Exome-wide analysis of rare deleterious variants in 3,569 sarcoma cases and 21,788 controls from multiple international data sources reveals no novel susceptibility genes.

TP53, NF1

Burden of rare loss-of-function and/or pathogenic or likely pathogenic variants: excess confirmed for TP53 and NF1, no novel susceptibility gene identified

This case-control study pooled germline exome or genome data from six case and four control datasets, totalling 3,569 sarcoma cases and 21,788 controls, analysed by gene-burden testing (SAIGE-GENE). The authors tested 92 autosomal dominant cancer susceptibility genes for loss-of-function and/or pathogenic or likely pathogenic variants, then ran an exome-wide association study (ExWAS) at two tiers: loss-of-function variants only (Tier 1), and loss-of-function plus protein-altering variants (Tier 2). TP53 and NF1, both established sarcoma susceptibility genes, showed a significantly increased variant burden in cases; after excluding known sarcoma genes, a residual excess persisted across the remaining cancer susceptibility genes combined. Despite about 80% power to detect a gene with a relative risk of ≥5 at a population frequency of ≥0.17%, no novel gene was identified. Undiscovered sarcoma susceptibility genes therefore likely have small effect sizes, low frequency, or associations limited to specific rare subtypes.

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

A well-powered negative result is rare and useful: it confirms TP53 and NF1 as the two genes to examine first and makes an additional major gene unlikely across subtypes. The residual excess across the other susceptibility genes combined nevertheless suggests not stopping interpretation at these two genes, which exome or genome sequencing already allows; the abstract does not specify which genes carry this signal. The limitation lies in the heterogeneity of more than 70 subtypes: a gene specific to a rare subtype escapes this design.

Analysis by Dr Thibaut Benquey