NCI-funded sequencing project aims to identify genetic links to colorectal cancer

Uncovering colon cancer's genetic roots is the focus of a new $13 million, four-year, National Cancer Institute-funded project at Fred Hutchinson Cancer Research Center. Ulrike (Riki) Peters, Ph.D., M.P.H., a member of the Hutchinson Center's Public Health Sciences Division, will lead the effort. She and her colleagues will use next-generation sequencing, a technique that captures entire genome sequences, to identify genetic links to colorectal cancer.

"This is an important step, to look at much of the genetic variation across the entire genome. We didn't have the opportunity to study this in the past with the technologies we had before," Peters said. "We are now able to investigate millions of common and rare variants across the genome. Next-generation sequencing is becoming more readily available to look at these variants on a large scale." Colorectal cancer is the third most common and second deadliest cancer in the U.S., killing more than 50,000 every year. About one-third of these cancers can be attributed to heritable factors, meaning genetic mutations play a role in the cancer's development. Some of these genetic variations can also affect a person's susceptibility to environmental risk factors. For example, smoking increases the risk of colorectal cancer, but it's possible that certain genetic factors in combination with smoking could even further increase that risk.

For the past four years, Peters and colleagues have been studying the genes linked to colorectal cancer through the Genetics and Epidemiology of Colorectal Cancer Consortium, a collaboration involving researchers from North America, Australia and Europe who have pooled data from approximately 40,000 study participants, approximately half of whom have colorectal cancer. The Hutchinson Center houses GECCO's coordinating center and Peters is its principal investigator.

Due to the infrastructure the team already has built and the knowledge gained from GECCO, they are well equipped for this next stage of work on heritable risk factors for colorectal cancer.

Peters' new study will use next-generation sequencing to reveal entire genome sequences of a subset of GECCO's samples. Her study is among the first NCI-funded projects to use this technology on such a large sample set.

Peters' past studies have also looked at genetic links to colorectal cancer in these same study participants, but using the traditional means of genotyping allowed her group to identify only the most common variants and only certain types of mutations. Next-generation sequencing will capture more rare variants and many more types of genetic irregularities that could be linked to heritable factors of colorectal cancer.

Identifying rare genetic variants involved in colorectal cancer could ultimately help everyone with or at risk for this disease, Peters said. Knowing which genes play a role in triggering the cancer will lead to a better understanding of how the cancer develops and could ultimately lead to improved drug development.

Peters' and other researchers' work has identified about 20 different common genetic links to colorectal cancer, which explains about 8 to 10 percent of inherited colorectal cancers. "Our new grant will allow us to identify some of the missing heritability that has not been found so far," Peters said.

Along with heritability, her group will study the interrelation between genes, environment and colorectal cancer. Several environmental risk factors, such as smoking, body mass index, physical activity and diet, contribute to colorectal cancer risk, but it turns out that one's DNA can change how much these factors play into that risk.