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Study reveals how inherited risk factors in ‘junk DNA’ affect breast cancer predisposition

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Novel method provides insights in biology of breast cancer

Matthew Freedman, MD

In light of recent large population studies, it’s known that some people carry inherited DNA changes that increase their lifetime risk of diseases, including breast and prostate cancer. To the surprise of scientists, scores of these “risk alleles” have been found in vast regions of the genome – sometimes called “junk DNA” or “dark matter” – that don’t carry the genetic code for proteins, so how they influence an individual’s cancer risk isn’t known.

In a new study, scientists at Dana-Farber Cancer Institute have shown that several such alleles affect DNA segments known as “enhancers” and turn on or off genes involved in breast cancer. Interestingly, four of the genes the research team pinpointed hadn’t previously been implicated in breast cancer. The scientists, led by Matthew Freedman, MD, PhD, reported their findings in the Jan. 31 issue of Cell.

“We can use this tool to show that the DNA variation that influences risk controls the expression of a nearby gene involved in cancer,” said Freedman, of Dana-Farber’s Center for Cancer Genome Discovery and Center Functional Cancer Epigenetics and the Broad Institute. Freedman explained that knowing this link gives scientists new insights into the biology of breast cancer. “If you can identify which pathway or gene is involved in the risk of developing cancer, primary cancer prevention efforts can be more rationally designed.”

In the past several years, investigations called genome-wide association studies (GWAS) have helped define the genetic root causes of many diseases, including cancer. These studies have identified large numbers of relatively common polymorphisms, or places in the human genome where the genetic code differs among individuals, that are associated with inherited, increased risks of cancer.

About 70 such variants – also known as single-nucleotide polymorphisms, or SNPs – have been identified in prostate cancer and an equal number in breast cancer. Although these risk alleles are common in the population, each one increases cancer risk by only a modest amount, according to Freedman. Some individuals may inherit enough risk variants, however, to make a significant difference that someday might prompt physicians to recommend preventive measures.

Freedman said that because the segments of DNA containing the variants lie in uncharted regions of the genome, “it has been a challenge to connect these variants to genes that influence cancer risk.” Clues to their function came in 2012, when reports based on a public database called ENCODE suggested that many of these SNPs are located within regions that regulate the activity of genes.

The Dana-Farber scientists tapped this information and another large publicly funded database, The Cancer Genome Atlas, which contains thoroughly analyzed samples of tumors and the corresponding normal tissue from cancer patients. They studied data on increased gene activity in tumor samples from 407 breast cancer patients. At the same time, they examined data on normal blood samples from those same patients, which revealed the number of breast cancer risk alleles the patients had been born with.

Sophisticated computational methods then linked the risk alleles’ promoter functions to six overactive genes within the breast cancers: two of the genes had already been implicated in breast cancer, but four were identified for the first time, the scientists reported. “Our data showed that the expression of these genes was under genetic control [of the DNA variants],” Freedman said.

He said that this study, the largest of its kind, “is just the beginning” of further work to understand how these variants affect the biology of breast cancer development.

First author of the report is Qiyuan Li, PhD, a postdoctoral fellow in the Freedman lab.

The research was supported in part by grants from the National Institutes of Health (U19CA148537 and R01 CA131341), the Mayer Foundation, the H.L. Snyder Medical Foundation, the Kohlberg Foundation, and the A. David Mazzone Awards Program.

At Dana-Farber/Brigham and Women’s Cancer Center, breast cancer is treated through the Susan F. Smith Center for Women’s Cancers Breast Oncology Program.

Courtesy of Dana-Farber Cancer Institute

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