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Pan-cancer landscape of homologous recombination deficiency

Author

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  • Luan Nguyen

    (University Medical Center Utrecht)

  • John Martens

    (Erasmus University Medical Center
    Center for Personalized Cancer Treatment)

  • Arne Hoeck

    (University Medical Center Utrecht)

  • Edwin Cuppen

    (University Medical Center Utrecht
    Hartwig Medical Foundation)

Abstract

Homologous recombination deficiency (HRD) results in impaired double strand break repair and is a frequent driver of tumorigenesis. Here, we develop a genome-wide mutational scar-based pan-cancer Classifier of HOmologous Recombination Deficiency (CHORD) that can discriminate BRCA1- and BRCA2-subtypes. Analysis of a metastatic (n = 3,504) and primary (n = 1,854) pan-cancer cohort reveals that HRD is most frequent in ovarian and breast cancer, followed by pancreatic and prostate cancer. We identify biallelic inactivation of BRCA1, BRCA2, RAD51C or PALB2 as the most common genetic cause of HRD, with RAD51C and PALB2 inactivation resulting in BRCA2-type HRD. We find that while the specific genetic cause of HRD is cancer type specific, biallelic inactivation is predominantly associated with loss-of-heterozygosity (LOH), with increased contribution of deep deletions in prostate cancer. Our results demonstrate the value of pan-cancer genomics-based HRD testing and its potential diagnostic value for patient stratification towards treatment with e.g. poly ADP-ribose polymerase inhibitors (PARPi).

Suggested Citation

  • Luan Nguyen & John Martens & Arne Hoeck & Edwin Cuppen, 2020. "Pan-cancer landscape of homologous recombination deficiency," Nature Communications, Nature, vol. 11(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-19406-4
    DOI: 10.1038/s41467-020-19406-4
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