title: Fatty acid synthase polymorphisms, tumor expression, body mass index, prostate cancer risk, and survival.
abstract: OBJECTIVE
  Fatty acid synthase (FASN) regulates de novo lipogenesis, body weight, and tumor growth. We examined whether common germline single nucleotide polymorphisms (SNPs) in the FASN gene affect prostate cancer (PCa) risk or PCa-specific mortality and whether these effects vary by body mass index (BMI).
  
  
  METHODS
  In a prospective nested case-control study of 1,331 white patients with PCa and 1,267 age-matched controls, we examined associations of five common SNPs within FASN (and 5 kb upstream/downstream, R(2) > 0.8) with PCa incidence and, among patients, PCa-specific death and tested for an interaction with BMI. Survival analyses were repeated for tumor FASN expression (n = 909).
  
  
  RESULTS
  Four of the five SNPs were associated with lethal PCa. SNP rs1127678 was significantly related to higher BMI and interacted with BMI for both PCa risk (P(interaction) = .004) and PCa mortality (P(interaction) = .056). Among overweight men (BMI > or = 25 kg/m(2)), but not leaner men, the homozygous variant allele carried a relative risk of advanced PCa of 2.49 (95% CI, 1.00 to 6.23) compared with lean men with the wild type. Overweight patients carrying the variant allele had a 2.04 (95% CI, 1.31 to 3.17) times higher risk of PCa mortality. Similarly, overweight patients with elevated tumor FASN expression had a 2.73 (95% CI, 1.05 to 7.08) times higher risk of lethal PCa (P(interaction) = .02).
  
  
  CONCLUSIONS
  FASN germline polymorphisms were significantly associated with risk of lethal PCa. Significant interactions of BMI with FASN polymorphisms and FASN tumor expression suggest FASN as a potential link between obesity and poor PCa outcome and raise the possibility that FASN inhibition could reduce PCa-specific mortality, particularly in overweight men.
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: Paul L
authors.initials: PL
authors.lastname: Nguyen
authors.forename: Jing
authors.initials: J
authors.lastname: Ma
authors.forename: Jorge E
authors.initials: JE
authors.lastname: Chavarro
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Freedman
authors.forename: Rosina
authors.initials: R
authors.lastname: Lis
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Fedele
authors.forename: Christopher
authors.initials: C
authors.lastname: Fiore
authors.forename: Weiliang
authors.initials: W
authors.lastname: Qiu
authors.forename: Michelangelo
authors.initials: M
authors.lastname: Fiorentino
authors.forename: Stephen
authors.initials: S
authors.lastname: Finn
authors.forename: Kathryn L
authors.initials: KL
authors.lastname: Penney
authors.forename: Anna
authors.initials: A
authors.lastname: Eisenstein
authors.forename: Fredrick R
authors.initials: FR
authors.lastname: Schumacher
authors.forename: Lorelei A
authors.initials: LA
authors.lastname: Mucci
authors.forename: Meir J
authors.initials: MJ
authors.lastname: Stampfer
authors.forename: Edward
authors.initials: E
authors.lastname: Giovannucci
authors.forename: Massimo
authors.initials: M
authors.lastname: Loda
mesh_terms: D000328:Adult; D000368:Aged; D015992:Body Mass Index; D064429:Fatty Acid Synthases / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000401:mortality; D012307:Risk Factors
chemical_list: D064429:Fatty Acid Synthases