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REF NO.: 205

SUBJECT: Scientific paper details rare stomach cancer mutations
DATE: June 5, 2007

Genetic mutations that are linked to a form of hereditary stomach cancer more common in Newfoundland are identified in a paper to be published in the June 6 issue of Journal of the American Medical Association (JAMA). The scientific paper was released online June 3 to coincide with its presentation at the annual meeting of the American Society of Clinical Oncology.
Dr. David Huntsman, a 1988 alumnus of Memorial’s medical school, is principle author of the study. He was recently awarded a $759,000 five-year grant from the Canadian Cancer Society to focus primarily on families in Newfoundland. His team includes Dr. Bridget Fernandez, a researcher in Memorial’s Faculty of Medicine. The project will help to determine if special screening programs for a mutation in a gene called CDH1 need to be developed to protect against breast cancer and stomach cancer.
In previous research funded by the Canadian Cancer Society, Dr. Huntsman and his team, based at the BC Cancer Agency in Vancouver, found that 70 per cent of people with the gene mutation went on to develop stomach cancer. Evidence is now emerging that it may also lead to lobular breast cancer, which accounts for eight to 15 per cent of all breast cancers.
The rate of stomach cancer in Newfoundland and Labrador is almost two times higher than in the rest of Canada, and the research team believes the genetic mutation might be the reason. International collaboration will also take place to gather additional cases to study.
The mutation is life-threatening for families who have it, said Dr. Huntsman. Gastric cancer is extremely difficult to diagnose and is usually incurable once it is advanced enough to be detected. If his research shows there is a clear link between the mutation and the later development of cancer, screening for it will be as simple as administering a blood test – a test that Dr. Huntsman developed during his previous Canadian Cancer Society grant.
“If individuals find they carry the defective gene, they can make decisions about preventive treatment,” he added. “For patients at risk of gastric cancer, that might mean a preventive stomach removal, a strategy that has already proved successful in preventing the disease in more than 50 people.” In the future, Dr. Huntsman hopes that a drug can be developed to target the mutation.
“It’s been both humbling and inspiring to work with these extremely courageous families who have dealt with this dread for generations,” said Dr. Huntsman. “What we’re doing is giving them the tools to face down their fear.”
According to background information in the JAMA article, gastric cancer is the second most common cause of cancer death worldwide. There are two major variants of this cancer: an intestinal type and a diffuse type. Hereditary diffuse gastric cancer (HDGC) is caused by mutations in the gene CDH1, and is characterized by an increased risk for diffuse gastric cancer and lobular breast cancer. The identification of CDH1 mutations offers the opportunity of cancer risk-reduction strategies for unaffected at-risk individuals.
The JAMA study assessed the frequency of mutations in the CDH1 gene and whether these mutations occurred due to independent mutational events or common ancestry. The study included 38 families diagnosed clinically with HDGC, who were analyzed for CDH1 mutations.

Twenty-six families had at least two gastric cancer cases with one case of diffuse gastric cancer in a person younger than 50 years; 12 families had either a single case of diffuse gastric cancer diagnosed in a person younger than 35 years or multiple cases of diffuse gastric cancer diagnosed in persons older than 50 years.

Thirteen mutations were identified in 15 of the 38 families (40 per cent detection rate). Two families from this study plus two additional families carrying the novel 2398delC mutation shared a common haplotype (a group of alleles of different genes on a single chromosome that are closely enough linked to be inherited usually as a unit), suggesting a founder effect (a population group with an unusual frequency of a gene due to there having been only a small number of original members, one or more of whom had that gene). All four families originate from the southeast coast of Newfoundland.
Due to concentrations of lobular breast cancer cases, two branches of this family had been diagnosed as having hereditary breast cancer and were tested for BRCA mutations. Within these four families, the cumulative risk by age 75 years in mutation carriers for clinically detected gastric cancer was 40 per cent for males and 63 per cent for females and the risk for breast cancer in female mutation carriers was 52 per cent.
The identification of this mutation could permit population-based screening of diffuse gastric cancer within specific regions of Newfoundland. Testing for the founder mutation will be particularly valuable for potential HDGC families from Newfoundland in which there is no known living relative with either diffuse gastric cancer or lobular breast cancer from whom a high-quality peripheral blood DNA sample can be obtained for full CDH1 genetic screening because testing a single mutation can be readily performed on suboptimal DNA from archival tissue samples.

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