Genetic Inequality
The lab of USC/Norris Comprehensive Cancer Center oncologist Heinz-Josef Lenz, M.D., has found another piece of the chemotherapy puzzle for colon cancer patients, showing that variations in a key gene are linked to a better response to platinum-based anti-cancer drugs.
Keck School of Medicine of USC medical resident David J. Park, M.D., Lenz, and colleagues explored the importance of a protein called Xeroderma pigmentosum group D, or XPD for short. XPD is a protein created in the body that is critical to repairing routinely damaged DNA.
The study is the first to show a relationship between variations in the XPD gene and patients' response to chemotherapy. It is part of an ongoing movement to understand how cancer differs from patient to patient, so that oncologists may design therapies that are customized for each individual.
"Our goal is to develop a genom-ic profile that allows us to tailor chemotherapy based on the individual genetic profile, which results in better and nontoxic therapy," explains Lenz, associate professor of medicine at the Keck School and scientific director of cancer genetics at USC/Norris. Park works with Lenz.
Cancer researchers know that the more efficient the body is at fixing its broken DNA, the more a cancerous tumor in the body will resist platinum-based chemotherapy drugs, such as oxaliplatin or cisplatin.
How well DNA is repaired de-pends on a whole family of genes, including XPD.
But from person to person, not all XPD genes are created equal. Certain small bits of the XPD gene-called polymorphisms-exist in several different forms in the human population.
These polymorphisms also affect how efficiently DNA is repaired. Park, Lenz and their colleagues knew that several common polymorphisms of the XPD gene seemed to be important. They might make a difference between tumor response to platinum-based chemotherapy and tumor resistance, they suspected.
The oncologists administered therapy consisting of 5-FU (fluorouracil) and oxaliplatin to more than 70 patients with advanced metastatic colorectal cancer who had already unsuccessfully gone through other chemotherapy regimens.
They also tested them for the specific polymorphisms in the XPD gene. Each polymorphism has three possible varieties that can be found in the population.
They found that in the group with a certain variety of one polymorphism in particular, 24 percent of patients (5 of 21) responded to the drugs-meaning tumors shrank by 50 percent or more for at least six weeks. They survived an average of more than 17 months after starting treatment.
In each of the other two patient groups with different types of the polymorphism, only 10 percent of patients responded. In one case, 4 of 39 responded, with patients living an average of nearly 13 months; in the other case, only 1 of 10 patients responded, with patients living an average of about three months.
The important polymorphism is called Lys751Gln, the researchers noted. Patients with tumors that responded best had a genotype called "Lys/Lys," while those who responded the least had a genotype called "Gln/Gln." The middle group had a genotype called "Lys/Gln."
"Patients with the Gln/Gln genotype were six to 12 times more likely to have progressive disease compared to either the Lys/Lys or Lys/Gln group," Park explains.
Lenz's group already has shown that several other DNA repair genes, such as ERCC1 and XRCC1, seem to predict how well certain chemotherapy drugs will combat colorectal and other cancers. The group intends to further study just how variations in the XPD gene affect DNA repair and other factors important in drug resistance.
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