full free text: Targeted Epigenetic Therapies: The Next Frontier? — J. Natl. Cancer Inst. (includes discussion regarding clear cell/ARIDIa mutation

Targeted Epigenetic Therapies: The Next Frontier?

1. Rabiya S. Tuma

When researchers look for mutations associated with cancer, they often expect to come up with alterations in signaling molecules or transcription factors. But an increasing number of the mutations found are in genes that regulate the epigenome—a system that alters DNA structure and regulates gene activity without changing the nucleotide sequence itself.

On Sept. 8, investigators published two independent reports online—one in Science and one in the New England Journal of Medicine—showing that mutations in an epigenetic regulatory gene, ARID1a, were associated with approximately half of the ovarian clear-cell cancers tested.

The two studies bolster the argument that epigenetics is important in tumor progression and possibly tumor formation, as well as that therapies targeted at specific epigenetic regulators or their effectors may improve patient outcomes. Although the approach's viability remains unproven, many groups and companies are already working on molecularly targeted compounds designed to restore the epigenetic system.

Frequent Mutations

In both studies, the authors initially discovered mutations in ARID1a by sequencing protein-coding genes in ovarian clear-cell tumors. In the Science paper, Siân Jones, Ph.D., of the Johns Hopkins Kimmel Cancer Center, and colleagues report that 24 (57%) of 42 ovarian clear-cell cancers carried mutations in ARID1a. In the New England Journal of Medicine, Kimberly C. Wiegand, from the British Columbia Cancer Agency in Vancouver, and colleagues report that 55 (46%) of 119 ovarian clear-cell cancers carried ARID1a mutations, as did 10 (30%) of 33 endometrioid cancers. The mutations that both studies detected suggest that ARID1a functions as a tumor suppressor gene and that its role in remodeling chromatin—which can include unwinding DNA to allow transcription machinery access—is required to prevent tumor formation...cont'd