PARP inhibitors are approved for the treatment of solid tumor types that frequently
harbor alterations in the key homologous recombination (HR) genes, BRCA1/2.
Other tumor types, such as lung cancer, may also be HR deficient, but the frequency
of such cases is less well characterized. Specific DNA aberration profiles (mutational
signatures) are induced by homologous recombination deficiency (HRD) and their presence
can be used to assess the presence or absence of HR deficiency in a given tumor biopsy
even in the absence of an observed alteration of an HR gene. We derived various HRD-associated
mutational signatures from whole-genome and whole-exome sequencing data in the lung
adenocarcinoma and lung squamous carcinoma cases from TCGA, and in a patient of ours
with stage IVA lung cancer with exceptionally good response to platinum-based therapy,
and in lung cancer cell lines. We found that a subset of the investigated cases, both
with and without biallelic loss of BRCA1 or BRCA2,
showed robust signs of HR deficiency. The extreme platinum responder case also showed
a robust HRD-associated genomic mutational profile. HRD-associated mutational signatures
were also associated with PARP inhibitor sensitivity in lung cancer cell lines. Consequently,
lung cancer cases with HRD, as identified by diagnostic mutational signatures, may
benefit from PARP inhibitor therapy.
