Last March, millions of people who receive the weekly magazineParade, folded into their Sunday newspaper, may have noticed anunusual want ad, headed: "You can help researchers find the gene orgenes that cause prostate cancer."
The announcement invited readers with "at least three blood relativeswho have been diagnosed with prostate cancer" to get in touch withPatrick Craig Walsh, of Johns Hopkins University, in Baltimore.
In response, individuals in 1,904 different families reported havingfrom three to seven close relatives with prostate cancer.
Walsh, who heads the Urologic Institute at Hopkins, is a co-seniorauthor of a paper in today's Science. Its title: "Major susceptibilitylocus for prostate cancer on chromosome 1 suggested by a genome-wide search."
Since the early 1990s, Walsh has been collecting families withmultiple prostate cancer members, in an effort to discover the geneticdefect that causes the hereditary form of this often lethal, men-onlymalignancy. By 1994, he had a data base of some 2,500 families.
Prostate cancer is bafflingly evasive in the face of attempts todistinguish its presumed inherited form from the spontaneous.
Not that prostate cancer (PC) is rare. Quite the contrary; some340,000 new cases are diagnosed each year in the U.S. alone, and41,000 deaths reported. (See BioWorld Today, July 17, 1996, p. 1.)Those high prevalence numbers complicate the task of determiningwhich of several cancers in a family arise from a defective gene, andwhich are simply sporadic.
Walsh and his colleagues narrowed their case file down initially to 66high-risk North American families, with an average of five afflictedmembers. Hopkins urologist William Isaacs, the Science article's firstco-author, told BioWorld Today: "We really did not differentiate thispopulation sample on the basis of age or ethnic group, or anything.We took all comers at random."
Late in 1994, he and Walsh took their familial PC cohort to theNational Institutes of Health's National Center for Human GenomeResearch (NCHGR), in Bethesda, Md. It undertook a genome-widescan of possible linkage between affected family members and DNAmarkers on their genomes. "Chromosome 1," Isaacs said, "came upout of that scan."
Luck's Role In Locus Location
He recalled: "We did not have a preconception, or any inkling, thatthis might be a region containing such a gene. So it really came asquite a surprise."
To mark this first chink in PC's genomic armor, as reported intoday's Science, the NCHGR held a press conference Thursday atWashington's National Press Club. It was co-hosted by Walsh andIsaacs, together with co-authors Francis Collins, director of NCHGRand Jeffrey Trent of that agency's cancer genetics laboratory.
In tracing the putative gene locus to a narrow region on the long armof human chromosome 1, the team analyzed 341 dinucleotide repeatmarkers, to complete a linkage map totaling more than 130,000genotypes.
Then, to confirm this familial chromosomal clustering, they repeatedthe analysis with another 13 American families, plus a set of 12pedigrees in Sweden, making a total of 91.
Of this over-all number, Isaacs pointed out, "34 percent appear to belinked to the chromosome 1 locus. And that same one-thirdproportion _ four of 12 _ came up in the Swedish sample as well. Soit's my guess," he continued, "that the consistent one-third presenceof this linkage in families that were not preselected, shows that thisgene is going to be widespread, not limited to any ethnic orgeographical region."
In Limited Data Set, No Ethnic Variability
African-Americans have higher PC incidence and mortality thanother groups in the U.S. Among the 91 data base families, Isaacssaid, "we had, unfortunately, only two African-American families.Interestingly, both show linkage to the chromosome 1 region.Obviously," he added, "the next step is to look at a larger number offamilies, and see whether or not the connection holds up."
From mapping a gene locus to pinpointing the gene can be a lengthy,uncertain ordeal. Isaacs offered a "not very valuable guesstimate"that isolation of the covert PC gene on chromosome 1 "would comewithin the coming year."
He grounds this optimism on a combination of things:
"One, there is a tremendous amount of interest out there, which willbe fed by today's Science article. Two, the Human Genome Project isplacing a tremendous number of complementary DNA sequences[single-stranded gene surrogates] on the map, on a daily basis. Andthree, the ability to find and characterize a sequence of genes at arapid rate, I think, is going to lead to a rapid rate of identification."
Once found, Isaacs surmises, that gene will turn out to "have a veryspecific function in regulating a critical aspect of prostate physiology,similar to recently discovered cancer susceptibility genes for breastand colorectal tumors."
He strongly suspects that the normal PC gene "could act as a prostatecancer tumor suppressor, or be involved in abnormally activatedprostate cell division _ so it could be an oncogene."
Right now, he and his team "are in the process of evaluating somecandidate genes in the chromosome 1 region, but most likely what wefind will turn out to be a novel gene, not identified previously."
If independent linkage analysis confirms their finding, the authors"propose the designation HPC1 (hereditary prostate cancer 1) for thislocus."
They conclude: "Because early diagnosis can be life-saving in PC,the ability to identify individuals at potentially high risk, by detectingalterations in this locus, especially when combined with methods thatdetect early signs of malignancy (physical exam, transrectalultrasound, and prostate-specific antigen) could ultimately be ofsignificant medical benefit." n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.