Multiple Hits for the Association of Uterine Fibroids on Human Chromosome 1q43

Abstract

Uterine leiomyomas (or fibroids) are the most common tumors in women of reproductive age. Early studies of two familial cancer syndromes, the multiple cutaneous and uterine leiomyomatosis (MCUL1), and the hereditary leiomyomatosis and renal cell cancer (HLRCC), implicated FH, a gene on chromosome 1q43 encoding the tricarboxylic acid cycle fumarate hydratase enzyme. The role of this metabolic housekeeping gene in tumorigenesis is still a matter of debate and pseudo-hypoxia has been suggested as a pathological mechanism. Inactivating FH mutations have rarely been observed in the nonsyndromic and common form of fibroids; however, loss of heterozygosity across FH appeared as a significant event in the pathogenesis of a subset of these tumors. To assess the role of FH and the linked genes in nonsyndromic uterine fibroids, we explored a two-megabase interval spanning FH in the NIEHS Uterine fibroid study, a cross-sectional study of fibroids in 1152 premenopausal women. Association mapping with a dense set of single nucleotide polymorphisms revealed several peaks of association (p = 10−2–8.10−5) with the risk and/or growth of fibroids. In particular, genes encoding factors suspected (cytosolic FH) or known (EXO1 - exonuclease 1) to be involved in DNA mismatch repair emerged as candidate susceptibility genes whereas those acting in the autophagy/apoptosis (MAP1LC3C - microtubule-associated protein) or signal transduction (RGS7 - Regulator of G-protein and PLD5– Phospoholipase D) appeared to affect tumor growth. Furthermore, body mass index, a suspected confounder altered significantly but unpredictably the association with the candidate genes in the African and European American populations, suggesting the presence of a major obesity gene in the studied region. With the high potential for occult tumors in common conditions such as fibroids, validation of our data in family-based studies is needed.

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

“…The characteristics of the participants available for the study were described in a previous report (16). Several covariates showed different distributions between the two major ethnic groups outlining the necessity to conduct separate analyses.…”

“…Because the participants to the NIEHS-UFS are predominantly of AA or EA descent, we downloaded SNP genotype data from the reference HapMap II and III populations relevant to these ethnic backgrounds and used TAGster (24) to select tag SNPs as described (16). We selected 537 tag SNPs for the top 15 candidate positional genes and 652 SNPs in the remaining 85 positional candidates.…”

“…Principal component analysis (PCA)-based race groups were determined by discriminant analysis of an extended set of 4,363 SNPs in a previous study (16). Early studies in NIEHS-UFS have assessed the levels of the ordinal covariates that influenced or modified the risk of UL (20, 22, 26); we therefore modeled these covariates accordingly.…”

“…Furthermore, genome-wide linkage scan in the affected sister study (ASP) (8) and fine association mapping across the FH -linked region in the NIEHS cohort (16) suggested the presence of a candidate 1q43 gene affecting the risk and size of UL. More recently, epidemiologic studies of UL in American women enrolled in the Right from the Start (RFTS) cohort and the BioVU DNA repository replicated the results of GWAS in a Japanese population for two of the three most significantly associated genes encoding BET1L (blocked early in transport 1 homolog) and TNRC6B (trinucleotide repeat containing 6B) (17, 18).…”

Thematic Review Series: Phospholipases: Central Role in Lipid Signaling and Disease

“…Despite having no catalytic activity, PLD5 has been linked to a number of diseases, including a profi brotic uterine phenotype that occurs during childbearing years, and PLD5 polymorphisms may be associated with an increased risk of tumor progression in multiple cutaneous and uterine leiomyomatosis syndrome ( 102 ).…”