Multisite analysis of high‐grade serous epithelial ovarian cancers identifies genomic regions of focal and recurrent copy number alteration in 3q26.2 and 8q24.3

Abstract

High‐grade serous epithelial ovarian cancer (HGS‐EOC) is a systemic disease, with marked intra and interpatient tumor heterogeneity. The issue of spatial and temporal heterogeneity has long been overlooked, hampering the possibility to identify those genomic alterations that persist, before and after therapy, in the genome of all tumor cells across the different anatomical districts. This knowledge is the first step to clarify those molecular determinants that characterize the tumor biology of HGS‐EOC and their route toward malignancy. In our study, ‐omics data were generated from 79 snap frozen matched tumor biopsies, withdrawn before and after chemotherapy from 24 HGS‐EOC patients, gathered together from independent cohorts. The landscape of somatic copy number alterations depicts a more homogenous and stable genomic portrait than the single nucleotide variant profile. Genomic identification of significant targets in cancer analysis identified two focal and minimal common regions (FMCRs) of amplification in the cytoband 3q26.2 (region α, 193 kb long) and 8q24.3 (region β, 495 kb long). Analysis in two external databases confirmed regions α and β are features of HGS‐EOC. The MECOM gene is located in region α, and 15 genes are in region β. No functional data are yet available for the genes in the β region. In conclusion, we have identified for the first time two FMCRs of amplification in HGS‐EOC, opening up a potential biological role in its etiopathogenesis.

Sox2 promotes expression of the ST6Gal-I glycosyltransferase in ovarian cancer cells

“…The 3q26 amplicon is one of the most pervasively amplified chromosomal regions in cancer, and is known for promoting stem-like cancer cell characteristics [48]. This particular amplicon is estimated to occur in greater than 20% of all human cancers [48], with amplification rates as high as 75% in invasive lung SCC [75], and between 25 and 30% in ovarian cancer [51,76,77]. In addition to lung SCC and ovarian cancer, 3q26 amplification has been documented in esophageal SCC, head and neck SCC, and cervical cancer [49,50,[78][79][80].…”

RRM2Bis frequently amplified across multiple tumor types: non-oncogenic addiction and therapeutic opportunities

“…However, supportively, a recent study in the highly heterogenous ovarian serous grade carcinomas consistently found amplifications (starting from 8q22.3 region) in ovarian tumor biopsies from different regions of the ovary, and also in the relapsed tumor tissue [50]. Future studies addressing inter-and intra-tumor heterogeneity in other cancer types will further highlight the potential clinical significance of amplifications in the 8q-region.…”

RRM2B Is Frequently Amplified Across Multiple Tumor Types: Implications for DNA Repair, Cellular Survival, and Cancer Therapy

“…However, this study did not extend the analysis to other genes on chromosome 8. A recent study on therapeutic resistance in the highly heterogenous ovarian serous grade carcinomas consistently found amplifications in the 8q-region (starting from 8q22.3) in biopsies from different regions of the tumor, and the relapsed tumor tissue (Ballabio et al, 2019). These data suggest potential clinical significance of amplifications in the 8q-region.…”