BACKGROUND: Uterine leiomyomas are benign but affect the health of millions of women. A better understanding of the molecular mechanisms involved may provide clues to the prevention and treatment of these lesions. METHODS: We performed whole-genome sequencing and gene-expression profiling of 38 uterine leiomyomas and the corresponding myometrium from 30 women. RESULTS: Identical variants observed in some separate tumor nodules suggested that these nodules have a common origin. Complex chromosomal rearrangements resembling chromothripsis were a common feature of leiomyomas. These rearrangements are best explained by a single event of multiple chromosomal breaks and random reassembly. The rearrangements created tissue-specific changes consistent with a role in the initiation of leiomyoma, such as translocations of the HMGA2 and RAD51B loci and aberrations at the COL4A5-COL4A6 locus, and occurred in the presence of normal TP53 alleles. In some cases, separate events had occurred more than once in single tumor-cell lineages. CONCLUSIONS: Chromosome shattering and reassembly resembling chromothripsis (a single genomic event that results in focal losses and rearrangements in multiple genomic regions) is a major cause of chromosomal abnormalities in uterine leiomyomas; we propose that tumorigenesis occurs when tissue-specific tumor-promoting changes are formed through these events. Chromothripsis has previously been associated with aggressive cancer; its common occurrence in leiomyomas suggests that it also has a role in the genesis and progression of benign tumors. We observed that multiple separate tumors could be seeded from a single lineage of uterine leiomyoma cells. (Funded by the Academy of Finland Center of Excellence program and others.).
BACKGROUND: Uterine leiomyomas are benign but affect the health of millions of women. A better understanding of the molecular mechanisms involved may provide clues to the prevention and treatment of these lesions. METHODS: We performed whole-genome sequencing and gene-expression profiling of 38 uterine leiomyomas and the corresponding myometrium from 30 women. RESULTS: Identical variants observed in some separate tumor nodules suggested that these nodules have a common origin. Complex chromosomal rearrangements resembling chromothripsis were a common feature of leiomyomas. These rearrangements are best explained by a single event of multiple chromosomal breaks and random reassembly. The rearrangements created tissue-specific changes consistent with a role in the initiation of leiomyoma, such as translocations of the HMGA2 and RAD51B loci and aberrations at the COL4A5-COL4A6 locus, and occurred in the presence of normal TP53 alleles. In some cases, separate events had occurred more than once in single tumor-cell lineages. CONCLUSIONS: Chromosome shattering and reassembly resembling chromothripsis (a single genomic event that results in focal losses and rearrangements in multiple genomic regions) is a major cause of chromosomal abnormalities in uterine leiomyomas; we propose that tumorigenesis occurs when tissue-specific tumor-promoting changes are formed through these events. Chromothripsis has previously been associated with aggressive cancer; its common occurrence in leiomyomas suggests that it also has a role in the genesis and progression of benign tumors. We observed that multiple separate tumors could be seeded from a single lineage of uterine leiomyoma cells. (Funded by the Academy of Finland Center of Excellence program and others.).
Authors: James H Segars; Estella C Parrott; Joan D Nagel; Xiaoxiao Catherine Guo; Xiaohua Gao; Linda S Birnbaum; Vivian W Pinn; Darlene Dixon Journal: Hum Reprod Update Date: 2014-01-08 Impact factor: 15.610
Authors: Lauren A Wise; Todd R Sponholtz; Lynn Rosenberg; Lucile L Adams-Campbell; Wendy Kuohung; Michael P LaValley; Julie R Palmer Journal: Cancer Causes Control Date: 2016-02-29 Impact factor: 2.506
Authors: David M Hyman; Michael W Sill; Heather A Lankes; Richard Piekarz; Mark S Shahin; Mildred R Ridgway; Floor Backes; Meaghen E Tenney; Cara A Mathews; James S Hoffman; Carol Aghajanian; Martee L Hensley Journal: Gynecol Oncol Date: 2016-10-27 Impact factor: 5.482
Authors: Seung-Hyun Jung; Min Sung Kim; Sung-Hak Lee; Hyun-Chun Park; Hyun Joo Choi; Leeso Maeng; Ki Ouk Min; Jeana Kim; Tae In Park; Ok Ran Shin; Tae-Jung Kim; Haidong Xu; Kyo Young Lee; Tae-Min Kim; Sang Yong Song; Charles Lee; Yeun-Jun Chung; Sug Hyung Lee Journal: Proc Natl Acad Sci U S A Date: 2016-09-06 Impact factor: 11.205