A subset of lung cancer cases shows robust signs of homologous recombination deficiency associated genomic mutational signatures

Miklos Diossy, Zsofia Sztupinszki, Judit Borcsok, Marcin Krzystanek, Viktoria Tisza, Sandor Spisak, Orsolya Rusz, Jozsef Timar, István Csabai, Janos Fillinger, Judit Moldvay, Anders Gorm Pedersen, David Szuts, Zoltan Szallasi*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

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Abstract

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.

Original languageEnglish
Article number55
Journaln p j Precision Oncology
Volume5
Issue number1
Number of pages8
ISSN2397-768X
DOIs
Publication statusPublished - 2021

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