Researchers Match Another "Mismatch" Repair Gene To Cancer Susceptibility In Mammals

November 13, 1997

Researchers at the Albert Einstein College of Medicine of Yeshiva University have shown for the first time that mutations in another member of the "mismatch repair" gene family, called MSH6, cause cancer susceptibility in mammals.

The finding, reported in the November 14 issue of the journal Cell, promises to aid diagnosis and open a new path for research in cancer predisposition and development in humans.

"This is a new cancer gene that has not been seen before," said Dr. Raju Kucherlapati, professor and chairman of molecular genetics at Einstein. He noted that "because our study involved mice, we were naturally eager to learn whether the finding would prove true for people as well."

Subsequent research by the research team found a germline MSH6 mutation in a human family with hereditary non-polyposis colon cancer, or HNPCC, which confirms the gene's role in cancer predisposition. Two other groups also have reported observing such mutations.

Dr. Kucherlapati's primary co-author on the Cell paper is Dr. Winfried Edelmann, assistant professor of cell biology at the medical school. Another key contributor is Dr. Richard Kolodner, a noted cancer researcher at Dana Farber Cancer Center who is now associated with the Ludwig Institute for Cancer Research in La Jolla, CA.

The finding in Cell added a new dimension to studies of the"mismatch repair" gene family, a sometimes dysfunctional genetic family under intense scrutiny by cancer researchers. Mismatch repair genes correct mismatches between the two complementary strands of DNA. But when the repair system fails, mutations in vital cell control genes accumulate, causing cancer in higher organisms.

So far 10 mismatch repair genes have been described in yeast, and many similar genes have been found in the cells of mammals, including humans. Mutations in four of the genes -- MSH2, MLHI, PMS1 and PMS2 have been blamed for most instances of HNPCC, a common cancer susceptibility syndrome. Families susceptible to HNPCC pass the mismatch repair gene mutations along to a certain proportion of each generation via their germline (egg and sperm) cells; the unlucky inheritors become far more likely to develop not only cancers of the colon but of the endometrium, ovary and other sites as well.

Until now, germline MSH6 mutations had not been observed in HNPCC families. While mutations in this gene had been observed in a small number of human colon tumor cells, mutations in other genes also had been found in those lines. It therefore remained a subject of scientific debate whether mutations in MSH6 play a role in cancer susceptibility.

Scientists suspected the possibility of a role for the gene, however, because hundreds of families with predispositions to HNPCC have not shown mutations in the four mismatch repair genes that had been implicated to that time.

The new results from the Einstein researchers and their collaborators clear up the controversy. When they generated "knockout" mice missing both copies of their MSH6 gene, 90 percent of the animals developed a spectrum of tumors, especially gastrointestinal tumors and B-and T-cell lymphomas.

Significantly the genomes of these tumor cells did not show microsatellite instability, the expansion of repeated regions of repetitive DNA that has characterized the genome of the HNPCC family members with mutations in other mismatch repair genes.

This chromosomal instability, which is caused by mutations in certain mismatch repair genes, served as the red flag that led researchers to find those cancer-causing genes. But because of MSH6's particular function -- it corrects single base pair errors -- failures in this gene's function do not show up as microsatellite instability. Therefore, HNPCC family members with this gene mutation have had no red flag to alert scientists to the presence of the mutation. Now, however, the knockout mutations have flagged the gene's importance, with the results having implications not only for hereditary cancers caused by mutations in germ-line cells, but also for certain "sporadic" cancers that arise in cells which are not characterized by microsatellite instability.

In addition to Drs. Kucherlapati, Edelmann and Kolodner, authors of the Cell paper include Kirland Lau, Joerg Heyer, Wolfgang Liedke and Jeffrey Pollard, all of Einstein; Kan Yang, Kunhaa Fan and Martin Lipkin of Strang Cancer Research Laboratory of Rockefeller University; Asad Mumar and Thomas Kunkel of the National Institutes of Health; Michael F. Kane of Dana Farber and now the Ludwig Institute; and Nianjun Ye and Gray F. Crouse of Emery University.
-end-
11/97

Albert Einstein College of Medicine

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