Clonal evolution of ovarian high grade serous carcinoma

Abstract

Ovarian high-grade serous carcinoma (HGSC) is usually diagnosed at late stage. I investigated whether late-stage HGSC has unique genomic characteristics consistent with acquisition of evolutionary advantage compared with early-stage tumours and the genomic dynamic changes in the evolution process of HGSC.

Targeted next-generation sequencing and shallow whole-genome sequencing (sWGS) were performed on samples from 43 chemotherapy-naive patients with FIGO stage I-IIA HGSC to investigate somatic mutations and copy-number (CN) alterations (SCNA). I compared results to pretreatment samples from 52 patients with late stage IIIC/IV HGSC from the BriTROC-1 study. In addition, I also collected p53 signatures, serous tubal intraepithelial carcinomas (STIC), primary and metastatic tumours from five patients as a separate cohort.

Age of diagnosis did not differ between early-stage and late-stage patients (median 61.3 years vs. 62.3 years, respectively). TP53 mutations were near-universal in both cohorts (89% early- stage, 100% late-stage), and there were no significant differences in the rates of other somatic mutations, including BRCA1 and BRCA2. I also did not observe cohort-specific focal SCNA that could explain biological behavior. However, ploidy was higher in late-stage (median, 3.0) than early-stage (median, 1.9) samples. Seven copy number signatures, recurrent patterns of copy number change that reflect the imprint of underlying mutational process, had previously been derived from late stage high grade serous carcinomas [1]. CN signature exposures were significantly different between cohorts, with greater relative signature 3 exposure in early-stage and greater signature 4 in late-stage. Signature 3 is associated with BRCA1/2 homologous recombination deficiency pathway and good overall survival. Signature 4 is associated with abnormalities in the PI3K/AKT signalling pathway as well as and whole genome duplication. Unsupervised clustering based on CN signatures identified three clusters that were prognostic. In the STIC cohort, all p53 signatures were diploid. Two patients showed no significant difference in ploidies across samples. However, in three patients, ploidy increase was apparent in STIC lesions as well as primary and metastatic lesions.

Early-stage and late-stage HGSCs have highly similar patterns of mutation and focal SCNA. However, CN signature analysis showed that late-stage disease has distinct signature exposures consistent with whole-genome duplication. The STIC cohort provides some evidence that complex genomic alterations can occur very early in the development of HGSC development.