DNA profiling of primary serous ovarian and Fallopian tube carcinomas with array comparative genomic hybridization and multiplex ligation‐dependent probe amplification

Abstract

Primary serous ovarian carcinoma (OVCA) and serous Fallopian tube carcinoma (FTC), both belonging to the BRCA-linked tumour spectrum, share many properties and are treated similarly. However, a detailed molecular comparison has been lacking. We hypothesized that comparative genomic studies of serous OVCAs and FTCs should point to gene regions critically involved in their tumorigenesis. Array comparative genomic hybridization (array CGH) analysis indicated that serous OVCAs and serous FTCs displayed common but also more distinctive patterns of recurrent changes. Targeted gene identification using a dedicated multiplex ligation-dependent probe amplification (MLPA) probe set directly identified EIF2C2 on 8q as a potentially important driver gene. Other previously unappreciated gained/amplified genes included PSMB4 on 1q, MTSS1 on 8q, TEAD4 and TSPAN9 on 12p, and BCAS4 on 20q. SPINT2 and ACTN4 on 19q were predominantly found in FTCs. Gains/amplifications of CCNE1 and MYC, often in conjunction with changes in genes of the AKT pathway, EVI1 and PTK2, seemed to be involved at earlier stages, whereas changes of ERBB2 were associated with advanced stages. The only BRCA1-mutated FTC shared common denominators with the sporadic tumours. In conclusion, the data suggest that serous OVCAs and FTCs, although related, exhibit differences in genomic profiles. In addition to known pathways, new genes/pathways are likely to be involved, with changes in an miRNA-associated gene, EIF2C2, as one important new feature. Dedicated MLPA sets constitute potentially important tools for differential diagnosis and may provide footholds for tailored therapy.

Ovarian cancer: Origin and factors involved in carcinogenesis with potential use in diagnosis, treatment and prognosis of the disease

“…Ovarian cancer is often characterized by genetic alterations including amplifications and deletions of large chromosomal regions. In our previous studies using Comparative Genomic Hybridization (CGH) method along with other cytogenetic methods in ovarian cancer [61,62], gains were observed on 3q, 1q and 20q chromosomal regions similarly to Nowee et al [63]. Similar results were observed also for losses on 4q, 4p and 18q; however, there were some different regions with observed amplifications and deletions.…”

Modeling high-grade serous ovarian carcinogenesis from the fallopian tube

“…Compared with other malignancies, HGSOC is most strongly characterized by its unusually high degree of genomic instability, resulting in numerous DNA copynumber alterations (28,29). Genomic analyses have consistently identified region 8q24, containing the c-Myc locus, as the most recurrently gained genomic region (≥60%) in HGSOC, which is often accompanied by high-level c-Myc gene amplification (23,29,30). To more accurately model HGSOC genetics, we replaced H-Ras V12 with c-Myc and, in doing so, demonstrated that a clinically relevant oncogene such as c-Myc can also transform FTSECs immortalized with hTERT and SV40 TAg.…”

“…Our study provides proof-of-principle evidence that FTSECs may indeed be a cell of origin for HGSOC and demonstrates a framework for defining their contribution to HGSOC development. Further work should focus on the transformative effects of other genetic alterations strongly associated with HGSOC, such as BRCA1/2 mutations and genes that recurrently undergo DNA copy-number changes such as CCNE, EVI1, PTK2, ERBB2, PRKCI, NF1, and PTEN (23,29,30). Our model also serves as a platform for investigating the many candidate oncogenes and tumor suppressors now being identified by The Cancer Genome Atlas and other large-scale genomic analyses of HGSOC (29,36,37).…”

Gene Expression Profiles of Luteal Phase Fallopian Tube Epithelium from BRCA Mutation Carriers Resemble High-Grade Serous Carcinoma

“…Although it is not possible to definitively prove the tubal origin of tubal intraepithelial carcinomas, these are likely primary lesions given the previously observed resistance of tubal mucosa to direct implantation (14,15). This concept is further supported by the finding that gene expression profiles of ovarian SerCa are more similar to normal FTE than the ovarian surface epithelium (16), as well as by the similar risk factors (17,18) and genomic alterations of ovarian and fallopian tube cancers (19,20).…”