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Abstract & Commentary
It has been well established that mutant brca1 or brca2 genes increase a woman’s lifetime risk of breast and ovarian cancer. When a family history of breast cancer is encountered, patients can be tested to determine whether they have normal expression of the BRAC1 and 2 genes. However, it now has become clear that there are histological differences in the tumors of patients with BRCA1 and 2 mutations, and these also differ from sporadic breast cancer cases. Although these differences have been noted, it is not absolutely possible to classify any given tumor based on the pathologic features alone, as there is considerable overlap among the 3 groups. The purpose of this paper was to determine whether distinctive patterns of gene expression could be determined that could differentiate BRCA1 mutant tumors from BRCA2 tumors. In addition, sporadic breast cancer tumors were included.
The material for this study included 7 patients with BRCA1 mutations, 7 patients with BRCA2 mutations, and 7 with sporadic primary breast cancer. Hedenfalk and colleagues used complimentary DNA samples representing 5361 unique genes. Appropriate laboratory handling of the specimens was performed. The statistical analyses were complicated, yet precise. Hedenfalk et al looked for associations between clinical variables and mutation type. Because of the large number of data points examined and the relatively small number of breast cancer samples, Hedenfalk et al used a technique called class-predication to help determine whether their classification was based on fact or chance. Several other complicated methods of analysis were used to help determine that their observed differences were not based on chance association.
Hedenfalk et al determined that it was possible to separate the BRCA1 mutation breast cancers from BRCA2 breast cancers based on significant differences in their gene-expression profiles. While histopathology and receptor analyses were able to grossly separate the lesions into BRCA1 and 2 types, this analysis was not as accurate as the development of the gene-expression profiles.
Hedenfalk et al did encounter 1 case of misclassification of a BRCA1 mutation. However, on further study of the patient, Hedenfalk et al found that while the BRCA1 was not mutated, the BRCA1 promoter region was abnormal, causing hypermethylation, which inactivates the BRCA1 gene.
Hedenfalk et al conclude that BRCA1 and 2 tumors can be differentiated based on their gene-expression patterns. (Hedenfalk I, et al. N Engl J Med. 2001;344:539-548).
COMMENT BY KENNETH L. NOLLER, MD
During the past several weeks, it has been almost impossible to turn on the nightly news without hearing some story about the completion of the "human genome project." According to these news sources, the sequencing of the human genome will now make it possible to wipe out all human disease, all congenital defects, obesity, and bad breath. While it is indeed likely that major breakthroughs in both the diagnosis and treatment of human disease will occur because of an increased knowledge of the human genome, it will occur only as a result of careful, detailed work such as that performed by Hedenfalk et al.
The reason I chose this article for review is that all of us in clinical medicine must now begin to learn an entirely new language. It will be virtually impossible to read the medical literature (and perhaps even to treat some patients) without better understanding the human genome and gene therapy. Unfortunately, to the present time, most of the work in this area has been buried deep in molecular biology journals and is written in some obscure laboratory babble. It was, therefore, refreshing to find an article, in what is perhaps the world’s best clinical medical journal, that can serve as an introduction to gene jargon for many of us. I would definitely suggest seeking out the article but would also suggest that it be read in the following sequence: First, read the accompanying editorial, then read the article itself, then reread the editorial. Perhaps by spending a bit of time reading and rereading some of these articles that are presented in clinical journals (and some like this one even have color pictures), we may be able to understand the literature of gene therapy, eventually. It will be hard but necessary work.