Researchers at Jefferson Medical College are finding that certain characteristics of hereditary colorectal cancer tumors may help forecast a patient's prognosis, and in turn help doctors better understand tumor biology.
Bruce M. Boman, M.D., Ph.D., Robert L. Capizzi Professor of Medicine at Thomas Jefferson University in Philadelphia, and his colleagues there and at Jefferson's Kimmel Cancer Center studied several biomarkers, including microsatellite instability (MSI). Biomarkers are proteins in tumor cells which may predict response to treatment, as well as allow better tumor classification and insight to tumor biology.
The researchers classified hereditary colorectal cancer tumor samples on the basis of MSI, according to whether it was absent, low or high. A high degree of MSI corresponds to a lack of genes responsible for DNA mismatch repair, which is vital to DNA replication. Faulty repair plays an important role in colon cancer development.
About 15 to 20 percent of colon cancer tumors, including hereditary non-polyposis colorectal cancer (HNPCC), the most common type of inherited colon cancer, have MSI, due to either an inherited or acquired mutation in a mismatch repair gene.
The scientists showed that "MSI is valuable as a pretest for DNA mismatch repair inactivation and possibly hereditary colon cancer," explains Dr. Boman, who is also director of the Division of Medical Oncology and Medical Genetics in the Department of Medicine at Jefferson Medical College. They also found "the status of microsatellite instability provides insight into the cell cycle biology of colorectal cancer."
He presents his team's findings May 15 at the annual meeting of the American Society of Clinical Oncology in Atlanta.
When mismatch repair genes go awry, the result may be colon cancer. Such genes are part of the intricate molecular machinery that fixes the cell when DNA damage occurs in repetitive DNA sequences.
"MSI presence can be used as a pretest for HNPCC," says Dr. Boman. "Many individuals in the general population may have MSI, but the key is how to pick them up. You need family history and other factors to be able to test for MSI."
Interestingly, he notes, "It's generally thought that those with MSI have a more favorable prognosis."
Only two mismatch repair genes -- MSH2 and MLH1 -- are altered frequently in HNPCC, which accounts for some 10 to 15 percent of all colorectal cancers.
"We tested HNPCC tumors for MSI, and examined other biomarkers as well," Dr. Boman explains. "We stained for MSH2 and MLH1 proteins, which are mismatch repair gene products. Those tumors with high MSI displayed loss of one or the other DNA mismatch repair proteins, indicating this was a good pretest for loss of DNA mismatch repair genes."
The scientists also examined four other markers involved in cell cycle regulation. For a cell to grow, it has to pass through a cycle of particular biochemical steps. Cancer is characterized by the loss of control of such cell growth mechanisms.
The researchers found associations with the absence or presence of MSI with other cell cycle proteins, suggesting that deficiencies in DNA repair may play a role in cell cycle biology. Characterizing the cell cycle pathways controlling growth might help improve the understanding of cancer.
"MSI is a simple straightforward test for tumors to narrow the subset of patients who need to be tested for germline mutations," Dr. Boman says.
The next step is to "begin to look at molecular cell cycle pathways related to DNA mismatch repair mechanisms," he says. "These could provide information allowing us to identify targets for new therapeutic approaches to colorectal cancer."