Fatty acid synthase polymorphisms, tumor expression, body mass index, prostate cancer risk, and survival.
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.
Nguyen
Paul L
PL
Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Ma
Jing
J
Chavarro
Jorge E
JE
Freedman
Matthew L
ML
Lis
Rosina
R
Fedele
Giuseppe
G
Fiore
Christopher
C
Qiu
Weiliang
W
Fiorentino
Michelangelo
M
Finn
Stephen
S
Penney
Kathryn L
KL
Eisenstein
Anna
A
Schumacher
Fredrick R
FR
Mucci
Lorelei A
LA
Stampfer
Meir J
MJ
Giovannucci
Edward
E
Loda
Massimo
M
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
D064429:Fatty Acid Synthases