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Whole exome sequencing in a random sample of north American women with leiomyomas identifies MED12 mutations in majority of uterine leiomyomas

McGuire, MM and Yatsenko, A and Hoffner, L and Jones, M and Surti, U and Rajkovic, A (2012) Whole exome sequencing in a random sample of north American women with leiomyomas identifies MED12 mutations in majority of uterine leiomyomas. PLoS ONE, 7 (3).

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Uterine leiomyomas (uterine fibroids) arise from smooth muscle tissue in the majority of women by age 45. It is common for these clonal tumors to develop from multiple locations within the uterus, leading to a variety of symptoms such as pelvic pain, abnormal uterine bleeding, and infertility. We performed whole exome sequencing on genomic DNA from five pairs of leiomyomas and corresponding normal myometrium to determine genetic variations unique to leiomyomas. Whole exome sequencing revealed that the gene encoding transcription factor MED12 (Mediator complex subunit 12) harbored heterozygous missense mutations caused by single nucleotide variants in highly conserved codon 44 of exon 2 in two of five leiomyomas. Sanger re-sequencing of MED12 among these five leiomyomas confirmed the two single nucleotide variants and detected a 42 base-pair deletion within exon 2 of MED12 in a third leiomyoma. MED12 was sequenced in an additional 143 leiomyomas and 73 normal myometrial tissues. Overall, MED12 was mutated in 100/148 (67%) of the genotyped leiomyomas: 79/148 (53%) leiomyomas exhibited heterozygous missense single nucleotide variants, 17/148 (11%) leiomyomas exhibited heterozygous in-frame deletions/insertion-deletions, 2/148 (1%) leiomyomas exhibited intronic heterozygous single nucleotide variants affecting splicing, and 2/148 (1%) leiomyomas exhibited heterozygous deletions/insertion-deletions spanning the intron 1-exon 2 boundary which affected the splice acceptor site. Mutations were not detected in MED12 in normal myometrial tissue. MED12 mutations were equally distributed among karyotypically normal and abnormal uterine leiomyomas and were identified in leiomyomas from both black and white American women. Our studies show an association between MED12 mutations and leiomyomas in ethnically and racially diverse American women. © 2012 McGuire et al.


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Item Type: Article
Status: Published
CreatorsEmailPitt UsernameORCID
McGuire, MM
Yatsenko, Aany23@pitt.eduANY23
Hoffner, L
Jones, M
Surti, Usurti@pitt.eduSURTI
Rajkovic, Aalr110@pitt.eduALR110
ContributionContributors NameEmailPitt UsernameORCID
Date: 12 March 2012
Date Type: Publication
Journal or Publication Title: PLoS ONE
Volume: 7
Number: 3
DOI or Unique Handle: 10.1371/journal.pone.0033251
Schools and Programs: School of Medicine > Obstetrics, Gynecology, and Reproductive Sciences
Refereed: Yes
MeSH Headings: Base Sequence; DNA, Complementary--genetics; Exome--genetics; Female; Genetic Association Studies; Genetic Predisposition to Disease--genetics; Humans; Leiomyomatosis--epidemiology; Leiomyomatosis--genetics; Mediator Complex--genetics; Molecular Sequence Data; Mutation--genetics; North America--epidemiology; Sequence Analysis, DNA; Uterine Neoplasms--epidemiology; Uterine Neoplasms--genetics
Other ID: NLM PMC3299761
PubMed Central ID: PMC3299761
PubMed ID: 22428002
Date Deposited: 13 Sep 2012 20:25
Last Modified: 04 Feb 2019 15:56


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