Fibroids' Genomic Landscape Revealed

Ricki Lewis, PhD

June 07, 2013

Whole-genome sequencing and gene expression profiling of uterine fibroids has uncovered a chromosome-shattering process formerly associated only with aggressive cancers, according to a study published online June 5 in the New England Journal of Medicine.

More than three quarters of women have fibroid tumors (leiomyomas), and the growths are typically multiple, although benign. About half of leiomyomas have specific cytogenetic rearrangements, involving deletions of the long arm of chromosome 7 (7q) and rearrangements involving the short arm of chromosome 6 (6p21) or the long arm of chromosome 12 (12q15). Tumors with cytogenetic abnormalities are larger, with more rapidly dividing cells, than tumors with normal chromosomes.

Miika Mehine, MSc, from the Department of Medical Genetics, Genome-Scale Biology Research Program, University of Helsinki, Finland, and colleagues analyzed 38 uterine leiomyomas and the myometrium from 30 women. Sixteen of the leiomyomas had mutations in the MED12 oncogene that regulates transcription, 4 leiomyomas had loss-of-function mutations in the tumor suppressor gene that encodes fumarate hydratase (part of the citric acid cycle), and the other 18 leiomyomas did not have either of these previously identified mutations.

The researchers interrogated 6 tumors from 4 women, using whole-genome sequencing, which revealed that tumors in different women share many characteristics and that tumors from an individual are clonally related. The investigators also looked for insertions and deletions, copy number variants, and rearrangements, which are not revealed in sequencing. They used gene expression profiling to measure 37,217 transcripts.

The goal of the study was to identify genetic or genomic characteristics that might serve as the basis of preventive measures or treatments.

Some of the findings were negative: no newly identified mutations were found in TP53 or other single genes, as well as no insertions or deletions, and no large amplified sequences.

The experiments did reveal what the researchers call "interconnected complex chromosomal rearrangements" (CCRs) — a shattering of a few chromosomes. Breakage to the point of pulverization of chromosomes leads to apoptosis, but more limited damage results in the CCRs.

The researchers hypothesize that CCRs are a manifestation of chromothripsis, a phenomenon associated with aggressive cancers, many of which have TP53 mutations. In cancer, chromothripsis seems to result from a single catastrophic event, but in fibroids, it appears to be the result of multiple events in some cases.

In either benign or malignant states, the chromosome shattering is a consequence of failed DNA repair at the chromosomal level. The researchers define CCRs in fibroids as having 3 or more double-strand breaks, generating 6 or more DNA ends.

"Our data suggest that the oncogenic effect of chromothripsis may be less dramatic than indicated by previous studies of malignant tumors," the researchers conclude. They argue that the emerging molecular classification of uterine fibroids is "a prerequisite for the development of targeted therapies against these lesions."

This study was supported by the Academy of Finland, the Sigrid Jusélius Foundation, the Cancer Society of Finland, and the Jane and Aatos Erkko Foundation. The researchers have disclosed no relevant financial relationships.

N Engl J Med. Published online June 5, 2013. Full text


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