Amplification of 1q32.1 refines the molecular classification of endometrial carcinoma

Purpose: Molecular classification of endometrial cancer (EC) identified distinct molecular subgroups. However, the largest subset of ECs remains poorly characterized and is referred to as the 'non-specific molecular profile' (NSMP) subgroup. Here, we aimed at refining the classification of this subgroup by profiling somatic copy number aberrations (SCNAs). Experimental Design: SCNAs were analyzed in 141 ECs using whole-genome SNP arrays and pooled with 361 ECs from The Cancer Genome Atlas. Genomic Identification of Significant Targets In Cancer (GISTIC) identified statistically-enriched SCNAs and penalized Cox regression assessed survival effects. The prognostic significance of relevant SCNAs was validated using multiplex ligation-dependent probe amplification in 840 ECs from the PORTEC-1/2 trials. Copy number status of genes was correlated with gene expression to identify potential cancer drivers. One plausible oncogene was validated in vitro using antisense oligonucleotide-based strategy. Results: SCNAs affecting chromosome 1q32.1 significantly correlated with worse relapse-free survival (RFS) in the NSMP subgroup (HR=2.12; 95%CI, 1.26-3.59; P=0.005). This effect was replicated in NSMP ECs from PORTEC-1/2 (HR=2.34; 95%CI, 1.17-4.70; P=0.017). A new molecular classification including the 1q32.1 amplification improved risk prediction of recurrence. MDM4 gene expression strongly correlated with 1q32.1 amplification. Silencing MDM4 inhibited cell growth in cell lines carrying 1q32.1 amplification, but not in non-amplified cell lines. Vice versa, increasing MDM4 expression in non-amplified cell lines stimulated cell proliferation. Conclusions: 1q32.1 amplification was identified as a prognostic marker for poorly-characterized NSMP ECs, refining the molecular classification of this subgroup. We functionally validated MDM4 as a potential oncogenic driver in the 1q32.1 region.

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