br Methods Whole exome sequencing MC data from
Methods. Whole-exome sequencing MC3 data from primary endometrioid and serous carcinomas (n = 232) and uterine carcinosarcomas (n = 57) from The Cancer Genome Atlas (TCGA), and matched primary and metasta-tic ECs (n = 61, 26 patients) were reanalyzed, subjected to mutational signature analysis using deconstructSigs, and correlated with clinicopathologic and genomic data.
Results. POLE (ultramutated) and MSI (hypermutated) molecular subtypes displayed NPS-2143 mutational sig-natures associated with POLE mutations (15/17 cases) and microsatellite instability (55/65 cases), respectively. Most endometrioid and serous carcinomas of copy-number low (endometrioid) and copy-number high (serous-like) molecular subtypes, and carcinosarcomas displayed a dominant aging-associated signature 1. Only 15% (9/
60) of copy-number high (serous-like) ECs had a dominant signature 3 (homologous recombination DNA repair deficiency (HRD)-related), a prevalence significantly lower than that found in high-grade serous ovarian carcino-mas (54%, p b 0.001) or basal-like breast cancers (46%, p b 0.001). Shifts from aging- or POLE- to MSI-related mu-tational processes were observed in the progression from primary to metastatic ECs in a subset of cases. Conclusions. The mutational processes underpinning ECs vary even among tumors of the same TCGA molecular subtype and in the progression from primary to metastatic ECs. Only a minority of copy-number high (serous-like) ECs display genomics features of HRD and would likely benefit from HRD-directed therapies.
Corresponding author at: Department of Pathology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA. E-mail address: [email protected] (B. Weigelt).
1 Equal contribution.
Endometrial cancer (EC) is the fourth most common female malig-nancy in the United States . Since 2000, both the incidence and death rates in EC have been steadily increasing, and despite advances in therapy, when compared to 1975, the overall 5-year relative survival
for patients with EC has decreased . Hence, it is imperative to gain more insights into the biology of EC to improve management of the dis-ease and advance the use of targeted therapies. In 2013, The Cancer Ge-nome Atlas (TCGA) identified four distinct EC molecular subtypes, which carry prognostic and predictive information, including the POLE (ultramutated) subtype characterized by polymerase epsilon (POLE) exonuclease domain mutations (EDMs) and very high mutation rates, the MSI (hypermutated) subtype of microsatellite unstable tumors with high mutation rates, the copy-number low (endometrioid) sub-type characterized by CTNNB1 mutations, and the copy-number high (serous-like) subtype characterized by high levels of copy number alter-ations and recurrent TP53 mutations . Heterogeneity in the clinical behavior of tumors of the same molecular subtype has been docu-mented. For instance, patients with ECs of POLE subtype are reported to have a favorable prognosis, however POLE ECs with recurrent disease are on record, suggesting that molecular heterogeneity may be present in this seemingly homogenous subtype . A formal classification of uterine carcinosarcomas into the molecular subtypes has not been re-ported to date, however extensive copy-number alterations and recur-rent somatic mutations akin to those observed in both endometrioid and serous ECs have been found . Whilst TCGA focused on primary untreated ECs, whole-exome sequencing (WES) analysis of primary ECs and matched abdominopelvic metastases revealed novel recurrent alterations in metastatic ECs, temporal heterogeneity of driver genetic alterations, and demonstrated that b50% of somatic mutations were conserved from primary to metastasis within ECs .