Fine mapping of the uterine leiomyoma locus on 1q43 close to a lncRNA in the RGS7-FH interval.

Brahim Aissani,Kui Zhang,Fred H Menko,Howard W Wiener,Arjen R Mensenkamp

doi:10.1530/erc-15-0208

Abstract

Mutations in fumarate hydratase (FH) on chromosome 1q43 cause a rare cancer syndrome, hereditary leiomyomatosis and renal cell cancer (HLRCC), but are rare in nonsyndromic and common uterine leiomyoma (UL) or fibroids. Studies suggested that variants in FH or in a linked gene may also predispose to UL. We re-sequenced 2.3 Mb of DNA spanning FH in 96 UL cases and controls from the multiethnic NIEHS-uterine fibroid study, and in 18 HLRCC-associated UL probands from European families then selected 221 informative SNPs for follow-up genotyping. We report promising susceptibility associations with UL peaking at rs78220092 (P=7.0×10−5) in the RGS7-FH interval in African Americans. In race-combined analyses and in meta-analyses (n=916), we identified promising associations with risk peaking upstream of a non-protein coding RNA (lncRNA) locus located in the RGS7-FH interval closer to RGS7, and associations with tumor size peaking in the distal phospholipase D family, member 5 (PLD5) gene at rs2654879 (P=1.7×10−4). We corroborated previously reported FH mutations in nine out of the 18 HLRCC-associated UL cases and identified two missense mutations in FH in only two nonsyndromic UL cases and one control. Our fine association mapping and integration of existing gene profiling data showing upregulated expression of the lncRNA and downregulation of PLD5 in fibroids, as compared to matched myometrium, suggest a potential role of this genomic region in UL pathogenesis. While the identified variations at 1q43 represent a potential risk locus for UL, future replication analyses are required to substantiate our observation.

Highlights

Uterine leiomyoma (UL) are benign neoplasms that arise from the smooth muscle cells of the uterus
A possible explanation to these genotyping failures is the proximity among single nucleotide polymorphisms (SNPs), which can hinder the multiplex GoldenGate assay even by observing the minimal inter-SNP distance of 60 bp recommended by the manufacturer
We observed a total of 154 SNPs in the 22 kb-long fumarate hydratase (FH) gene (21 variants in coding and regulatory regions) in 113 quality control samples (93 NIEHS-UFS and 20 hereditary leiomyomatosis and renal cell cancer (HLRCC) samples) and confirmed the presence of FH mutations (Table 1) in nine of the 18 tested HLRCC probands as previously reported (Smit et al 2011)

Summary

Introduction

Uterine leiomyoma (UL) are benign neoplasms that arise from the smooth muscle cells of the uterus. Despite their benign nature, UL are responsible for significant gynecologic morbidities including excessive bleeding, pelvic pain, urinary incontinence, infertility, and pregnancy complications (Stewart 2001, Walker & Stewart 2005). Cumulative exposure to estrogen is believed to be a major etiologic factor 1996) and factors that may influence the hormonal milieu, such as obesity, are believed to be associated with risk (Schwartz et al 2000). Established risk factors are age (increasing risk with increasing premenopausal age), menopause (risk decreases with menopause) and African American (AA) ethnicity (higher risk compared with that of non-Hispanic Whites) (Baird et al 2003)

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