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Uterine Leiomyoma Risk Linked to Inherited SRCAP Complex Mutations

NEW YORK – New research by investigators at the University of Helsinki suggests susceptibility to benign uterine leiomyoma (UL) smooth muscle tumors may stem from inherited alterations falling in components of a SRCAP complex involved in depositing histone H2A.Z marks on chromatin.

"Our results establish inactivation of genes encoding SRCAP complex subunits as a central contributor to moderate-penetrance UL predisposition," co-senior and co-corresponding authors Auli Karhu and Lauri Aaltonen, with the University of Helsinki's medical and clinical genetics department and the school's Applied Tumor Genomics Research Program, and their colleagues wrote.

The latest findings build on previous studies looking at somatic alterations found in ULs, they explained, noting that SRCAP complex alterations affecting subunit genes such as MED12, HMGA2, or FH appear to be mutually exclusive relative to Cullin 3-RING E3 ligase neddylation gene mutations.

As they reported in the American Journal of Human Genetics on Friday, the researchers used exome sequencing data for 233,614 female UK Biobank participants of European ancestry — including 19,270 individuals with ULs and another 39,439 individuals with a related phenotype, a history of hysterectomy surgery — to search for relatively rare UL-associated loss-of-function variants in nearly 18,900 genes.

The team's initial analyses pointed to an overrepresentation of moderate-penetrance non-synonymous variants in the SRCAP complex subunit-coding genes in YEATS4, ZNHIT1, DMAP1, and ACTL6A in individuals with UL, along with a rise in SRCAP complex mutations in individuals with earlier diagnoses or more severe forms of the disease requiring hysterectomy.

"Identification of predisposing genes associated with development of ULs enables targeted testing of family members, active family planning, and follow-up of the individuals," the authors explained. "It has been shown that the molecular subclass of the UL has an influence on the treatment response, so the genetic background of the tumor may have implications for the new management and prevention strategies tailored to an individual's genetic defect."

Based on UL-associated variants and gene-based associations found in the UK Biobank analysis, along with results from a prior phenome-wide association analysis on UK Biobank participants, the team went on to search for suspicious germline variants with targeted sequence, whole-genome sequence, and/or RNA sequence data on fresh-frozen UL and matched normal myometrium samples from 860 participants in the Finland Myoma Study.

"The large-scale UKB exome-sequencing cohort enabled us to define a focused set of candidate genes for the germline screening of our own sample collection of individuals with ULs," the authors explained, noting that "we were able to identify causative inherited defects in the associated genes encoding SRCAP complex subunits."

In the Finnish cohort, the investigators found four UL cases involving missense, nonsense, or splice-site mutations in the SRCAP complex subunit gene DMAP1 and two UL-affected individuals with missense mutations falling in the YEATS4 gene. One UL patient carried a splice site mutation in ACTL6A, they noted, while second hit somatic mutations turned up in some of these individuals.

"In our sample collection of Finnish individuals with ULs, examination of tumors from individuals with a germline mutation showed that, similar to the somatic setting, genes encoding SRCAP complex subunits frequently displayed a second hit, inactivating the remaining normal allele," the authors explained. "This follows the classical two-hit theory, where tumors arise from two inactivating mutations targeting both alleles of a tumor suppressor gene."