Inherited determinants of ovarian cancer survival.
OBJECTIVE
Due to variation of outcome among cases, we sought to examine whether overall survival in ovarian cancer was associated with common inherited variants in 227 candidate genes from ovarian cancer-related pathways including angiogenesis, inflammation, detoxification, glycosylation, one-carbon transfer, apoptosis, cell cycle regulation, and cellular senescence.


METHODS
Blood samples were obtained from 325 women with invasive epithelial ovarian cancer diagnosed at the Mayo Clinic from 1999 to 2006. During a median follow-up of 3.8 years (range, 0.1-8.6 years), 157 deaths were observed. Germline DNA was analyzed at 1,416 single nucleotide polymorphisms (SNP). For all patients, and for 203 with serous subtype, we assessed the overall significance of each gene and pathway, and estimated risk of death via hazard ratios (HR) and 95% confidence intervals (CI), adjusting for known prognostic factors.


RESULTS
Variation within angiogenesis was most strongly associated with survival time overall (P = 0.03) and among patients with serous cancer (P = 0.05), particularly for EIF2B5 rs4912474 (all patients HR, 0.69; 95% CI, 0.54-0.89; P = 0.004), VEGFC rs17697305 (serous subtype HR, 2.29; 95% CI, 1.34-3.92; P = 0.003), and four SNPs in VHL. Variation within the inflammation pathway was borderline significant (all patients, P = 0.09), and SNPs in CCR3, IL1B, IL18, CCL2, and ALOX5 which correlated with survival time are worthy of follow-up.


CONCLUSIONS
An extensive multiple-pathway assessment found evidence that inherited differences may play a role in outcome of ovarian cancer patients, particularly in genes within the angiogenesis and inflammation pathways. Our work supports efforts to target such mediators for therapeutic gain.
Goode
Ellen L
EL
Mayo Clinic College of Medicine, Rochester, Minnesota, USA. egoode@mayo.edu
Maurer
Matthew J
MJ
Sellers
Thomas A
TA
Phelan
Catherine M
CM
Kalli
Kimberly R
KR
Fridley
Brooke L
BL
Vierkant
Robert A
RA
Armasu
Sebastian M
SM
White
Kristin L
KL
Keeney
Gary L
GL
Cliby
William A
WA
Rider
David N
DN
Kelemen
Linda E
LE
Jones
Monica B
MB
Peethambaram
Prema P
PP
Lancaster
Johnathan M
JM
Olson
Janet E
JE
Schildkraut
Joellen M
JM
Cunningham
Julie M
JM
Hartmann
Lynn C
LC
D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007249:Inflammation / Q000235:genetics; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000235:genetics; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000401:mortality*; D020641:Polymorphism, Single Nucleotide