Genome-wide Linkage and Association Analyses Implicate FASN in Predisposition to Uterine Leiomyomata

Abstract

Uterine leiomyomata (UL), the most prevalent pelvic tumors in women of reproductive age, pose a major public health problem given their high frequency, associated morbidities, and most common indication for hysterectomies. A genetic component to UL predisposition is supported by analyses of ethnic predisposition, twin studies, and familial aggregation. A genome-wide SNP linkage panel was genotyped and analyzed in 261 white UL-affected sister-pair families from the Finding Genes for Fibroids study. Two significant linkage regions were detected in 10p11 (LOD = 4.15) and 3p21 (LOD = 3.73), and five additional linkage regions were identified with LOD scores > 2.00 in 2q37, 5p13, 11p15, 12q14, and 17q25. Genome-wide association studies were performed in two independent cohorts of white women, and a meta-analysis was conducted. One SNP (rs4247357) was identified with a p value (p = 3.05 × 10(-8)) that reached genome-wide significance (odds ratio = 1.299). The candidate SNP is under a linkage peak and in a block of linkage disequilibrium in 17q25.3, which spans fatty acid synthase (FASN), coiled-coil-domain-containing 57 (CCDC57), and solute-carrier family 16, member 3 (SLC16A3). By tissue microarray immunohistochemistry, we found elevated (3-fold) FAS levels in UL-affected tissue compared to matched myometrial tissue. FAS transcripts and/or protein levels are upregulated in various neoplasms and implicated in tumor cell survival. FASN represents the initial UL risk allele identified in white women by a genome-wide, unbiased approach and opens a path to management and potential therapeutic intervention.

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

“…However, little is known on the associations between these SNPs and cancer risk as well as patient prognosis. 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).…”

“…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.…”

Follow-up to genome-wide linkage and admixture mapping studies implicates components of the extracellular matrix in susceptibility to and size of uterine fibroids

“…No candidate susceptibility genes have consistently emerged from the few linkage scans and genome-wide association studies (GWAS) reported so far (8–11). Exome sequencing in 18 UL tumors and matched normal myometria has implicated the mediator complex subunit 12 ( MED12 ) gene (12) and further examinations of exomes and gene-expression profiling in a set of 38 UL and matched myometria led to the hypothesis that a chromothripsis-like event drives the pathogenesis of UL leading to translocations of the HMGA2 and RAD51B loci and to other chromosomal aberrations including the COL4A5-COL4A6 locus (13).…”

“…We conducted an independent follow-up fine mapping of extended candidate regions that were identified in a genome-wide linkage scan in ASP (11) and mapping by admixture linkage disequilibrium (MALD) in the Black Women’s Health Study (BWHS)(10). We report data in both the African American (AA) and European American (EA) study groups implicating variant members of the collagen gene family encoding components of the extracellular matrix suspected in fibrosis (19).…”

Polymorphisms in Genes of the De Novo Lipogenesis Pathway and Overall Survival of Hepatocellular Carcinoma Patients Undergoing Transarterial Chemoembolization

“…Excepting for amino acid change, SNPs directly affect gene functions through various translational or post-translational mechanisms, such as altering miRNA binding, gene splicing, protein folding or mRNA degradation (Chamary et al, 2006). There were several studies have investigated the association between polymorphisms of DNL genes and development or prognosis of cancers (Nguyen et al, 2010;Eggert et al, 2012). Previously, our group has identified that SNPs in ACLY and FASN genes are significantly associated with clinical outcomes in non-small cell lung cancer patients (Jin et al, 2014).…”