Integrated genomic and histopathological analysis of low grade serous ovarian carcinoma identifies clinically distinct disease subtypes

BackgroundLow-grade serous ovarian carcinoma (LGSOC) is a distinct, under-investigated and relatively chemotherapy-resistant ovarian cancer type. Understanding the molecular landscape is crucial to maximise the impact of molecularly-targeted therapy. MethodsWhole exome sequencing and copy number data were integrated with histopathological patterns, ER/PR expression, and detailed clinical annotation, including survival, in a carefully curated LGSOC cohort. Results63 tumours were analysed in the largest comprehensive genomic LGSOC study to date. Three genomic subgroups were identified: canonical MAPK mutant (cMAPKm: 52%, KRAS/BRAF/NRAS), MAPK-associated mutation (27%, 14 MAPK-associated genes) and MAPK wild-type (MAPKwt: 21%). MAPKwt patients were younger at diagnosis (median 47 versus 62 years in the cMAPKm subgroup) and demonstrated shorter survival [multivariable HR (mHR) 4.17]. The inferior survival in the MAPKwt subgroup was due to shorter post-relapse survival (mHR 5.22) rather than shorter time to first progression (mHR 1.15). Patients in the MAPK-associated mutation subgroup had similar survival to cMAPKm cases. The cMAPKm subgroup more frequently demonstrated macropapillary invasion. Desmoplasia and micropapillary invasion were independently associated with poor survival. NOTCH pathway activation occurred independently of MAPK subgroup. ConclusionsLGSOC comprises multiple genomic subgroups with distinct clinical, molecular and histopathological features. True MAPKwt cases represent around a fifth of patients: they are younger but have poorer survival. New therapeutic strategies with activity in this subgroup are urgently required. NOTCH inhibitors represent a therapeutic strategy worthy of exploration.