Genomic landscape of endometrial carcinomas of no specific molecular profile.

ABSTRACT

Endometrial carcinomas (ECs) classified by The Cancer Genome Atlas (TCGA) as copy number-low (also referred to as "no specific molecular profile" [NSMP]) have a prognosis intermediate between POLE-mutated and copy number-high ECs. NSMP-ECs are a heterogeneous group, however, comprising both relatively indolent and aggressive ECs. We identified a total of 472 NSMP-ECs among 1,239 ECs that underwent clinical sequencing of 410-468 cancer-related genes. Somatic mutation and copy number alteration data were subjected to unsupervised hierarchical clustering, which identified three genomic clusters. Random sampling with stratification was used to choose ~80 endometrioid ECs from each cluster, resulting in a study size of 240 endometrioid ECs as well as an additional 44 non-endometrioid NSMP-ECs. Cluster 1 (C1, n = 80) consisted primarily of NSMP-ECs with PTEN and PIK3R1 mutations, Cluster 2 (C2, n = 81) of tumors with PTEN and PIK3CA mutations and Cluster 3 (C3, n = 79) of NSMP-ECs with chromosome 1q high-level gain and lack of PTEN mutations. The majority (72.7%) of non-endometrioid NSMP-ECs mapped to C3. NSMP-ECs from C3 were more likely to be FIGO grade 3 (30%), estrogen receptor-negative/weak (54.5%) and FIGO stages III or IV. In multivariate analysis, molecular clusters were associated with worse overall survival outcomes with C3 tumors having the worst (hazard ratio 4) and C1 tumors having the best outcome. In conclusion, NSMP-ECs are a heterogenous group of tumors and comprise both aggressive and clinically low-risk ECs that can be identified based on mutation and copy number data.