N19: Colorectal Cancer Risk Is Not Increased In NTHL1 Heterozygous Mutation Carriers

A. Ragunathan1, 3, M. Clendenning1, K. Mahmood1, B. J. Pope1, D. J. Park1, H. Jayasekara1, J. E. Joo1, C. Rosty2, T. Green1, S. Preston1, N. O’Callaghan1, F. A. Macrae3, I. M. Winship3, A. K. Win1, J. L. Hopper1, P. Newcomb4, S. Gallinger5, M. A. Jenkins1, D. D. Buchanan1

1 – University of Melbourne. 2 – University of Queensland. 3 – The Royal Melbourne Hospital. 4 – Fred Hutchinson Cancer Research Center. 5 – Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital.


Aim: Bilallelic loss-of-function germline mutations in the base excision repair gene NTHL1 result in an increased risk of colorectal polyps and different cancer types, resulting in the inclusion of this gene on many multi-gene cancer predisposition panels.  However, the impact of heterozygous germline NTHL1 mutations on colorectal cancer (CRC) risk is unclear.

Method: 1953 CRC-affected individuals and 1207 controls from the Colon Cancer Family Registry Cohort were screened for coding single nucleotide and short indels variants in NTHL1 using a targeted multiplex PCR-based sequencing approach (Hi-PLEX).  Variants were filtered on sequencing depth and allele proportions.  Variants were predicted to be pathogenic if they were novel or rare (gnomAD < 0.05%), protein truncating variants or missense variants predicted to be deleterious (based on CADD>20 or REVEL>0.5).

Results: We detected 22 (1.13%) predicted pathogenic variants in cases and 17 (1.41%) in controls (OR=0.79, 95% CI=0.42-1.48, p=0.51), all carriers were heterozygotes.  The loss-of-function variants identified were not different in frequency between CRC cases (n=5, 0.26%) and controls (n=5, 0.41%; OR=0.62, 95%CI=0.18-2.14, p=0.52), and of similar frequency to rare NTHL1 loss-of-function variants observed in gnomAD (0.199%).

Conclusion: The effect of heterozygous NTHL1 predicted pathogenic variants on CRC risk, if any, is not likely to be more than 1.5 fold.