Gene Mutation May Shift Endometriosis Toward Ovarian Cancer

Janis C. Kelly

September 09, 2010

September 9, 2010 — The loss of function of an apparent tumor suppressor gene might be an early step in the progression of endometriosis to ovarian clear-cell carcinoma, according to 2 new studies.

In both studies, mutations in the ARID1A gene were found in about half of ovarian clear-cell carcinomas. In 1 of the studies, the mutations were also found in 30% of endometrioid carcinomas, but not in serous ovarian carcinomas.

Both studies point to abnormal chromatin remodeling as a factor in the stepwise progression from endometriosis to cancer.

In the first study, Canadian researchers sequenced ARID1A in 210 ovarian carcinomas and measured the expression of BAF250a (a key component of the SWI–SNF chromatin remodeling complex that is encoded by ARID1A)in 455 ovarian carcinomas. They found ARID1A mutations in 55 of 119 ovarian clear-cell carcinomas (46%) and in 10 of 33 endometriod carcinomas (30%), but not in any of 76 high-grade serous ovarian carcinomas. Tumors with ARID1A mutations also usually lost BAF250a expression.

The work was published online September 8 in the New England Journal of Medicine.

Senior author David G. Huntsman, MD, from the Centre for Translational and Applied Genomics at the British Columbia Cancer Agency in Vancouver, told Medscape Medical News that, in 2 patients, the discovery of ARID1A mutations and the loss of BAF250a expression in the tumors and contiguous atypical endometriosis — but not in their distant endometriotic lesions — were a surprise, and suggest that this is an early step in the transformation of endometriosis to cancer.

"The finding of the mutations in the contiguous endometriosis was an exciting aspect, and the strength of the correlation with the subtype was beyond our expectations," Dr. Huntsman said. He noted that the SWI–SNF chromatin remodeling complex that is encoded by ARID1A links genetic and epigenetic factors in the development of ovarian cancer.

The authors conclude that ARID1A is a classic tumor-suppressor gene and note that, unlike BRCA or TP53 mutations, which can be found in the germ-line DNA, all truncating ARID1A mutations were somatic.

"It is possible that defects in genes that alter the accessibility of transcription factors to chromatin, such as ARID1A, in addition to mutations in the WNT and PI3 kinase pathways, will help to define ovarian clear-cell carcinomas and endometrioid carcinomas. If such a model is correct, other abnormalities affecting the ARID1A locus or dysregulation of other chromatin-remodeling genes may be found in ovarian clear-cell and endometriod carcinomas that are negative for an ARID1A mutation. This idea is supported by the clinical similarities between ovarian clear-cell carcinomas positive for and those negative for an ARID1A mutation," the authors write.

Dr. Huntsman predicted that the ARID1A discovery might lead to a screening tool to help physicians identify endometriosis patients who are at high risk for clear-cell carcinoma and to new treatment approaches for the notoriously treatment-resistant cancer.

Mutations in chromatin are under study in other cancers, and Dr. Huntsman suggested that although abnormalities in DNA repair mark many high-grade cancers, mutations in chromatin remodeling complexes might dominate intermediate- and lower-grade cancers.

However, cancer gene researcher David Reisman, MD, PhD, who reviewed the paper by Huntsman et al for Medscape Medical News, warned against overinterpretation of the results and pointed out that the researchers provide no functional data to support their contention that ARID1A mutations play a critical role in many cases of ovarian clear-cell and endometriod carcinomas.

"Although this study has far-reaching implications, there is nothing in this report showing that it actually forwards the progression of the cancer. What the authors show is that if you sequence every single transcript in the tumor, you are likely to find mutations in this gene," said Dr. Reisman, who is from the University of Michigan Comprehensive Cancer Center in Ann Arbor.

Different Approach, Some Similar Findings

In the second study, Siân Jones, PhD, and colleagues from the Johns Hopkins Kimmel Cancer Center in Baltimore, Maryland, report that 4 genes are mutated in ovarian clear-cell tumors: 2 that have previously been implicated in these cancers (PIK3CA and KRAS ) and 2 that have not previously been associated with ovarian clear-cell carcinoma (ARID1A and the oncogene PPP2R1A).

The work was published online September 8 in Science.

Like the Canadian investigators, these researchers found ARID1A mutations in about half (57%) of 42 ovarian clear-cell carcinomas. They also found PPP2R1A mutations in 7% of those tumors.

ARID1A and PPP2R1A have not previously been linked to ovarian cancer, and "they may provide opportunities for developing new biomarkers and therapies that target those genes," said senior author Nickolas Papadopoulos, PhD, associate professor of oncology and director of translational genetics at the Ludwig Center for Cancer Genetics & Therapeutics at the Johns Hopkins Kimmel Cancer Center.

The researchers say mutated ARID1A can now be linked to so-called "epigenetic" changes — alterations to DNA occurring outside of the genome; in this case, the chromatin. "The mutations in ARID1A provide an important new link between genetic and epigenetic mechanisms in human cancer and may help identify epigenetic changes that can be targeted with therapies," said coauthor Victor Velculescu, MD, PhD, associate professor of oncology at the Johns Hopkins Kimmel Cancer Center.

The researchers have disclosed no relevant financial relationships.

N Engl J Med. Published online September 8, 2010.
Science.2010; Published online September 8, 2010.

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