Abstract:High-grade serous ovarian cancer (HGSOC) originates in the fallopian tube epithelium and is characterized by ubiquitous TP53 mutation and extensive chromosomal instability (CIN). While the direct causes of CIN are errors during DNA replication and/or chromosome segregation, mutations in genes encoding DNA replication and mitotic factors are rare in HGSOC. Thus, the drivers of CIN remain undefined. We therefore asked whether the oncogenic lesions that are frequently observed in HGSOC are capable of driving CIN … Show more
“…Although the rates of CCNE1 amplification here did not differ significantly between our early-stage and late-stage cohorts, our data support the idea that high ploidy is associated with advanced HGSC and poorer prognosis, a concept first explored over 20 years ago (37). HGSC has profound levels of segregation error during cell division, an essential precursor of aneuploidy and WGD (38), and recent data suggest that WGD can emerge in hTERT-immortalized human fallopian tube epithelial cells with loss of wild-type p53 function in the presence of BRCA1 mutation and MYC overexpression, but not with TP53 mutation alone (39).…”
Purpose:
Ovarian high-grade serous carcinoma (HGSC) is usually diagnosed at late stage. We investigated whether late-stage HGSC has unique genomic characteristics consistent with acquisition of evolutionary advantage compared with early-stage tumors.
Experimental Design:
We performed targeted next-generation sequencing and shallow whole-genome sequencing (sWGS) on pretreatment samples from 43 patients with FIGO stage I–IIA HGSC to investigate somatic mutations and copy-number (CN) alterations (SCNA). We compared results to pretreatment samples from 52 patients with stage IIIC/IV HGSC from the BriTROC-1 study.
Results:
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. We 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. CN signature exposures were significantly different between cohorts, with greater relative signature 3 exposure in early-stage and greater signature 4 in late-stage. Unsupervised clustering based on CN signatures identified three clusters that were prognostic.
Conclusions:
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. Further analyses will be required to ascertain whether these differences reflect genuine biological differences between early-stage and late-stage or simply time-related markers of evolutionary fitness.
“…Although the rates of CCNE1 amplification here did not differ significantly between our early-stage and late-stage cohorts, our data support the idea that high ploidy is associated with advanced HGSC and poorer prognosis, a concept first explored over 20 years ago (37). HGSC has profound levels of segregation error during cell division, an essential precursor of aneuploidy and WGD (38), and recent data suggest that WGD can emerge in hTERT-immortalized human fallopian tube epithelial cells with loss of wild-type p53 function in the presence of BRCA1 mutation and MYC overexpression, but not with TP53 mutation alone (39).…”
Purpose:
Ovarian high-grade serous carcinoma (HGSC) is usually diagnosed at late stage. We investigated whether late-stage HGSC has unique genomic characteristics consistent with acquisition of evolutionary advantage compared with early-stage tumors.
Experimental Design:
We performed targeted next-generation sequencing and shallow whole-genome sequencing (sWGS) on pretreatment samples from 43 patients with FIGO stage I–IIA HGSC to investigate somatic mutations and copy-number (CN) alterations (SCNA). We compared results to pretreatment samples from 52 patients with stage IIIC/IV HGSC from the BriTROC-1 study.
Results:
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. We 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. CN signature exposures were significantly different between cohorts, with greater relative signature 3 exposure in early-stage and greater signature 4 in late-stage. Unsupervised clustering based on CN signatures identified three clusters that were prognostic.
Conclusions:
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. Further analyses will be required to ascertain whether these differences reflect genuine biological differences between early-stage and late-stage or simply time-related markers of evolutionary fitness.
“…Although the rates of CCNE1 amplification did not differ significantly between our early and late stage cohorts, our data support the idea that WGD is associated with advanced HGSC and poorer prognosis. HGSC generally has profound levels of segregation error during cell division, an essential precursor of aneuploidy and WGD (38), and recent data suggest that WGD can emerge in hTERT -immortalised human fallopian tube epithelial cells with loss of wild-type p53 function in the presence of BRCA1 mutation and MYC over-expression, but not with TP53 mutation alone (39). However, one outstanding question is whether WGD per se promotes rapid dissemination in HGSC, or whether it is a time-related consequence and is thus more likely to be observed in late stage than early stage disease: detailed multi-site analysis of disseminated HGSC and in vitro models will be required as well as further analyses of early stage samples to address this question.…”
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.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.