Molecular Subclasses of Clear Cell Ovarian Carcinoma and Their Impact on Disease Behavior and Outcomes

Abstract

Purpose: To identify molecular subclasses of clear cell ovarian carcinoma (CCOC) and assess their impact on clinical presentation and outcomes.

Experimental design: We profiled 421 primary CCOCs that passed quality control using a targeted deep sequencing panel of 163 putative CCOC driver genes and whole transcriptome sequencing of 211 of these tumors. Molecularly defined subgroups were identified and tested for association with clinical characteristics and overall survival.

Results: We detected a putative somatic driver mutation in at least one candidate gene in 95% (401/421) of CCOC tumors including ARID1A (in 49% of tumors), PIK3CA (49%), TERT (20%), and TP53 (16%). Clustering of cancer driver mutations and RNA expression converged upon two distinct subclasses of CCOC. The first was dominated by ARID1A-mutated tumors with enriched expression of canonical CCOC genes and markers of platinum resistance; the second was largely comprised of tumors with TP53 mutations and enriched for the expression of genes involved in extracellular matrix organization and mesenchymal differentiation. Compared with the ARID1A-mutated group, women with TP53-mutated tumors were more likely to have advanced-stage disease, no antecedent history of endometriosis, and poorer survival, driven by their advanced stage at presentation. In women with ARID1A-mutated tumors, there was a trend toward a lower rate of response to first-line platinum-based therapy.

Conclusions: Our study suggests that CCOC consists of two distinct molecular subclasses with distinct clinical presentation and outcomes, with potential relevance to both traditional and experimental therapy responsiveness. See related commentary by Lheureux, p. 4838.

Figure 1.

Mutational landscape of 401 clear cell ovarian carcinomas with a detectable mutation. A, Proportion of patients with mutations in commonly mutated genes. B, Mutation variant allele frequency (VAF) by genes mutated in at least 10% of individuals. C, Number of mutated genes per individual. D, Variant effect and nucleotide substitution change for single nucleotide variants.

Figure 2.

Frequency of somatic mutations by clinical characteristics including age at diagnosis (A), endometriosis (B), stage (C), and race (D). Genes that were mutated in at least 20 individuals with nonmissing values for the clinical characteristic were included. Shown are q-values (FDR corrected P values) based on Fisher exact test. *, q < 0.05; **, q < 0.01.

Figure 3.

The transcriptome of clear cell ovarian cancer samples. A, Sankey plot showing the correspondence of the sample annotations RNA clusters and DNA clusters. B, Heatmap showing the normalized gene expression of the top 50 most differentially expressed genes between RNA cluster 1 and RNA cluster 2.

Figure 4.

Association between CCOC molecular subgroups and all-cause mortality. Shown are the Kaplan–Meier plots for the survival probability over 5 years following CCOC diagnosis stratified by mutational clusters defined by ARID1A/TP53 mutation status (A) and RNA-seq expression clusters (B).