The genomic landscape of early stage ovarian high grade serous carcinoma

Abstract

PurposeHigh grade serous carcinoma (HGSC) is the commonest type of ovarian cancer. Nearly all HGSC cases are diagnosed at late stage and it is not clear whether early stage HGSC has unique characteristics compared to late stage tumours.Experimental DesignWe analysed samples from 45 patients with FIGO stage I - IIA HGSC - 40 from the pathology archives of three large UK cancer centres and 5 from the BriTROC-1 study. We performed shallow whole genome sequencing (sWGS) and targeted next generation sequencing to investigate somatic mutations and copy number alterations. We compared results to 51 stage IIIC/IV HGSC patients from the BriTROC-1 study.ResultsThere was no difference in median age between the early stage (median 61.3 years, range 40-84) and late stage (median 62.3 years, range 34-76) patients at diagnosis. TP53 mutations were near-universal (92% early stage, 100% late stage samples) and there were no significant differences in the rates of other somatic mutations, including BRCA1 and BRCA2, or focal copy number alterations between early- and late-stage cohorts. There were also no unique amplifications or deletions in either cohort. However, median ploidy was greater in late stage (median 3.1) than early stage (median 2.0) samples. In addition, there were higher numbers of breakpoints per 10MB and per chromosome arm and higher absolute copy number in late stage than early stage cohorts; early stage samples had longer segment length. Overall copy number signature exposures were significantly different between early and late stage samples with greater signature 3 exposure in early stage and greater signature 4 in late stage. Both simplex plot and unsupervised hierarchical clustering suggested that a subset of late stage samples retain early stage appearances with high signature 3 and co-clustering with the early stage samplesConclusionsThese data suggest that there are no unique mutations or focal copy number alterations in early stage HGSC. However, whole genome duplication is significantly more common in late-stage disease, suggesting evolution during disease progression. However, a subset of late stage HGSC retains early-stage features, which are associated with improved overall survival.

High-grade serous ovarian carcinoma organoids as models of chromosomal instability

“…1d) from TCGA, PCAWG and BriTROC (N = 692) and compared these with the PDO profiles. Unsupervised hierarchical clustering of the clinical samples showed two main groups with the major group characterized by high activities for s4 and low activities for s3 suggesting frequent WGD and consistent with previous observations 4,19 . The smaller group was predominantly composed of s1 mitotic errors and s3 HRD and may represent near diploid tumours.…”

Long-term tumour dormancy in aBRCA1heterozygote

“…Further supporting a common origin for these tumours, we found identical TP53 mutations (NM_000546.6:c.701A>G, p.Tyr234Cys) in the FTC and PC (figure 2C). Higher ploidy and whole genome duplication have been reported in late stage rather than early stage HGSC and are linked with TP53 mutation and poor survival 7. HGSC has high levels of segregation error during cell division, which facilitates the development of aneuploidy and whole genome duplication 8…”