By identifying BRCA1 as a mutant gene that lurks in the genomes ofabout half of all women genetically susceptible to breast cancer, anarmy of scientists not only paved the way for a diagnostic test, theyopened a can of genes containing their next targets, BRCA2 andBRCA3.Two research reports detailing the BRCA1 discovery are scheduled toappear in the Oct. 7 issue of Science, titled respectively, "Isolation ofBRCA1, the 17q-linked breast and ovarian cancer susceptibility gene,"and "BRCA1 mutations in primary breast and ovarian carcinomas."(For more on the initial announcement, see BioWorld Today, Sept. 15,p. 1.)Geneticist Mark Skolnick, a founder and research vice-president ofMyriad Genetics Inc., Salt Lake City, was the first paper's principalauthor; Roger Wiseman of the National Institutes of Health's (NIH)National Institute of Environmental Health Sciences, (NIEHS)Research Triangle Park, N.C., that of the second article. Paper numberone counted 45 co-authors from a consortium of seven researchcenters; number two, 27 contributors.As Skolnick, who also teaches medical informatics at the University ofUtah, told BioWorld Today: "You could say, `the race is over; the racehas begun.' We don't get a chance to catch our breath."BRCA2 has been localized to chromosome 13 by cancer researcherDouglas Easton, of the Cancer Research Institute in London. Now heand competing players will try to localize and define that second gene'sexact region, make a physical map, find the transcripts and identify themutations.Breast cancer is mainly a post-menopausal disease; it strikes its victimsout of the blue after they pass the age of 50. But about one woman in10 has a good hunch that she is marked to get the malignancy at amuch earlier age, because that's what happened to her sister, cousin,aunt or mother.Such breast-cancer-prone families offer geneticists a genomic handlefor tracking the mutant gene or genes which afflict such susceptiblepersons from birth. Grasping that handle half a decade ago, researchers,notably Mary Claire King at the University of Michigan, carried outgenetic linkage surveys among hundreds of such early-onset families,and localized the gene to a narrow region of chromosome 17's longarm.That region then became the dart-board at which she and rivalresearchers took aim to pinpoint the guilty gene sequences, anddiscover the mutations carrying their cancer-causing message.Skolnick's Myriad and Wiseman's Laboratory of GeneticCarcinogenesis at NIEHS picked up that challenge and, despite King'sheadstart, have now won that race. Skolnick explains why: "Either wewere lucky, or we took advantage of the large families that we havehere in Utah." This multiplicity of children "enabled us to identifyclearly gene carriers from non-gene carriers."Procedure Based On Positional CloningHis paper reports on eight kindreds _ extended families _ withfamilial breast-cancer. Presumably, many, if not most, of theirmembers carried the elusive gene. One individual in each of eightkindreds gave the researchers a tune full of her venous blood, fromwhich to extract and analyze the DNA. "The general concept of theprocedure we followed," Skolnick said, "is positional cloning." (Fortechnical details, see Monday's BioWorld Today.)Their paper pending in Science reports that four of the eight hadmutations in the gene now designated BRCA1. Since writing it,Skolnick said, "we have added a fifth." These mutations, scatteredalong the lengthy length of the gene, were varied. "We found frame-shifts, stop codons, a mis-sense substitution, putative regulatorymutants," he recalled, "so we said this particular gene must be the rightone."Full-length BRCA1 measures 5,589 base pairs, but strewn over100,000 bases in the genome. Predicted length of the gene product is1,863 amino acids.Now that they knew what to look for, the extended team beganscrutinizing tumor tissue biopsied from women with breast or ovariancancer, but selected without reference to any family history. Myriadand NIEHS shared 44 specimens. (Reported in the second Sciencepaper.) They found four mutations of the BRCA1 gene, three of 32breast tumors, one of 12 ovarian carcinomas. To their surprise, allwithout exception "turned out to have occurred in the germline ratherthan the somatic cells of each individual," Skolnick said. "Our reaction:shock!"That shocking finding implied that in the sporadic form of the disease,BRCA1 is uncommonly mutated. But further study revealed that themutant genes probably came from early-onset patients.Gene One Wears Two HatsBRCA1, like many other cancer-causing genes, is thought to be atumor-suppressor in its unmutated form. For women in early-onsetfamilies, this means having only one, rather than the normal two genevariants in her genome, protecting her from falling prey to the cancer-causing factors that beset society.BRCA1 and BRCA2 each account for perhaps 40 to 45 percent of theone in 10 women whose breast cancer is familial, That leaves 10 to 15percent for which a putative BRCA3 is responsible, and this thirdalleged perpetrator is also on the teams' hit list.It probably won't take another four years to unmask these newlyperceived villains, Skolnick explained, "because once you do one ofthese genes, the efforts that didn't work for the first one becomeresources for the second, and so on for the third."Meanwhile, the most immediate product of the BRCA1 endeavor is todevelop a diagnostic test. "That way," Skolnick said, "women whoeither have early-onset breast or ovarian cancer, or who have a closerelative with same, can find out if they are or are not susceptible."To generate such a diagnostic, he predicted, "will take a year or two.First, we must repeat our present research, screen hundreds, perhapseven thousands, of high-risk women, and develop a mutation profile, tospell-check all of the gene's mistakes."Skolnick summed up, "For the biotechnology community, this isperhaps the beginning of the genetic information business. Now thatsuch a common genetic susceptibility has been discovered, work willgo into creating the genetic profile of mutations, and their effects. Andas new technology develops around that, business will spring forth." n

-- David N. Leff Science Editor

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