It's almost an article of faith that mutant germline genes cause only asmall fraction of cancers _ the 8 percent or so that run in families. Incontrast to these inherited familial cases, the blame for sporadicmalignancies is laid on environmental factors _ e.g., smoking,radiation, infection, diet.
The cause of familial breast cancer is mutated BRCA1, a tumorsuppressor gene gone wrong. Last September, its discoverers, 45researchers at six centers, made headlines by pinpointing BRCA1 to aprecise site on the long arm of human chromosome 17. (SeeBioWorld Today, Sept. 15, 16, 19, 1994, p. 1.)
Breast and ovarian cancer tend to go together, at least statistically.Yet the BRCA1 researchers found no sign of that mutant gene havinga hand in the etiology of sporadic breast or ovarian cancer. Thisapparent non sequitur did not convince molecular oncologist SophiaMerajver at the University of Michigan in Ann Arbor.
"After a finding like that," Merajver told BioWorld Today, "you haveto go back and rethink the role of BRCA1. Maybe all sporadic canceris due to environmental factors; maybe heredity may not play a bigrole. Or else, different genes, other than those disclosed for familialcancer, may be involved."
She added, "I wasn't too happy with that conclusion, that BRCA1 isnot important in sporadic cancer. I felt that there ought to be someonelooking very carefully if indeed mutations couldn't be found."
Merajver set herself the task of examining the DNA in a largenumber of ovarian cancer tumor cells to try meticulously to findmutant BRCA1, and succeeded. She is first author of an article in thismonth's Nature Genetics, which presents her preliminary resultsunder the title, "Somatic mutations in the BRCA1 gene in sporadicovarian tumours."
That journal acclaimed it as "the first time that non-inheritedmutations in BRCA1 have been associated with the growth ofsporadic cancers."
Merajver analyzed archival cells from 47 common, sporadic, non-familial cases of ovarian carcinoma. At diagnosis, patients ranged inage from 15 to 80 years, for an average of 60. Four of them had asecond malignancy in the breast, but with no prior family history ofeither malignancy.
She and her co-authors _ including Francis Collins, who heads theNational Center for Human Genome Research at NIH _ detectedBRCA1 mutations, as well as outright loss of one parental (allelic)gene _ loss of heterozygosity _ in four of the 47 samples. Sincesubmitting her paper, that number stands today at seven out of 80,and still counting.
Meanwhile, Nature Genetics received a short report from LouiseHosking, et al. of the Imperial Cancer Research Fund in London.They tested tumors from 17 ovarian cancer patients, selected for lossof heterozygosity. One of these also displayed mutant BRCA1,bringing the published total to five of 48.
So far, no one has reported mutation of the gene in sporadic breastcancer. But Jeffrey Holt and his co-authors at Vanderbilt UniversitySchool of Medicine in Nashville, have thrown a different light on thisarea. His paper in the April issue of Nature Genetics bears the title,"Decreased expression of BRCA1 accelerates growth and is oftenpresent during sporadic breast cancer progression."
Holt has found that "both alleles are usually coordinately expressedin heterozygous sporadic cancers, [which] indicates that loss-of-heterozygosity is probably not the primary explanation for decreasedexpression of BRCA1 in sporadic tumors." What it does seem to"strongly implicate," he added, is "an altered upstream regulatorymechanism."
BRCA1 Intact In Sporadic Tumors
In other words, BRCA1 remains intact in sporadic tumors, but ismismanaged by other genes ahead of it on the chromosome.
Merajver explained why breast and ovarian tumors are like two sidesof the same coin. "In a broad sense," she said, "they are bothepithelial adenocarcinomas. The other thing that they have incommon, and with prostate tissue too, "is that all three are highlyhormonally regulated, both the normal and neoplastic tissues."
She predicted that "BRCA1 will be a very important gene inmammary and ovarian development; perhaps in utero, perhaps inadolescence." At the onset of a child's sexual maturation, she pointedout, it behooves the gene to remain dormant, thus permitting thegrowth of breasts and ovaries. But once this process is complete, thetumor suppressor "should be activated to prevent neoplasms fromarising. But if something goes awry with that activation, malignancyensues."
Asked if she foresees any therapeutic applications of herdemonstration that the mutant gene affects both familial and sporadiccancers, Merajver said, "Not right now. I think we're just a step awayfrom that. We need one more piece of major data, before we can starttalking about therapy. Once we know what the hormonal regulationof the BRCA1 gene is, we will immediately start having thoughtsabout prevention." She added archly, "It may already be in press.Who knows?"
One long-standing handicap in BRCA1 research was overcome aweek or so ago, Merajver revealed, her group, and by others as well,have raised monoclonal antibodies to the gene's protein product.How will they be used?
"The sky's the limit," she said. "We have to start at the beginning.Localize the protein. See what happens to it when it's mutated. "Wealready have some evidence that when this happens, the protein can'tenter the cell nucleus. But all this is preliminary."
Co-author Collins' contribution to the work," she volunteered, "wasvery interesting. He actually sat down with me when I started seeingthese mutations. For a few hours we pored over all the gels, andargued back and forth. He basically gave his opinion that the datawas good. That was very important as it appeared I was the onlyperson in the world finding these mutations." n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.