In 1990 a research team based at the Massachusetts General Hospital (MGH) discovered the gene responsible for most cases of Li-Fraumeni syndrome, a rare inherited condition that leads to the frequent occurrence of several types of cancer in affected families. That gene - p53 - subsequently has proven to be one of the most important genes involved in the development of human cancer. In addition to the gene's role in Li-Fraumeni, non-inherited mutations to p53 are found in half of all human tumors.
Now a team based in the same MGH research lab has identified another gene that is mutated in some families that, without having p53 mutations, appear to have Li-Fraumeni or a closely related syndrome. Like p53 the new gene, called CHK2, appears to play a key role in the cell cycle, the process by which cells grow and divide. Both genes control checkpoints at which cells with damaged DNA should either repair themselves or stop growing, avoiding the development of cancer.
"We have found that CHK2 is a tumor suppressor gene that, when mutated, produces effects similar to those of p53 mutations. The evidence suggests it is part of the same pathway for controlling cell growth and replication," says Daniel Haber, MD, PhD, director of Cancer Risk Analysis at the MGH and leader of the study, which appears in the Dec. 24 issue of Science.
Li-Fraumeni syndrome was first described in 1969 by Frederick Li, MD, now at Dana Farber Cancer Institute, and Joseph Fraumeni, MD, of the National Cancer Institute - both of whom are co-authors of the current study. The rare condition was one of the first instances in which increased vulnerability to several types of adult cancers was clearly inherited. Identification of the tumor suppressor role of p53, along with its role in the cell cycle, directly connected a breakdown in the cell cycle with the development of cancer. It also opened up a search for other inherited cancer-related genes. Among areas in which subsequent research focused was the 20 percent of Li-Fraumeni families who do not have mutations in p53 and another group of familes with a slightly different pattern of multiple cancers, a syndrome called Li-Fraumeni syndrome variant.
The research team analyzed genetic material from four families with Li-Fraumeni but no p53 mutations and from another 18 individuals with Li-Fraumeni syndrome variant, looking for mutations in the human version of CHK2, a gene that had previously been extensively studied in yeast. Among the Li-Fraumeni families, a mutation in CHK2 was found in the affected members of one family. Among the 18 people with Li-Fraumeni variant, two had CHK2 mutations.
Haber explains that the yeast CHK2 gene controls a checkpoint at a different point in the cell cycle from the one controlled by p53. The human version of CHK2 was just recently isolated and became a target of interest to researchers interested in its possible role in human cancer development. The current finding suggests that CHK2 maintains its repair-checkpoint function all the way from yeast to humans, something that is very rare. He says, "It's quite exciting to find such a direct connection between yeast genetics and human cancer development.
"In terms of non-inherited cancers, it doesn't appear that CHK2 mutations are going to be as important as p53 mutations," Haber notes, adding that the researchers found mutations in only one of 49 cells lines grown from sporadic tumors. "But identifying its role gives drug companies another target for developing new chemotherapy approaches. For example, by rendering cells less able to repair themselves, mutations in CHK2 could make cancer cells more vulnerable to chemotherapy drugs that damage DNA."
In addition to Haber, Li and Fraumeni, the study co-authors are Daphne Bell, PhD, Tara Szydlo, Deborah Kang, Doke Wahrer, Kristin Shannon, Marcie Lubratovich, and Kurt Isselbacher, MD, of the MGH Cancer Center; Jennifer Varley, PhD, of the Paterson Institute for Cancer Research, Manchester, England; Sigitas Verselis, and Judy Garber, MD, of Dana-Farber Cancer Institute, and Jillian Birch, MD, of Royal Manchester Children's Hospital. The study was supported in part by grants from the Dana-Farber-Harvard Gillette Women's Cancer Program, the Cancer Research Campaign and the Starr Foundation.
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Science