Abstract
BackgroundBRCA1 gene inactivation causes chromosomal instability, leading to rapid accumulation of chromosomal rearrangements and mutations. The loss of BRCA1 function due to either germline/somatic mutation or epigenetic silencing is observed in most high-grade serous carcinomas of the ovary.MethodsDNA ploidy and gene expression profile were used in order to compare gross genomic alteration and gene expression pattern between cases with BRCA1 loss through mutation, BRCA1 epigenetic loss, and no BRCA1 loss in cases of high-grade serous carcinoma with known BRCA1 and BRCA 2 status.ResultsUsing image cytometry and oligonucleotide microarrays, we analyzed DNA ploidy, S-phase fraction and gene expression profile of 28 consecutive cases of ovarian high-grade serous adenocarcinomas, which included 8 tumor samples with BRCA1 somatic or germline mutation, 9 samples with promoter hypermethylation of BRCA1, and 11 samples with no BRCA1 loss. None had BRCA2 mutations. The prevalence of aneuploidy and tetraploidy was not statistically different in the three groups with different BRCA1 status. The gene expression profiles were also very similar between the groups, with only two genes showing significant differential expression when comparison was made between the group with BRCA1 mutation and the group with no demonstrable BRCA1 loss. There were no genes showing significant differences in expression when the group with BRCA1 loss through epigenetic silencing was compared to either of the other two groups.ConclusionsIn this series of 28 high-grade serous carcinomas, gross genomic alteration characterized by aneuploidy did not correlate with BRCA1 status. In addition, the gene expression profiles of the tumors showed negligible differences between the three defined groups based on BRCA1 status. This suggests that all ovarian high-grade serous carcinomas arise through oncogenic mechanisms that result in chromosomal instability, irrespective of BRCA status; the molecular abnormalities underlying this in the BRCA intact tumors remains unknown.
Highlights
BRCA1 gene inactivation causes chromosomal instability, leading to rapid accumulation of chromosomal rearrangements and mutations
Gross genomic alteration by DNA ploidy DNA ploidy analysis was performed in 28 BRCA1 and BRCA 2 defined cases using an image cytometric method
We found that the gross genomic alteration and gene expression profiles were similar in high- grade serous carcinoma of the ovary with BRCA1 loss through mutation, BRCA1 epigenetic loss and no evidence of BRCA1
Summary
BRCA1 gene inactivation causes chromosomal instability, leading to rapid accumulation of chromosomal rearrangements and mutations. The loss of BRCA1 function due to either germline/somatic mutation or epigenetic silencing is observed in most high-grade serous carcinomas of the ovary. High-grade serous carcinoma accounts for 70% of all ovarian cancers, and a disproportionate number of deaths as these tumors are more likely to present with advanced stage disease [2]. In absence of functional BRCA1 or BRCA2, double stand DNA breaks are repaired by error-prone non-homologous end joining mechanism leading to further mutations and genomic instability [10]. According to the chromosomal instability model for the pathogenesis of BRCA-associated cancers, genetic alterations causing loss of cell-cycle checkpoints and chromosomal instability are crucial during oncogenesis [11,12]. Gross genomic alteration evidenced by aneuploidy is usually the result of chromosomal instability [15]
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