Abstract
Gene breakage, reversion mutations, and promoter fusions drive chemotherapy resistance in HGSC.
Major finding: Gene breakage, reversion mutations, and promoter fusions drive chemotherapy resistance in HGSC.
Approach: Whole-genome sequencing identified chemoresistance mechanisms in a large cohort of HGSCs.
Impact: The selective pressure of chemotherapy promotes structural variants that drive resistance in HGSC.
Recurrent chemotherapy-resistant high-grade serous ovarian cancer (HGSC) is a deadly disease with few therapeutic options. Genomic characterization of primary HGSC has highlighted frequent TP53 mutations, extensive copy-number changes, intratumoral heterogeneity, and inactivation of homologous recombination repair; however, little is known about the genomic drivers of resistant disease progression. To address this question, Patch and colleagues performed whole-genome sequencing combined with transcriptome, methylation, and microRNA analyses of primary sensitive and refractory HGSC, paired primary sensitive and relapsed-resistant tumors, and samples from patients with HGSC who underwent rapid autopsy. Analysis of 114 tumor samples from 92 patients based on their level of genomic alterations revealed a subset of tumors with many rearrangements and tumors with a low frequency of scattered breakpoints or numerous breaks in a few chromosomes. Of note, gene breakage events frequently inactivated the NF1, RB1, PTEN, and RAD51B tumor suppressor genes. Both age- and BRCA-associated mutational signatures were dominant across tumor samples. Comparison of genomic variation with primary tumor response highlighted the association of CCNE1 amplification with refractive disease. Analysis of tumor cells collected from ascites before and after relapse revealed that the overall mutational burden increased upon recurrence and with subsequent rounds of therapy, and that multiple subclonal reversion mutations in BRCA1 or BRCA2, loss of BRCA1 promoter methylation, and a change in HGSC molecular subtype were detected in tumors with acquired resistance. In addition, recurrent promoter fusion events involving ABCB1, which led to increased expression of the drug efflux pump multidrug resistance protein 1, were also identified in resistant tumors previously exposed to chemotherapy. Together, these data suggest that gene breakage represents a mechanism of tumor suppressor inactivation in HGSC and highlight diverse structural genomic aberrations that contribute to chemotherapy resistance in primary and recurrent tumors.