Multi-ancestry sequencing analysis in 293,141 participants identifies predisposition DNA repair genes associated with HCC risk.

Burden of rare predicted loss-of-function and damaging missense variants in DNA repair genes (MSH6, BRCA2) associated with hepatocellular carcinoma risk.

Whether Lynch- or BRCA1/BRCA2-associated predisposition syndromes relate to hepatocellular carcinoma was unknown. The authors analysed whole exome and whole genome sequencing data from 2,594 hepatocellular carcinoma cases and 290,547 cancer-free controls across five biobanks and cohorts (Penn Medicine BioBank, All of Us, Mayo Clinic, ESCALON, Million Veteran Program) grouped into six population groups, focusing on six DNA repair genes: BRCA2, BRIP1, MSH6, PMS2, CHEK2 and FANCA. In the European population, MSH6 showed the strongest association, with a 2.75-fold increased risk (OR 2.75; 95% CI 1.50-5.04; P = 0.001; q = 0.02) at a 1% minor allele frequency, while PMS2 reached only nominal significance (OR 1.90; 1.08-3.34; P = 0.03; q = 0.09). Combined analysis across all populations strengthened the MSH6 signal (OR 2.53; 1.43-4.49; q = 0.01) and revealed a BRCA2 association (OR 2.26; 1.39-3.67; q = 0.01) at a 0.1% minor allele frequency.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

An odds ratio around 2.5 for a cancer whose incidence depends heavily on acquired liver factors does not, on its own, justify a hepatic surveillance programme in MSH6 or BRCA2 carriers. What is missing to settle the question is the interaction with cirrhosis, viral hepatitis and steatotic liver disease, absent from this analysis. At this stage the contribution is to bring hepatocellular carcinoma into the discussion of the MSH6 tumour spectrum, not to change a surveillance protocol.

Analysis by Dr Thibaut Benquey