“Mutations in fumarate hydratase on chromosome 1q43 cause a rare cancer syndrome — the hereditary leiomyomatosis and renal cell cancer — but are rare in nonsyndromic and common uterine leiomyoma, or fibroids. Studies suggested that variants in FH or in a linked gene may also predispose to UL,” says Dr. Brahim Aissani, research assistant professor in the department of epidemiology at the University of Alabama at Birmingham. In collaboration with Dr. Howard W. Wiener, statistician in UAB’s department of epidemiology, and Dr. Kui Zhang, associate professor in the department of biostatistics, section on statistical genetics, as well as the Dutch HLRCC working group, Dr. Aissani recently re-sequenced 2.3 Mb of DNA spanning fumarate hydratase (FH) in 96 uterine leiomyoma (UL) cases and controls from the multiethnic National Institute of Environmental Health Services Uterine Fibroid Study (NIEHS-UFS) and in 18 hereditary leiomyomatosis and renal cell cancer (HLRCC)-associated UL probands from European families and identified 221 informative single nucleotide polymorphisms (SNPs) for follow-up genotyping.
The researchers found “promising susceptibility associations with UL peaking at rs78220092 (p= 7.0 x 10-5) in the RGS7-FH interval in African Americans”; in race-combined analyses and in meta-analyses (n=916), they “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 PLD5 gene at rs2654879 (p=1.7x 10-4).” The team confirmed previously reported FH mutations in 9 out of the 18 HLRCC-associated UL cases, in addition to identifying two missense mutations in FH only in two nonsyndromic UL cases and in 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 with matched myometrium suggest a potential role of this genomic region in UL pathogenesis,” observes Dr. Aissani. “While the identified variations at 1q43 represent a potential risk locus for UL, future replication analyses are required to substantiate our observation.”
Future assessment of the cis gene (RGS7, FH or a putative unannotated gene in the RGS7-FH interval) is an important undertaking to improve our understanding not only of UL pathogenesis but also of the genetic basis of syndromic (rare Mendelian diseases) versus nonsyndromic (common diseases) counterparts of diseases in general.
“Fine Mapping of the Uterine Leiomyoma Locus on 1q43 Close to a lincRNA in the RGS7-FH Interval” was published online in June in the journal Endocrine-Related Cancer.