Fatty Acid Synthase Polymorphisms, Tumor Expression, Body Mass Index, Prostate Cancer Risk, and Survival

Abstract

A B S T R A C T PurposeFatty 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). MethodsIn 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 Ͼ 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 ϭ 909). ResultsFour 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 ϭ .004) and PCa mortality (P interaction ϭ .056). Among overweight men (BMI Ն 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 ϭ .02). ConclusionFASN 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.

Fatty Acid Synthesis Pathway Genetic Variants and Clinical Outcome of Non-Small Cell Lung Cancer Patients after Surgery

“…It has been reported that SNP rs4247357 in the FASN gene is associated with the risk of uterine leiomyomata (Eggert et al, 2012). In addition, Nguyen PL et al have reported that SNP rs1127678 in the FASN gene is associated with the risk and mortality of prostate cancer (Nguyen et al, 2010). In line with these findings, we found that two SNPs (rs4246444 and rs4485435) in FASN gene were significantly associated with the risk of recurrence in NSCLC patients, while SNP rs9912300 in ACLY gene was associated with the OS of NSCLC patients.…”

“…Several studies have also discussed the relationship between polymorphisms of DNL genes and development and prognosis of cancers (Nguyen et al, 2010;Eggert et al, 2012). However, no studies have focused on the association between polymorphisms of ACLY, ACC and FASN and NSCLC prognosis until now.…”

Targeted therapy with fatty acid synthase inhibitors in a human prostate carcinoma LNCaP/tk-luc-bearing animal model

“…4,14 High level of FASN has also been linked with poor prognosis and reduced disease-free survival in prostate cancer patients. 15,16 It has been reported that overexpression of FASN induces transformation of immortalized prostate epithelial cells into invasive adenocarcinomas, and transgenic mice expressing FASN in the prostate develop intraepithelial neoplasia, suggesting that FASN has an important role in the development and progression of prostate cancer. 17 Therefore, this characteristic of cancer cells promises FASN to be a potential target for cancer therapy.…”

Research on Anti-oxidant Activity and Hypolipemic Mechanism of Aloes Flavonoids in Mice

“…FAS gene promoter activities were 4 to 6-fold higher in adipocytes of obese rats than in those of non-obese rats. It has been reported that FAS gene expression in human adipose tissue is associated with obesity and type 2 diabetes [32]. Chakravarthy et al (2009) have reported that a low level of FAS could protect mice from diet-induced obesity [33].…”