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USC study in Nature Genetics pinpoints subtype of colorectal cancer

Peter Laird

Photo/Steven Heller

USC researchers have helped identify a subset of colorectal cancer patients whose disease shares an unusual genetic “fingerprint” and their findings appear in the current issue of the journal Nature Genetics.

The finding could lead to advances in treatment for patients in the group, said Peter Laird, associate professor of surgery, biochemistry and molecular biology and director of basic research surgery at the Keck School of Medicine and one of the lead researchers in the study.

The research also lays to rest a debate over whether there is a distinct group of colorectal tumors with an exceptionally high frequency of DNA methylation in CpG islands (referred to as CpG Island Methylator Phenotype, or CIMP), Laird said.

CpG islands are short stretches of DNA usually found near gene regulatory regions. Aberrant DNA methylation of CpG islands is seen in many types of cancer and is associated with gene silencing when it occurs in certain areas.

Whether there is, in fact, a distinct subgroup with CIMP has been a matter of some debate, said Laird. “So we first tried to show that this is a distinct subgrouping and then provide a better, more accurate way to find this type.”

“This is not a marker for colorectal cancer, but for a subset of about 15-20 percent of all cases,” he noted. “It’s hard to pin down, but when you are able to identify this group, the tumors encompass some other features that may play a role in the cancer, like microsatellite instability and BRAF mutations.”

The clinical significance of the CIMP subgrouping “isn’t really clear at this point,” he added. “There are many papers that describe the unique features of these tumors, but in the past they’ve been done with a fairly loose definition. Now that we’ve tightened up the methodology, we can do studies that look at this group’s outcomes.”

Laird believes the CIMP group will be shown to have a differential prognosis and that it may also have a different response to 5-FU, the main chemotherapy used to treat colorectal cancer.

Laird’s laboratory is pursuing studies that look at the CIMP grouping and relationship to clinical outcomes.

“Now that we have a good way of identifying these tumors, it’s easier to segregate them and take a good look at how they respond,” he said.

Laird collaborated with colleagues at USC, the Molecular Cancer Epidemiology Laboratory in Australia, Seoul National University in Korea, University College London in England, the RBWH Foundation Clinical Research Centre in Australia, the Mayo Clinic and McGill University in Montreal, Canada.

Daniel J. Weisenberger, Kimberly D. Siegmund, Mihaela Campan, Joanne Young, Tiffany I. Long, Mark A Faasse, Gyeong Hoon Kang, Martin Widschwendter, Deborah Weener, Daniel Buchanan, Hoey Koh, Lisa Simms, Melissa Barker, Barbara Leggett, Joan Levine, Myungjin Kim, Amy J. French, Stephen N. Thibodeau, Jeremy Jass, Robert Haile, Peter W. Laird, “A Distinct CpG Island Methylator Phenotype in Human Colorectal Cancer is the Underlying Cause of Sporadic Mismatch Repair Deficiency and is Tightly Associated with BRAF Mutation,” Nature Genetics, July 2006, Volume 38, Number 7, pp 787-793.

USC study in Nature Genetics pinpoints subtype of colorectal cancer

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