Exome mutation burden predicts clinical outcome in ovarian cancer carrying mutated BRCA1 and BRCA2 genes

Nicolai Juul Birkbak, Bose Kochupurakkal, Jose Maria Gonzalez-Izarzugaza, Yang Li, Joyce Liu, Zoltan Imre Szallasi, Ursula Matulonis, Andrea L. Richardson, J. Dirk Iglehart, Zhigang C. Wang

    Research output: Contribution to journalConference abstract in journalResearchpeer-review

    Abstract

    Reliable biomarkers predicting resistance or sensitivity to anti-cancer therapy are critical for oncologists to select proper therapeutic drugs in individual cancer patients. Ovarian and breast cancer patients carrying germline mutations in BRCA1 or BRCA2 genes are often sensitive to DNA damaging drugs and relative to non-mutation carriers present a favorable clinical outcome following therapy. Genome sequencing studies have shown a high number of mutations in the tumor genome in patients carrying BRCA1 or BRCA2 mutations (mBRCA). The present study used exome-sequencing and SNP 6 array data of The Cancer Genome Atlas (TCGA) to correlate the total exome mutation number (Nmut) to progression-free survival (PFS) and overall survival (OS) in the patients (n = 316) with high grade serous ovarian cancer (HGSOC) after debulking surgery and platinum-based chemotherapy. HGSOC in 70 patients of this cohort had either germlines or somatic mutations of BRCA1 or BRCA2 genes. The results revealed that the Nmut was significantly lower in the chemotherapy-resistant mBRCA HGSOC defined by progression within 6 months after completion of first line platinum-based chemotherapy. We found a significant association between low Nmut and shorter PFS and OS in mBRCA HGSOC by Cox regression and Kaplan-Meier analyses. The association was also significant when the analysis was limited to germline BRCA1 or BRCA2 mutated patients with SNP array-determined loss of heterozygosity of the BRCA1 or BRCA2 locus in the tumors. In the mBRCA HGSOC tumors, Nmut was correlated with the genome fraction with loss of heterozygosity and with number of telomeric allelic imbalance, genomic measures evaluating chromosomal instability. However, no significant association between Nmut and PFS or OS was found in HGSOC carrying wild-type BRCA1 and BRCA2 genes. These results suggest that in cancers with DNA repair deficiency caused by functional BRCA loss, higher versus lower Nmut may reflect the status of deficiency or rescue by alternative mechanism(s) for DNA repair, with lower Nmut predicting for resistance to DNA-damaging drugs in mBRCA HGSOC. Our observations are consistent with the new concept that BRCA1/2 critically regulate error-free repair of nucleotide damage to suppress mutation formation, and may imply an activation of alternative repair mechanism(s) capable of bypassing the BRCA defect and restoring error-free DNA repair.
    Original languageEnglish
    JournalCancer Research
    Volume73
    Issue numberS1
    ISSN0008-5472
    DOIs
    Publication statusPublished - 2013
    EventAACR 104th Annual Meeting 2013 - Washington, United States
    Duration: 6 Apr 201310 Apr 2013

    Conference

    ConferenceAACR 104th Annual Meeting 2013
    Country/TerritoryUnited States
    CityWashington
    Period06/04/201310/04/2013

    Bibliographical note

    Late breaking poster presentation - Genomic profiling tumors. Abstract LB-255.

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