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Defect in alpha-1 antitrypsin gene found to increase colorectal cancer risk

Mayo Clinic

Risk greatly magnified by cigarette smoking

ROCHESTER MINN. -- Mayo Clinic scientists have discovered that carriers of a genetic defect previously linked to emphysema have a threefold increased risk of developing a type of sporadic colorectal cancer. Carriers who currently smoke have a 20-fold increased risk.

"This study provides important new insight into the controversy surrounding the link between cigarette smoking and colorectal cancer, confirming a strong association in a subgroup of colorectal cancers," says Dr. Ping Yang, Mayo Clinic clinical epidemiologist and principal investigator of the study.

The genetic defect, alpha-1 antitrypsin deficiency, presents an inadequate level of the protease inhibitor alpha-1 antitrypsin, which protects the surfaces of multiple organs. Alpha-1 antitrypsin is synthesized primarily in the liver and in a small amount of the gastrourinary systems. In individuals who lack this inhibitor, the protease destroys the membrane system, leaving the colon and rectum vulnerable to colorectal cancer development.

The investigators believe that cigarette smoking causes a similar effect, further exacerbating tissue destruction for carriers of alpha-1 antitrypsin deficiency, since smoking is a strong inactivator of the protease inhibitor alpha-1 antitrypsin.

In this study, published in Molecular Genetics and Metabolism, 161 Mayo Clinic patients newly diagnosed with colorectal cancer were compared to 191 controls. The relative risk of developing colorectal cancer demonstrating microsatellite instability, a nonhereditary type of colorectal cancer, was 3.1 for alpha-1 antitrypsin deficiency carriers; among current and past smokers who were not carriers, the risk of developing this type of colorectal cancer was 6.6 and 2.7, respectively. The risk for those who were both alpha-1 antitrypsin deficiency carriers and current smokers, relative to never smokers who lacked the genetic defect, was elevated 20 times.

Since alpha-1 antitrypsin deficiency previously has been associated with emphysema, the investigators suggest those with severe, early-onset emphysema in their families inquire of their physicians regarding their potential carrier status for alpha-1 antitrypsin deficiency. Phenotyping (a protein test) is currently available to detect alpha-1 antitrypsin deficiency carrier status.

Mayo Clinic scientists, under the leadership of Dr. Stephen Thibodeau, molecular biologist, and Dr. Jerry Katzmann, immunopathologist, are investigating new, potentially more efficient genotyping, or DNA testing, methods.

The study investigators indicate there is one step people can take that will definitely reduce their risk of colon cancer. "One thing people can do for sure is not smoking," says Dr. Yang., "Smokers should be aware that they are not only at risk for lung cancer and heart diseases, but colorectal cancer as well."

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Source: Molecular Genetics and Metabolism, Volume 71, Number 4, December 2000.

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