By David N. Leff
At least a dozen genetic research groups on both sides of the Atlantic are racing toisolate and sequence BRCA1, the gene most closely linked with breast cancer.
Of the 180,000 women in the U.S. alone diagnosed with breast cancer, some 44,000 die ofthe disease. The elusive BRCA1 gene is clearly guilty in the 5 percent to 10 percent ofhereditary breast cancers, and strongly suspected of complicity in the remaining 90percent of sporadic cases.
One in every 200 American women -- some 600,000 -- have inherited susceptibility tobreast cancer. They presumably pass down this familial predisposition via a mutatedgermline BRCA1 gene. “The biggest gap is to see whether what goes on in thesefamilial cases is also related to the sporadic ones,“ the American Cancer Society'ssenior vice president for research, John Laszlo, told BioWorld.
Two research teams report on their quest for the breast cancer gene in today's Journalof the American Medical Association (JAMA). Molecular biologist Mary-Claire King ofthe University of California School of Public Health in Berkeley located the highlyputative gene to the long arm of chromosome 17 in 1990, by genetic linkage analysis ofrestriction fragment length polymorphisms (RFLPs).
So far, 44 such DNA markers have been mapped over the 50 million-base-pair region onchromosome 17.
“The gene is known to lie within a region of a few million nucleotides onchromosome 17q21, King writes in JAMA, “and as a last resort, could eventuallybe identified by scrutinizing every gene in that region.“ Instead, as a first resort,she is scrutinizing “genes that are altered in breast and ovarian tumors.“
At the University of Michigan, molecular geneticist Francis Collins, co-author of thesecond JAMA paper, expects that the Human Genome Project will accelerate thelinkage analysis and positional cloning “to identify increasing numbers ofdisease-related genes and to use this information to develop presymptomatic testing.“
Collins has been named to direct the National Institutes of Health's genome project,succeeding DNA pioneer James Watson.
Until BRCA1 can be tracked down and sequenced, these groups and others (see table atbottom) are focused on analyzing large numbers of families whose mothers, aunts anddaughters are unusually prone to contract breast cancer or ovarian cancer; they do so atan early age. Once scientists find the specific BRCA1 sequence in the genetic code, theywill be able to type women at this locus for high-risk BRCA1 alleles, and screen for thehereditary tendency in the population at large.
Meanwhile, they have determined that unsymptomatic women i such “breast-cancerfamilies“ share a long, identical sequence of the aberrant DNA on chromosome 17,which must harbor the mutated gene they are hunting down. For such women, the risk ofcontracting breast cancer by age 50 is over 50 percent; by 65 years of age, 80 percent.
How long until a research team finally finds BRCA1? With so many contenders in therace, “a matter of months, to a year at the most,“ foresees King's co-author,epidemiologist Sarah Rowell.
'All Hell Could Break Loose'
What then? “Finding BRCA1 will give us a great tool,“ Rowell told BioWorld,“but no great choices.“ In fact, she added, “all hell could break loose,especially with the insurance companies.“
The Michigan paper spells out this new and added risk factor: “... once a test forBRCA1 mutations is clinically available, results will be documented on hospital charts.Insurance companies reviewing them should be particularly interested in these resultssince they help to accurately predict risk (of inheriting breast or ovarian cancer).
Collin's group suggests that the members of susceptible families who test negative willwish to inform their insurance carriers, while those found to carry the mutation will tryto conceal this fact.
The Michigan group also surmises that “the demand for such (BRCA1) testing willquickly overwhelm the current extremely limited resources available for DNA testing.“
Right now, a women whose family background suggests her heightened susceptibility tobreast or ovarian cancer faces grim preventive options:
• Surgery: Bilateral prophylactic mastectomy and/or oophorectomy (removal ofovaries, which, interestingly, reduces breast cancer, as well as ovarian cancer, risk).
• Surveillance: Earlier and more frequent mammography, which is ofteninconclusive.
• Hormone: Enrollment in a multicenter, randomized, clinical trial of tamoxifen, anon-steroidal estrogen antagonist, which may or may not forestall the BRCA1-relatedtumors. This trial, limited to 15,000 women, is coordinated by Bernard Fisher of theUniversity of Pittsburgh.
Among high-risk patients, three case histories make the point:
• In Michigan, a 33-year-old woman, already scheduled to have both breasts removedprophylactically, was informed that she was 98 percent unlikely to be a BRCA1 mutationcarrier. She promptly canceled the surgery.
• A 30-year-old woman in the California study, whose sister, mother, aunt, greataunt and great grandmother all contracted breast cancer, was counseled as to her ownhigh-risk genetic profile. A mammogram and physical exam revealed a tumor that had not yetspread. She underwent total mastectomy “and is doing well.“
• A 46-year-old, symptom-free California woman, whose sister, mother, and twoaunts all had breast cancer, also decided on prophylactic mastectomy. Three months later,she was diagnosed with advanced ovarian cancer, a disease unknown in her family history.
The BRCA1 gene is thought to cause both breast and ovarian cancer, and is suspected ofimplication in prostate cancer as well.
King cautions, “In order to identify women with inherited risk in the generalpopulation (as opposed to the familial) we must know the sequence of BRCA1.“
Multinational Hunt for BRCA1
Collaborative competition among the eight-nation congeries of breast cancer genemappers ranges -- and fluctuates -- from friendly to fierce. They all contributed BRCA1research reports to the April 1993 issue of the Journal of Human Genetics:
Team Leader Location
(in alphabetical order)
Adalgeir Arason Reykjavik,Iceland
Anne Bowcock SouthwesternMedical Center, Dallas
B. Cohen Edinburg,Scotland
Francis S. Collins Universityof Michigan, Ann Arbor
Douglas Easton Universityof Leeds, England
Mary-Claire King Universityof California, Berkeley
Gilbert Lenior InternationalAgency for Research in Cancer, Lyon, France
Steve Narod InternationalAgency for Research in Cancer, Lyon, France
Bruce Ponder CambridgeUniversity, England
Ellen Solomon ImperialCancer Research Fund, London
Mark Skolnick Universityof Utah, Salt Lake City
Ray White Universityof Utah, Salt Lake City
W. Zimmerman Germany