Deadly Legacy

Genetic flaw signals cancer

Some families seem to be lightning rods for cancer. Malignant tumors of the breast, colon and other organs appear in family members with distressing frequency through the generations. Though these families can be identified, there has been no way to predict which individuals will develop cancer and thus no way to assure that their cancers will be detected early and treated. But now, for one such family, all that is changed. At Boston's Beth Israel Hospital, doctors for the first time have discovered an inherited chromosomal defect that seems to be a marker of cancer within a family.

The investigation leading to the discovery, reported last week in the New England Journal of Medicine, was launched three years ago when John Q, 37, checked in to the Boston hospital for surgery. He had malignant tumors in both kidneys, a condition that occurs in only 1% to 2% of all Americans with renal cancer and almost never before age 50. While taking the patient's history, doctors were startled to learn that one of his aunts also had kidney cancer. Turning sleuths, a team led by Dr. Robert S. Brown studied 40 family members spanning three generations. The resulting statistics were extraordinary. Of the 40, ten had renal cancer, six of them in both kidneys.

Analyzing blood cells, doctors discovered that the cancer victims shared a specific defect in two of each cell's 23 paired chromosomes. Part of chromosome No. 3 was attached to chromosome 8 and vice versa, a condition that geneticists call balanced reciprocal translocation. Brown and his team speculate that the interchange first occurred in an ancestor, perhaps through spontaneous mutation. It affected genes on the chromosomes that may direct normal kidney growth or protect against kidney cancer. Passed on through the generations, the translocation seems to be a visible warning sign that its bearer has a good chance of developing cancer.

Family members with the chromosome abnormality but without the disease will be screened regularly in hopes of catching it early. Also, in a pregnancy, amniocentesis can determine if the fetus has inherited the defect, giving parents the option of abortion.

Whether the translocation will have implications outside John Q's family is still unclear. People with renal cancer do not necessarily have the chromosomal switch, and those with the translocation do not always develop cancer. The doctors have taken cells from family members and frozen them, preserving them for the day when they have more sophisticated techniques for studying individual genes within the chromosomes. But until then they will be at a loss to explain exactly why a translocation can make a family cancer prone. Says Brown: "What we found may be a breakthrough. The fact is we don't know how to use it."

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