Functional complementation studies identify candidate genes and common genetic variants associated with ovarian cancer survival.
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.
Quaye
Lydia
L
Gynaecological Oncology Unit, UCL EGA Institute for Women's Health, University College London, UK.
Dafou
Dimitra
D
Ramus
Susan J
SJ
Song
Honglin
H
Gentry-Maharaj
Aleksandra
A
Maharaj
Aleksandra Gentry
AG
Notaridou
Maria
M
Hogdall
Estrid
E
Kjaer
Susanne Kruger
SK
Christensen
Lise
L
Hogdall
Claus
C
Easton
Douglas F
DF
Jacobs
Ian
I
Menon
Usha
U
Pharoah
Paul D P
PD
Gayther
Simon A
SA
D000328:Adult; D000368:Aged; D002352:Carrier Proteins / Q000235:genetics*; D020169:Caspases / Q000235:genetics*; D002887:Chromosomes, Human, Pair 18 / Q000235:genetics; D004706:Endodeoxyribonucleases; D005260:Female; D017353:Gene Deletion; D005838:Genotype; D006801:Humans; D019656:Loss of Heterozygosity; D008875:Middle Aged; D009687:Nuclear Proteins / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000401:mortality*; D020641:Polymorphism, Single Nucleotide; D013534:Survival; D044465:White People / Q000235:genetics
D002352:Carrier Proteins; D009687:Nuclear Proteins; D004706:Endodeoxyribonucleases; C410741:RBBP8 protein, human; C099217:CASP5 protein, human; D020169:Caspases