Integrated genomic analyses of ovarian carcinoma

Abstract

Summary The Cancer Genome Atlas (TCGA) project has analyzed mRNA expression, miRNA expression, promoter methylation, and DNA copy number in 489 high-grade serous ovarian adenocarcinomas (HGS-OvCa) and the DNA sequences of exons from coding genes in 316 of these tumors. These results show that HGS-OvCa is characterized by TP53 mutations in almost all tumors (96%); low prevalence but statistically recurrent somatic mutations in 9 additional genes including NF1, BRCA1, BRCA2, RB1, and CDK12; 113 significant focal DNA copy number aberrations; and promoter methylation events involving 168 genes. Analyses delineated four ovarian cancer transcriptional subtypes, three miRNA subtypes, four promoter methylation subtypes, a transcriptional signature associated with survival duration and shed new light on the impact on survival of tumors with BRCA1/2 and CCNE1 aberrations. Pathway analyses suggested that homologous recombination is defective in about half of tumors, and that Notch and FOXM1 signaling are involved in serous ovarian cancer pathophysiology.

NovelBRCA1andBRCA2Tumor Test as Basis for Treatment Decisions and Referral for Genetic Counselling of Patients with Ovarian Carcinomas

“…The highest response rates to treatments with olaparib were observed in OC patients with mutations affecting the homologous recombination genes BRCA1 (MIM# 113705) or BRCA2 (MIM# 600185) [Audeh et al., 2010; Ledermann et al., 2014]. Since genomic aberrations affecting BRCA1 and BRCA2 are among the most prevalent mutations observed in OCs [Cancer Genome Atlas Research, 2011; Kanchi et al., 2014; Patch et al., 2015], a substantial number of OC patients may benefit from treatments with PARP inhibitors.…”

“…Genomic aberrations affecting BRCA1 and BRCA2 are frequently encountered in both sporadic and familial OCs [Cancer Genome Atlas Research, 2011; Kanchi et al., 2014] (OMIM #604370 and #612555). Approximately 10%–15% of all OC patients carry a pathogenic germline aberration in BRCA1 or BRCA2 [Daly et al., 2010; Hennessy et al., 2010; Kanchi et al., 2014].…”

“…Loss of heterozygosity (LOH) of the wild‐type allele is the tumor‐initiating second hit in the majority of these patients [Foster et al., 1996; Berchuck et al., 1998]. Somatic mutations in BRCA1 and BRCA2 are observed in approximately 3.5%–8.5% and 2.5%–4% of OCs without an underlying germline mutation, respectively [Merajver et al., 1995; Foster et al., 1996; Berchuck et al., 1998; Cancer Genome Atlas Research, 2011; Kanchi et al., 2014]. Hypermethylation of the promoter of BRCA1 is observed in approximately 10%–15% of these carcinomas [Baldwin et al., 2000; Bianco et al., 2000; Esteller et al., 2000; Cancer Genome Atlas Research, 2011].…”

“…Somatic mutations in BRCA1 and BRCA2 are observed in approximately 3.5%–8.5% and 2.5%–4% of OCs without an underlying germline mutation, respectively [Merajver et al., 1995; Foster et al., 1996; Berchuck et al., 1998; Cancer Genome Atlas Research, 2011; Kanchi et al., 2014]. Hypermethylation of the promoter of BRCA1 is observed in approximately 10%–15% of these carcinomas [Baldwin et al., 2000; Bianco et al., 2000; Esteller et al., 2000; Cancer Genome Atlas Research, 2011]. Importantly, germline mutations, somatic mutations, and promoter hypermethylation appear mutually exclusive in OCs [Cancer Genome Atlas Research, 2011; Dworkin et al., 2009].…”

“…Hypermethylation of the promoter of BRCA1 is observed in approximately 10%–15% of these carcinomas [Baldwin et al., 2000; Bianco et al., 2000; Esteller et al., 2000; Cancer Genome Atlas Research, 2011]. Importantly, germline mutations, somatic mutations, and promoter hypermethylation appear mutually exclusive in OCs [Cancer Genome Atlas Research, 2011; Dworkin et al., 2009]. In total, BRCA1 and BRCA2 are mutated in 19%–22% of OCs and, consequently, these patients may benefit from PARP‐inhibitor treatment [Hennessy et al., 2010; Cancer Genome Atlas Research, 2011; Kanchi et al., 2014].…”