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Human Genome News Archive Edition

Human Genome News, March 1992; 3(6)

Gene Mapping May Yield Insights into Breast Cancer Development

Researchers at the University of California, Berkeley (UCB), are using genetic mapping techniques to zero in on a gene that may be responsible for many cases of hereditary breast cancer and may also play a role in ovarian cancer.

Mary-Claire King, professor of genetics and epidemiology at UCB, recently told an audience at the NIH Human Genome Lecture Series that locating the gene could enrich understanding of breast cancer in general, leading to earlier detection and eventually to more-effective treatment.

The suspect gene, BRCA1, is known to lie on the long (q) arm of chromosome 17. By identifying DNA markers linked to the gene in certain families, King's group and others around the world are attempting to pinpoint the gene's exact location.

Scientists believe several different genes are implicated in breast cancer, with variation among individuals. According to this model, a tumor will develop only after a critical number of genes are damaged by mutations. These mutations may be inherited from a parent, or the genetic damage may occur de novo in a single breast cell.

Most breast cancer is not caused by an inherited predisposition. The disease is so widespread, however, that even the small familial proportion of cases constitutes a large number of affected individuals and is thus an important genetic condition, King said. Basing her estimate on the families her group has studied, King said that the BRCA1 gene may cause breast or ovarian cancer by age 50 in about 1 of 170 women.

Modern Disease

Breast cancer is a disease characteristic of modern women's lives, King said, because its increased incidence in industrialized countries appears to be due in part to societal changes. Earlier menstruation resulting from better nutrition, coupled with delay or absence of childbearing as women pursue education and careers, make for much longer periods of time in which breast cells are "bathed in a hormonal milieu that is very supportive for division," she noted.

"Unlike . . . lung cancer, there's no single risk factor we can change or would want to change," she said. "We're not going back to the ways our grandmothers lived, so it's up to modern women, with the help of modern men, to solve the problem."

Genetic Markers

Genetic epidemiologists like King construct pedigrees of families that have multiple cases of breast cancer across generations, often locating the families with the help of physicians treating the women. DNA testing must be done on blood samples from large numbers of family members, both male and female, to determine whether a genetic marker is associated with breast cancer in a particular family. King said that these markers simply detect a site on chromosome 17 that can be tracked in the family by tracking the marker.

Progress in gene mapping comes through identifying new markers progressively more closely linked to the putative disease-gene site. The closer the linkage, the narrower the piece of chromosome on which researchers can focus their efforts.

To be useful, a marker must be highly polymorphic-many forms, or alleles, must exist in the population. In a case of perfect linkage within a family, a specific form of the marker shows up in the DNA of all women with breast cancer and in none who are unaffected. The reality is usually more complicated. Women showing the marker may be "susceptibles," carrying the breast cancer gene but not having the disease because they are still relatively young or because they are protected in some way. Conversely, sporadic occurrences of environmentally caused cancers may arise in women who lack both the marker and the gene.

DNA Rearrangements

Another possibility is what geneticists call a recombination event, in which a parent's own chromosomal DNA is rearranged during meiosis (sperm or egg production). Offspring who carry the breast cancer gene will then have a different form of the marker from the parent and ancestors who carried it.

Although recombination adds uncertainty to the study of pedigrees in one sense, it serves as an important tool in nailing down a gene's precise location. When further pedigree analysis shows that recombination has occurred between a marker and the gene, parts of the chromosome proximal or distal to the marker can be eliminated from consideration.

Even as the search narrows, however, several suspect genes are known to lurk in the 17q21 neighborhood of the markers. "We are now down to a region of about 6 cM (gene map units, based on recombination frequency), where a year ago [the distance] was about 50," King said. "There are probably about 250 genes in the region."

Among them are genes for HERZ, a truncated form of epidermal growth factor that acts as an oncogene in some cells; the retinoic acid receptor (RARA), a possible anticarcinogen; and 17HSD, an enzyme that converts the active form of estrogen to a relatively inactive form.

"Now we are trying to develop these genes as highly polymorphic markers and see if any of them are perfectly coinherited with breast cancer in early-onset families," King said.

Finding a gene for breast cancer might make possible earlier diagnosis via blood testing. "If we can back up diagnosis by . . . 10 cell divisions [earlier than is now possible with mammography], we gain a lot in terms of the likelihood that cells have broken off and are on their way to killing the host," King noted.

More speculative is the possibility of using the errant gene to design new therapies. For example, monoclonal antibodies might be created that would carry drugs to cancer cells that may have strayed throughout the body. An even more enticing (though currently remote) goal would be to target treatments directly to the malfunctioning gene or its product, reversing the disease process.

"Can we actually reverse the altered phenotype?" King asked. "It's not out of the question, but we won't know until we know what the altered phenotype is."

Reported by Tom Reynolds
NIH National Cancer Institute

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