Many of breast cancer's perennial puzzles get partial but promisingsolutions in the pages of this month's Nature Genetics.
For example: Do the now-celebrated BRCA1 and BRCA2 genes (seeBioWorld Today, Nov. 3, 1955, p. 1), express intact proteins thatsuppress mammary and ovarian tumors, as well as mutants thatprovoke these malignancies? Are those deformed gene products _discovered in 1994 as risk factors for familial, germline, cancers _also to blame for sporadic, somatic-cell malignancies? How tight istheir link to ovarian cancer? To male breast cancer?
BRCA1 and BRCA2 between them are deemed responsible forapproximately 90 percent of early-onset, hereditary breast andovarian cancers.
BRCA1 is a predisposition gene that increases individuals' risks ofcontracting breast and ovarian cancer, when they have a mutation inthat gene. The BRCA1 gene is deemed responsible for about 50percent of early-onset, hereditary breast cancer, and about 90 percentof hereditary ovarian cancer.
If a woman carries this particular gene, instead of the normalpopulation risk of 10 percent breast cancer, her risk increases to 86percent. And instead of a normal 1 percent population risk ofcontracting ovarian cancer, she has nearly a 50 percent chance. TheBRCA2 gene is very different. It also is held responsible for a largepercentage of early-onset, hereditary breast cancer, probably 40percent or so.
The president and CEO of Myriad Genetics Inc., Peter Meldrum,recited these risk data to BioWorld Today and said that amultinational team led by Myriad has completely sequenced the11,385-base-pair cDNA of the BRCA2 gene. It resides on the longarm of human chromosome 13, and encodes a protein of 3,418 aminoacids, nearly twice that of BRCA1.
Myriad, which is based in Salt Lake City, published the completeBRCA2 gene sequence in the March issue of Nature Genetics. The51-author consortium represented six centers in the U.S., two each inCanada and France, plus one in Iceland. Their report bears the title:"The complete BRCA2 gene and mutations in chromosome 13q-linked kindreds."
Myriad Opens Genetic Testing Lab
"Availability of the full sequence will now allow researchers tocharacterize BRCA2 mutations by screening women in many familieswith a history of breast cancer. We're hopeful that one day this willlead to a treatment for these cancers. Meanwhile," he said "these datawill distinguish normal population variants from disease-causingmutations. Information on whether a patient bears a geneticpredisposition to breast cancer may be useful when advising womenon monitoring and on treatment options."
Myriad is going ahead to do just that.
It has set up a state-of-the-art genetic testing laboratory in Salt LakeCity, Meldrum said, "managed by a board-certified moleculargeneticist. It will do full-sequence-based tests on small blood samplesover-nighted to it by physicians. The lab will process the specimen,and fax results back to the patient's doctor.
His company plans to launch its test for BRCA1, "which is extremelyimportant in identifying women who have a heightened risk for bothbreast and ovarian cancer, during the second half of this year,"Meldrum said. The BRCA2 test should be added in the first half of1997.
Although the two genes are strikingly similar in genomic organization_ both expressed at high levels in testis, for example _ theirsequence and mutation patterns differ sharply. The paper describes15 aberrations in the DNA sequence of BRCA2, all involvingdeletions of one to 76 nucleotides. In BRCA1, on the other hand,only half the mutations are of truncated DNA. The other half involveinsertions or other alterations in gene sequence.
Male breast cancer too can be laid at the door of mutated BRCA2 .This suggested to the Myriad authors that tumor suppression by intactBRCA1 and BRCA2 genes may operate by separate cell-growth-inhibiting pathways.
For openers in their gene sequencing exercise, the consortium lookedat a region of chromosome 13, 1.4 million DNA base pairs in length.They singled out BRCA2 from among 13 candidate genes byscreening DNA from individual members of 18 susceptible families.Of these kindreds, ten contained an altered gene.
But in cancer-free, non-susceptible family members, they found nosuch mutations. This ruled out the happenstance that the alterationsthey did find were merely "normal" sequence variants.
International Patent Contention In Offing
Myriad has applied to patent its BRCA2 gene sequence. But it's notalone. An editorial accompanying its Nature Genetics paper recalls:"Last December . . . Michael Stratton [at Britain's Institute of CancerResearch, in Surrey] and colleagues reported that they had identifiedpart of the massive BRCA2 gene on chromosome 13 and identifiedsix mutations in families with breast and ovarian cancer, includingsome cases of male breast cancer."
It continued: "Not to be outdone, however, scientists at MyriadGenetics . . . rushed to submit a patent application for BRCA2 . . . ."
The editorial concluded: "Even as the process of evaluating these[patent] claims begins, there is the possibility that the two teams willreach some form of cross-licensing agreement."
Myriad's Meldrum said: "Stratton's group published in Nature afragment of the BRCA2 gene that contained nine of the 27 exons thatmake up that gene. Myriad Genetics, the day before the Nature paperwas published, that is, on Dec. 20, 1995, deposited in GenBank thecomplete DNA sequence, including all 27 exons."
He made the point: "Under current U.S. patent law, you need to havethe complete coding sequence in order to get a composition-of-matterpatent on a gene. So Myriad feels confident it has a strong patentposition."
Editor's note: Three other papers round out breast-cancer researchreports in this month's Nature Genetics. They deal with BRCA1'sbehavior during pregnancy, milk secretion's possible connection toan obscure secretory protein named granin, and the possible role ofother genes in ovarian cancer. BioWorld Today will cover thesereports later this month. n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.