Profiles of genomic instability in high-grade serous ovarian cancer predict treatment outcome

Abstract

Purpose: High-grade serous cancer (HGSC) is the most common cancer of the ovary and is characterized by chromosomal instability. Defects in homologous recombination repair (HRR) are associated with genomic instability in HGSC, and are exploited by therapy targeting DNA repair. Defective HRR causes uniparental deletions and loss of heterozygosity (LOH). Our purpose is to profile LOH in HGSC and correlate our findings to clinical outcome, and compare HGSC and high-grade breast cancers.

Experimental design: We examined LOH and copy number changes using single nucleotide polymorphism array data from three HGSC cohorts and compared results to a cohort of high-grade breast cancers. The LOH profiles in HGSC were matched to chemotherapy resistance and progression-free survival (PFS).

Results: LOH-based clustering divided HGSC into two clusters. The major group displayed extensive LOH and was further divided into two subgroups. The second group contained remarkably less LOH. BRCA1 promoter methylation was associated with the major group. LOH clusters were reproducible when validated in two independent HGSC datasets. LOH burden in the major cluster of HGSC was similar to triple-negative, and distinct from other high-grade breast cancers. Our analysis revealed an LOH cluster with lower treatment resistance and a significant correlation between LOH burden and PFS.

Conclusions: Separating HGSC by LOH-based clustering produces remarkably stable subgroups in three different cohorts. Patients in the various LOH clusters differed with respect to chemotherapy resistance, and the extent of LOH correlated with PFS. LOH burden may indicate vulnerability to treatment targeting DNA repair, such as PARP1 inhibitors.

Conflict of interest statement

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

©2012 AACR

Figures

Figure 1

LOH-based hierarchical clustering of HGSC. A, LOH-based clustering of 47 ovarian cancers. The clustering dendrogram is depicted at the top, and each column represents the genome-wide status of heterozygosity; yellow, region of retained heterozygosity; blue, region of LOH. Chromosome location is indicated on the vertical axis. B, box plots depicting fraction of LOH (FLOH) for HGSC in cluster Lo and cluster HiA and HiB from A. The horizontal line within the box is the median value of FLOH. C, box plots showing number of chromosomal segments containing allelic imbalance (AI) per cancer genome.

Figure 2

Genome-wide prevalence of LOH in HGSC. Chromosome location is on the horizontal axis. Horizontal red lines represent a threshold P value ≤ 0.05 by genome-wide permutation. A, genome-wide prevalence of LOH. B, frequency of genome-wide copy number gain and loss. Frequency of absolute copy gain ≥3 (red) and copy loss ≤1.4 (blue) for each SNP is shown on the vertical axis. The light vertical lines separate the short and long arms.

Figure 3

BRCA1 promoter methylation, FLOH and BRCA1 transcript levels in HGSC. A, frequency of BRCA1 promoter methylation in HGSC. P value was obtained by using 2-way contingency analysis and Chi square. B, BRCA1 promoter methylation and FLOH in HGSC. FLOH was compared between cases with BRCA1 promoter methylation (B1M) and cases without BRCA1 methylation (B1UM). C, BRCA1 promoter methylation and BRCA1 mRNA levels. P value is determined by Mann–Whitney U tests.

Figure 4

Genomic profiles of HGSC in AOCS and TCGA SNP array datasets. A, hierarchical clustering and visualization based on LOH patterns in the AOCS dataset. B, hierarchical clustering in the TCGA dataset.

Figure 5

FLOH and rate of resistance to platinum-based chemotherapy in subclusters of HGSC from three independent cohorts. A and B, chemotherapy resistance and mean FLOH in tumors from subclusters Lo, HiA, and HiB for patients with stage III disease and residual disease ≤1 cm after optimal debulking, pooled from the 3 cohorts. C and D, results from all patients including those with stages II and IV cancer and residual disease >1 cm. P values are derived from Chi square analysis using 2-way contingency tables in A and C, and from t test in Band D. *, **, and *** represent P values <0.05, <0.001, and <0.00001, respectively.

Figure 6

Progression-free survival (PFS) after surgery and chemotherapy. Kaplan–Meier analysis was done in patients with stage III disease and 1 cm or less residual cancer after surgery; all patients received platinum and taxane combination chemotherapy. A, the AOCS cohort; B, the Boston cohort. Patients were divided into quartiles of FLOH (from low to high) in their tumors. P values are calculated by log-rank test. Patients who were progression-free at the time of last follow-up were censored (+).