Whole-genome sequencing-based characterization of endometrial serous carcinoma

To define the structural variants, mutational signatures, and DNA repair defects in serous endometrial carcinoma (EC) using whole-genome sequencing (WGS).

Ten primary untreated classic serous ECs diagnosed between 2012 and 2018 were selected. Tumor and matched normal DNAs were subjected to WGS, and sequencing data were analyzed using state-of-the-art bioinformatics methods.

All serous ECs harbored TP53 somatic mutations (100 %), as well as recurrent PIK3CA (60 %), FBXW7 (40 %), PPP2R1A (30 %) mutations, CCNE1 (50 %) and AKT2 amplification (30 %). All serous ECs were homologous recombination DNA repair (HR)-proficient by HRDetect, and all but one case had dominant aging/clock- or ABOPEC-related mutational signatures. The levels of genomic instability varied, with a median fraction of genome altered (FGA) of 45 % (range 17-68 %). Seven serous ECs had high levels of copy number alterations (CNAs) (distinct CNA size ≥1Mbp, median 59; range 26-86) and three had low levels of CNAs (median 12 distinct CNA size ≥1Mbp; range 6-23). While there was no difference in age or stage of disease between patients with high versus low CNA levels, all three serous EC patients with lower CNA levels are still alive to date (68-99 months follow-up), as opposed to only one of seven serous EC patients with higher CNA levels (range 16-69 months follow-up) after 58 months of follow-up.

Although serous ECs are characterized by TP53 mutations and generally high levels of CNAs, genomic features of HR-deficiency are not prominent. Larger prospective studies of the impact of chromosomal instability on outcome in serous EC patients are warranted.