PHILADELPHIA (September 10, 2015) – The genetic mutations responsible for most inherited colorectal cancers are unknown, hindering diagnosis and treatment options for about 20% of all patients with colorectal cancer in the United States. Fox Chase Cancer Center researchers now show that mutations in specific genes involved in DNA repair occur more frequently in the blood cells of patients with familial colorectal cancer than in the general population. The findings, reported September 10th in Gastroenterology, pave the way for the development of a simple, inexpensive blood-based diagnostic test and could potentially improve personalized therapeutic strategies.
“Our study broadly increases our understanding of cancer risk and thus may help in improving genetic counseling of patients who have a family history of cancer but test negative for genes on a panel,” said first study author Sanjeevani Arora, PhD, a postdoctoral fellow at Fox Chase. “We also hope that these studies will be a foundation for developing simple blood-based tests to understand defects in DNA repair genes that are not on a panel but may be the underlying cause of the cancers in a family. Further development of such tests may help in earlier screening within such families and inform those at actual risk.”
Familial colorectal cancer is characterized by early disease onset and the occurrence of the disease in multiple family members. Currently, clinical guidelines recommend that individuals with a family history of colorectal cancer undergo frequent screening for the disease. But this approach is not ideal because family members who are not genetically predisposed may be subjected to unnecessary costs and invasive procedures, while some of those actually at risk may be under screened. Although no common molecular defect underlying inherited colorectal cancer has been identified, a recent study that examined one family affected by this disease discovered a mutation that causes genome instability in immune cells called peripheral blood lymphocytes—the cells most readily obtained from patients.
Based on this finding, Arora and a team of Fox Chase researchers suspected that it might be possible to develop a blood-based test to detect mutations associated with familial colorectal cancer. To test this idea, they sequenced DNA from peripheral blood lymphocytes using blood samples from the Family Risk Assessment Program at Fox Chase.
The team identified 35 mutations in genes associated with DNA repair in 17 out of 20 patients with inherited colorectal cancer, and in four out of five individuals who had many polyps and thus were at risk for developing the disease. Moreover, the cells showed a high frequency of double-strand breaks caused by DNA damaging treatments, and specific biochemical assessment of the mutated form of the proteins found in the patients confirmed defective activity. These mutations, and the accompanying DNA damage, were much less frequent in control subjects without a personal or family history of colorectal cancer. Together, the work integrated the expertise of a clinical geneticist, Dr. Michael Hall; a gastroenterologist, Dr. Greg Enders; and basic scientists skilled in studying cell cycle and DNA damage, Drs. Erica Golemis, Timothy Yen, and Hong Yan.
“Understanding these genetic determinants could help evaluate those at risk in a family, thereby avoiding over or under screening and aiding in earlier intervention for at-risk individuals,” Golemis said. “These studies may also form the basis for future studies combining drugs that are more effective in tumors with impaired DNA repair. For example, the recently FDA-approved PARP inhibitors may yield more therapeutic benefit in patients with familial colorectal cancer.”
Because DNA repair is important in many types of tumor, the findings may apply more broadly to other inherited types of cancer. “Currently, we are extending our studies to familial prostate and kidney cancers. We are also planning to test whether our methods could be used to predict clinical outcomes,” Arora said. “We are optimistic that these studies will lead to better screening approaches and personalized treatment strategies for a broad range of cancer patients.”