Heterozygous NTHL1 Variant. PMID:34367820

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