WASHINGTON - A new study identifying 38 mutations of a gene associated with breast cancer represents an important step towards developing a method for screening and early diagnoses of breast cancer, reported researchers at an American Medical Association briefing.

Last year genetic researchers at the University of Utah reported locating the BRCA1 gene, a defective form of which is believed to be associated with some breast cancers. Since that time the researchers have compiled a survey of mutations on the gene which appear to be associated with an increased susceptibility to both breast and ovarian cancer.

In a collaborative effort, researchers from nine laboratories in North America and the United Kingdom evaluated BRCA mutations in the DNA of 372 patients with either breast or ovarian cancer. Most of the patients came from families with a history of these cancers. The researchers then tested an additional 714 patients with breast or ovarian cancer for two common recurrent gene mutations. The researchers identified 38 distinct mutations on the BCRA gene in seven percent of the patients, three of which occurred frequently. Specific testing for the two most common mutations uncovered them in 17 additional patients.

"At present, failure to find a mutation in an at-risk individual is only useful clinically if a BRCA1 mutation has been identified in an affected first-degree relative. At risk women who have not inherited the mutant BRCA1 allele preset in their affected relatives would have breast and ovarian cancer rates equal to those in the general population. Familles in which no BRCA1 mutation has been identified will have a risk that combines the probability of nondetection with risk based on empiric data for women with a particular family history," notes Dr. Mark Skolnick, one of the original discoverers of the BRCA1 gene.

The researchers used a variety of methods to detect the mutations. These included direct DNA sequencing, single strand conformation polymorphism assays and clamped denaturing gel electrophoresis. Once a mutation is found, allele specific detection is accomplished by allele-specific oligonucleotide hybridization.

Further investigation revealed that many of mutations produced a truncated form of the BRCA1 protein. This is considered an important findings, since it may be easier to develop a test for that specific protein abnormality rather than for the whole gene. Further identification and characterization of breast cancer susceptibility genes should provide better risk estimation for a individuals risk of developing the disease.

The BRCA1 gene is large, containing 5,592 nucleotides spread over some 100,000 bases of genomic DNA. It is made up of 22 coding exons producing a protein of 1863 amino acids. Several kinds of mutations were seen in the study. These included missense mutations, when a substitution but does not affect the remainder of the protein translation, and nonsense mutations when a single nucleotide substitution produces a stop codon. Frameshift mutations involving insertion or deletion of one or more nucleotides were also observed. Mutations in the gene's regulatory region were also observed.

Breast cancer is the most common cancer among women and the second leading cause of death from cancer in women (after lung cancer). The average woman in the U.S. has a one in nine chance of developing breast cancer by the age of 85. Ovarian cancer accounts for five percent of cancers among women.

This study appears in JAMA, Vol.273, No.7, 2/15/95, Skolnick et al. Cancer statistics from the American Cancer Society.

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