Functional complementation studies identify candidate genes and common genetic variants associated with ovarian cancer survival

TY - JOUR

T1 - Functional complementation studies identify candidate genes and common genetic variants associated with ovarian cancer survival

AU - Quaye, Lydia

AU - Dafou, Dimitra

AU - Ramus, Susan J

AU - Song, Honglin

AU - Gentry-Maharaj, Aleksandra

AU - Maharaj, Aleksandra Gentry

AU - Notaridou, Maria

AU - Hogdall, Estrid

AU - Kjaer, Susanne Kruger

AU - Christensen, Lise

AU - Hogdall, Claus

AU - Easton, Douglas F

AU - Jacobs, Ian

AU - Menon, Usha

AU - Pharoah, Paul D P

AU - Gayther, Simon A

N1 - Keywords: Adult; Aged; Carrier Proteins; Caspases; Chromosomes, Human, Pair 18; European Continental Ancestry Group; Female; Gene Deletion; Genotype; Humans; Loss of Heterozygosity; Middle Aged; Nuclear Proteins; Ovarian Neoplasms; Polymorphism, Single Nucleotide; Survival

PY - 2009

Y1 - 2009

N2 - Common germline genetic variation and/or somatic alterations in tumours may be associated with survival in women diagnosed with ovarian cancer. The successful identification of genetic associations relies on a suitable strategy for identifying and testing candidate genes. We used microcell-mediated chromosome transfer approach and expression microarray analysis to identify genes that were associated with neoplastic suppression in ovarian cancer cell lines. Sixty-five tagging single nucleotide polymorphisms (tSNPs) in nine candidate genes were genotyped in approximately 1700 invasive ovarian cancer cases to look for associations with survival. For two of these genes, loss of heterozygosity (LOH) analysis of tSNPs in 314 ovarian tumours was used to identify associations between somatic gene deletions and survival. We identified significant associations with survival for a tSNP in caspase 5 (CASP5) [hazard ratio (HR) = 1.13 (95% CI: 1.00-1.27), P = 0.042] and two tSNPs in the retinoblastoma binding protein (RBBP8) gene [HR = 0.85 (95% CI: 0.75-0.95), P = 0.007 and HR = 0.83 (95% CI: 0.71-0.95), P = 0.009]. After adjusting for multiple prognostic factors in a multivariate Cox regression analysis, both associations in RBBP8 remained significant (P = 0.028 and 0.036). We then genotyped 314 ovarian tumours for several tSNPs in CASP5 and RBBP8 to identify gene deletions by LOH. For RBBP8, 35% of tumours in 101 informative cases showed somatic allelic deletion; LOH of RBBP8 was associated with a significantly worse prognosis [HR = 2.19 (95% CI: 1.36-3.54), P = 0.001]. In summary, a novel in vitro functional approach in ovarian cancer cells has identified RBBP8 as a gene for which both germline genetic variation and somatic alterations in tumours are associated with survival in ovarian cancer patients.

AB - Common germline genetic variation and/or somatic alterations in tumours may be associated with survival in women diagnosed with ovarian cancer. The successful identification of genetic associations relies on a suitable strategy for identifying and testing candidate genes. We used microcell-mediated chromosome transfer approach and expression microarray analysis to identify genes that were associated with neoplastic suppression in ovarian cancer cell lines. Sixty-five tagging single nucleotide polymorphisms (tSNPs) in nine candidate genes were genotyped in approximately 1700 invasive ovarian cancer cases to look for associations with survival. For two of these genes, loss of heterozygosity (LOH) analysis of tSNPs in 314 ovarian tumours was used to identify associations between somatic gene deletions and survival. We identified significant associations with survival for a tSNP in caspase 5 (CASP5) [hazard ratio (HR) = 1.13 (95% CI: 1.00-1.27), P = 0.042] and two tSNPs in the retinoblastoma binding protein (RBBP8) gene [HR = 0.85 (95% CI: 0.75-0.95), P = 0.007 and HR = 0.83 (95% CI: 0.71-0.95), P = 0.009]. After adjusting for multiple prognostic factors in a multivariate Cox regression analysis, both associations in RBBP8 remained significant (P = 0.028 and 0.036). We then genotyped 314 ovarian tumours for several tSNPs in CASP5 and RBBP8 to identify gene deletions by LOH. For RBBP8, 35% of tumours in 101 informative cases showed somatic allelic deletion; LOH of RBBP8 was associated with a significantly worse prognosis [HR = 2.19 (95% CI: 1.36-3.54), P = 0.001]. In summary, a novel in vitro functional approach in ovarian cancer cells has identified RBBP8 as a gene for which both germline genetic variation and somatic alterations in tumours are associated with survival in ovarian cancer patients.

U2 - 10.1093/hmg/ddp107

DO - 10.1093/hmg/ddp107

M3 - Journal article

C2 - 19270026

SN - 0964-6906

VL - 18

SP - 1869

EP - 1878

JO - Human Molecular Genetics

JF - Human Molecular Genetics

IS - 10

ER -