title: Genome wide DNA copy number analysis of serous type ovarian carcinomas identifies genetic markers predictive of clinical outcome.
abstract: Ovarian cancer is the fifth leading cause of cancer death in women. Ovarian cancers display a high degree of complex genetic alterations involving many oncogenes and tumor suppressor genes. Analysis of the association between genetic alterations and clinical endpoints such as survival will lead to improved patient management via genetic stratification of patients into clinically relevant subgroups. In this study, we aim to define subgroups of high-grade serous ovarian carcinomas that differ with respect to prognosis and overall survival. Genome-wide DNA copy number alterations (CNAs) were measured in 72 clinically annotated, high-grade serous tumors using high-resolution oligonucleotide arrays. Two clinically annotated, independent cohorts were used for validation. Unsupervised hierarchical clustering of copy number data derived from the 72 patient cohort resulted in two clusters with significant difference in progression free survival (PFS) and a marginal difference in overall survival (OS). GISTIC analysis of the two clusters identified altered regions unique to each cluster. Supervised clustering of two independent large cohorts of high-grade serous tumors using the classification scheme derived from the two initial clusters validated our results and identified 8 genomic regions that are distinctly different among the subgroups. These 8 regions map to 8p21.3, 8p23.2, 12p12.1, 17p11.2, 17p12, 19q12, 20q11.21 and 20q13.12; and harbor potential oncogenes and tumor suppressor genes that are likely to be involved in the pathogenesis of ovarian carcinoma. We have identified a set of genetic alterations that could be used for stratification of high-grade serous tumors into clinically relevant treatment subgroups.
authors.affiliation: Department of Statistics, Brigham Young University, Provo, Utah, United States of America.
authors.forename: David A
authors.initials: DA
authors.lastname: Engler
authors.forename: Sumeet
authors.initials: S
authors.lastname: Gupta
authors.forename: Whitfield B
authors.initials: WB
authors.lastname: Growdon
authors.forename: Ronny I
authors.initials: RI
authors.lastname: Drapkin
authors.forename: Mai
authors.initials: M
authors.lastname: Nitta
authors.forename: Petra A
authors.initials: PA
authors.lastname: Sergent
authors.forename: Serena F
authors.initials: SF
authors.lastname: Allred
authors.forename: Jenny
authors.initials: J
authors.lastname: Gross
authors.forename: Michael T
authors.initials: MT
authors.lastname: Deavers
authors.forename: Wen-Lin
authors.initials: WL
authors.lastname: Kuo
authors.forename: Beth Y
authors.initials: BY
authors.lastname: Karlan
authors.forename: Bo R
authors.initials: BR
authors.lastname: Rueda
authors.forename: Sandra
authors.initials: S
authors.lastname: Orsulic
authors.forename: David M
authors.initials: DM
authors.lastname: Gershenson
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Birrer
authors.forename: Joe W
authors.initials: JW
authors.lastname: Gray
authors.forename: Gayatry
authors.initials: G
authors.lastname: Mohapatra
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002874:Chromosome Mapping; D018284:Cystadenocarcinoma, Serous / Q000235:genetics* / Q000401:mortality* / Q000628:therapy; D056915:DNA Copy Number Variations / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D005819:Genetic Markers / Q000235:genetics*; D006801:Humans; D008875:Middle Aged; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D020411:Oligonucleotide Array Sequence Analysis; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000401:mortality* / Q000628:therapy; D011379:Prognosis; D011446:Prospective Studies; D015996:Survival Rate
chemical_list: D005819:Genetic Markers