The genomic landscape of breast- and non-breast cancers from individuals with germline CHEK2-deficiency.

CHEK2 is considered to be involved in homologous recombination repair (HRR). Individuals who have germline pathogenic variants (gPVs) in CHEK2 are at increased risk to develop breast cancer and likely other primary cancers. PARP inhibitors (PARPi) have been shown to be effective in the treatment of cancers that present with HRR-deficiency, for example caused by inactivation of BRCA1/2. However, clinical trials have shown little-to-no efficacy of PARPi in patients with CHEK2 gPVs. Here, we show that both breast and non-breast cancers from individuals who have biallelic gPVs in CHEK2 (germline CHEK2-deficiency) do not present with molecular profiles that fit with HRR-deficiency. This finding provides a likely explanation why PARPi therapy is not successful in the treatment of CHEK2-deficient cancers.

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© The Author(s) 2024. Published by Oxford University Press.