Gross genomic alterations and gene expression profiles of high- grade serous carcinoma of the ovary with and without BRCA1 inactivation.
BACKGROUND
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.


METHODS
DNA 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.


RESULTS
Using 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.


CONCLUSIONS
In 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.
Pradhan
Manohar
M
Department of Pathology and Laboratory Medicine, University of British Columbia and Vancouver General Hospital, Vancouver, British Columbia, Canada.
Risberg
Björn A
BA
Tropé
Claes G
CG
van de Rijn
Matt
M
Gilks
C Blake
CB
Lee
Cheng-Han
CH
D019313:BRCA1 Protein / Q000037:antagonists & inhibitors / Q000235:genetics*; D024682:BRCA2 Protein / Q000037:antagonists & inhibitors / Q000235:genetics*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015331:Cohort Studies; D018284:Cystadenocarcinoma, Serous / Q000235:genetics* / Q000473:pathology; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D042822:Genomic Instability; D018095:Germ-Line Mutation / Q000235:genetics*; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000473:pathology; D011003:Ploidies; D011401:Promoter Regions, Genetic / Q000235:genetics; D016196:S Phase
D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D014408:Biomarkers, Tumor