The pleiotropic landscape of rare variant associations with multiple cancers in large biobanks.

Rare germline loss-of-function or missense variants in pleiotropic genes, including CHEK2 and RTEL1, associated with the risk of several cancer types.

Association studies of rare germline variation and cancer risk have mostly covered a limited number of cancers in clinical samples of predominantly European genetic ancestry. The authors ran exome-wide rare variant association analyses across more than 70 cancer types in over 729,000 participants from the UK Biobank and the All of Us Research Program, using generalized linear mixed models with gene-based and single-variant tests of predicted loss-of-function (pLoF) and missense variants across six biologically and aetiologically defined cancer groups. Significant genes were then tested against 27 individual cancer types with at least 500 cases. Of 33 candidate pleiotropic genes, 16 showed consistent associations with three or more individual cancers. Carrying at least one CHEK2 pLoF variant was associated with higher odds of 14 different cancers (OR range 1.34-3.21), whereas at least one RTEL1 missense variant was associated with lower odds of 9 cancers (OR range 0.67-0.88).

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

The scale and the use of two independent cohorts are the strengths here, but most reported odds ratios are modest and are not converted into age-specific absolute risks, the only figures that would justify widening surveillance for a CHEK2 pLoF carrier beyond the organs already covered. Cancer status in these biobanks relies on registry and self-reported data of uneven quality, and the protective signal for RTEL1 missense variants needs replication and functional support before it can be used in genetic counselling. As it stands this is a map that should direct targeted follow-up studies rather than a document that changes carrier management.

Analysis by Dr Thibaut Benquey