By David N. Leff

An unsolved mystery of oncology is why Japanese women who move to the U.S. quadruple their risk of breast cancer.

An exercise in "molecular epidemiology," conducted by scientists at the City of Hope National Medical Center at Duarte, Calif., puts up some road arrows on the path to elucidating this transnational riddle.

Mammary carcinomas have some basic differences from other solid tumors, the City of Hope epidemiologists point out. In the January 1997 issue of Trends in Genetics, they suggest that a number of different substances may contribute to gene damage in breast cancers, compared to other common malignancies.

They point to fat-soluble, diet-derived mutagens, which accumulate in breast tissue because of its unusual architecture. These lipophilic mutagens concentrate in adipose cells,

Mammary epithelial cells, which give rise to nearly all breast cancers, exist as many tiny islands of tumor-susceptibility in a sea of fat cells. As the former grow, so does their risk of exposure to the latter's mutagens.

"The possibility," suggested John Kovach, City of Hope vice president for medical and scientific affairs, "that lipophilic mutagens are present in excess in the breast tissue of Japanese-American women compared to the breast tissue of women in Japan, is a testable hypothesis. If true, it might facilitate identification of specific compounds contributing to breast cancer."

He and his co-authors zeroed in on somatic mutations in the p53 gene, provoked by mutagenic food molecules picked up by the mammary fat cells, and passed on to their neighboring epithelial cells.

Steve Sommer, director of molecular genetics and diagnosis at City of Hope, hypothesized that "breast cancer would differ from certain other common cancers in which one predominant pattern of damage in the p53 gene reflects the action of a specific type of DNA-damaging agent."

Sommer cited the connections of lung cancer to cigarette smoke and ultraviolet light to skin cancer. "The 'fingerprints' of these mutagens," he said, "are found in the p53 gene of skin cancers and lung cancers of smokers, regardless of ethnicity and residence, whereas a diversity of patterns of DNA damage are present in the p53 gene of breast cancers across ethnic and geographic boundaries."

The researchers examined patterns of p53 gene alteration in breast tumors from patients at 15 sites in Japan, the U.S., Scandinavia, Scotland, France and Austria. Their global statistical meta-analysis synthesized data from 66 recent journal papers, dating from 1991 to 1997. *