Molecular Landscape of Mullerian Clear Cell Carcinomas Identifies The Cancer Genome Atlas-like Prognostic Subgroups

Mullerian clear cell carcinoma (CCC) is often aggressive and chemoresistant. The prognostic significance of molecular subclassification of endometrioid carcinomas is well established. However, less is known about the molecular landscape of CCC. The aim of this study was to better characterize the genetic landscape of a large cohort of CCC and correlate these findings with clinicopathologic features. CCC of the ovary (n = 72), endometrium (n = 24), and peritoneum/abdominal wall (n = 5) were retrospectively identified. Tumors had undergone tumor-only targeted sequencing using a hybrid capture next-generation sequencing panel. Median tumor mutational burden was 6.8 mutations/megabase (range, 1.3-185, 21% were ≥10 mutations/Mb). The most frequently mutated genes were ARID1A (48%), PIK3CA (45%), TP53 (23%), and PTEN (10%). ERBB2 amplification occurred in 4%. When classified according to the Cancer Genome Atlas/the Proactive Molecular Risk Classifier for Endometrial Cancer endometrial carcinoma molecular subgroups, 3 (3%) were POLE ultramutated, 5 (5%) were microsatellite instability-high (MSI-H), 20 (20%) were TP53-mutant subgroup, and 73 (72%) were no specific molecular profile (NSMP). Immunohistochemical expression of estrogen receptor, progesterone receptor, and programmed death-ligand 1 were not associated with the molecular subgroup. POLE and MSI-H tumors were characterized by an excellent prognosis, and the TP53-mutant subgroup had a worse disease-free survival than NSMP. NSMP tumors could be further substratified as high-risk NSMP if they lacked PIK3CA, PIK3R1, and ARID1A mutations, and/or harbored a TERT-promoter mutation. The Cancer Genome Atlas and NSMP-specific stratifications were prognostic for both the entire cohort and the subset of stage I ovarian tumors. On multivariable analysis, stage, lymphovascular invasion, and tumor mutational burden were prognostic for disease-free survival, whereas advanced stage and TP53-mutant subgroup - but not a TP53 mutation in isolation - were negative prognostic factors for overall survival. These data suggest that routine molecular profiling of Mullerian CCC may be warranted for both prognosis and identification of potential targeted treatments, such as immunotherapy and anti-HER2 agents.