The Role of Methylated BRCA1 in Breast Cancer
Popular Press vs. Scientific Reports
This web page was produced as an assignment for an undergraduate course at Davidson College.
Each week, the evening news reports findings of a new gene, a gene linked to one disease and dubbed as the cause of that disease. Using this knowledge of genetics to medically correct the defect appears to be the next logical step. Our hears pound at the prospect of eating more at dinner since there will be a pill to correct our "fat gene". After an abbreviated description of the scientific procedure behind locating the gene, there is always one or two take home messages. We are all doomed to suffer from this particular disease as understanding this gene is only one tiny step in a cascade of mysterious processes. Or worse almost, by locating this gene, doctors can solve all cases of the respective disease. We mentally plan to talk with our doctors about beginning treatment.
While these popular press reports are rarely blatantly dishonest, they most all misconstrue the real message. This more realistic message includes that genetics is bringing to the forefront of medicine the prospects of new cures and treatments tailored around one's genetic makeup. Yet the discovery of a gene rarely if ever leads directly to a "cure". The discovery does however begin the understanding of a disease and all the other genes or cellular processes involved in the manifestation of the disease.
In 1994, scientists at the University of Utah and Myriad Genetics Inc. discovered that having a mutated form of a gene called BRCA1 led to a susceptibility of breast and ovarian cancer (Associated Press 1994). Scientists reported that a mutated version of this gene put men and women at risk for breast cancer. Since there are many different sources of mutation, scientists began to study exactly how BRCA1 was mutated to lead to breast cancer.
According to an April 15, 2000 Science News Online article, a normal BRCA1 gene encodes a cancer-suppressing protein that aids in DNA repair (Seppa 2000). This article states that the cause of breast cancer in some women is due to a hypermethylated promoter region for BRCA1. "Although the gene itself remains intact, a nearby stretch of DNA that switches on the gene has become inpaired" (Seppa 2000). This defective promoter silences the gene such that there is no direct protein production (Seppa 2000). The hypermethylation prevents necessary proteins from binding to BRCA1's promoter making it shut down. The BRCA1 gene is unable to produce the protein necessary for DNA repair. The article ends by stating that the finding of this hypermethylated region adds support to the notion that multiple forms of breast cancer may not be inherited.
The FASEB Journal
According to a study published in The FASEB Journal by Magdinier et al. (2000), regional methylation of the 5' end of the CpG island of BRCA1 is associated with reduced gene expression. Often, the CpG islands are located at this 5' end and contain the promoter for the first exon of the associated gene. Normally these island sequences are unmethylated. Magdinier et al. (2000) found that hypermethylation of CpG islands is associated with gene silencing and has been linked to crucial regulation of cell growth during cancer progression. "Differences in DNA methylation are associated with differentiation and carcinogenesis, CpG methylation correlating with the silencing of many genes" (Magdinier et al. 2000).
The gene BRCA1 is an 81 kb region located on chromosome 17. Its cytogenic map location is 17q21, and the gene is composed of 24 exons of which 22 are coding exons. There is a high density of Alu repitition and a low density of other repititions. Recently, the function of this gene was revealed as participating in repairing breaks in double stranded DNA due to radiation exposure. According to the human protein report, this gene encodes the DNA repairing protein Xrcc1. This protein is 1863 amino acids in length.
Figure 1: This illutrates the protein structure of Xrcc1 encoded from the gene BRCA1. Image taken from this PDB file. Seeking permission from RCSB for image.
This study made use of cell cultures from human breast cell lines, cervix cell lines, and kidney cell lines (Magdinier et al. 2000). The cell cultures were digested with a specific restriction enzyme and PCR amplification was performed. Because successful methylation is very difficult, the goal was to isolate only a vector containing the 5' end of the BRCA1 gene and hence the promoter. In vitro methylation was performed and completeness of methylation was verified with corresponding restriction enzymes (Magdinier et al. 2000). Finally, Southern blot analysis was used to determine methylation patterns.
This paper points out that some promoters are only minimally inhibited by in vitro methylation. Thus the study used of an abbreviated form of the gene, in the vector containing the 5' end of BRCA1, in order to promote methylation. This study also points out that it is not simply methylation that inhibits the promoter but rather the density of methylated sites.
Comparing the two sources
It is difficult to compare the two articles though they are both essentially reporting the same facts. In both articles it is apparent that methylation of the promoter for the BRCA1 gene has been linked to some cases of breast cancer. The popular press article simply states this fact without really providing any detailed description of a scientific study or even a reference to a particular study. The article has quotes from various doctors yet does not cite any specific study or method. The popular press article does however, give several sets of numbers such as that DNA hypermethylation was found in 33 of 184 cases of breast tumors. This is supposed to prove a link between hypermethylation and breast cancer, yet there is no explanation as to if the numbers are unusually large or small. The scientific study does not make such bold statements as to hypermethylation and a direct cause of cancer. The scientific paper does give a detailed account of a scientific study and the conclusions that can be drawn from that study. The intention of scientific papers is not to extrapolate a great deal from the experiment into future implications. The scientific study also states that it is the density of hypermethylation not one hypermethylated promoter that causes the cancer susceptibility. This is unlike the popular press article which indicates that one hypermethylated region can cause susceptibility. This indicates that the popular press article presents a simplified discussion.
To its credit, the popular press article was not overly optimistic or gloomy. Also, the popular press article did not misrepresent the BRCA1 gene by announcing a direct cause and effect relationship between breast cancer and the presence of the gene, though it does link hypermethylation to cancer. The article simply states that having a mutated version of the gene has been linked to breast cancer. I find the greatest source of error in this article to be that the last line does not seem supported by any information in the article. The last line says that the findings regarding hypermethylation support the notion that a mutation in BRCA1 may not be inherited. It is not possible for most audiences to deduce this from the facts of the article since the article does not address how hypermethylation comes about in an individual.
The role of each article is different. The goal of the popular press article is to briefly report on scientific findings without giving false information. The scientific study's goal is to report all the findings and provide conclusions from that study. Both appear to have successfully met these agendas.
Associated Press. 1994. NIH Battles Over Patent on Breast Cancer Gene: Private Firm Succeeded in Quest with Government Funded Research. The Washington Post.
Magdinier, Frederique, Lise-Marie Billard, Gaelle Wittmann, Lucien Frappart, Mehdi Benchaib, Gilbert M. Lenoir, Jean Francois Guerin, and Robert Dante. 2000. Regional methylation of the 5' end of CpG island of BRCA1 is associated with reduced gene expression in human somatic cells. The FASEB Journal. Vol. 14: 1585-1594.
Seppa, N. 2000. Silencing the BRCA1 gene spells trouble. Science News Online. <http://www.findarticles.com/m1200/16_157/62195128/p1/article.jhtml> Accessed 2001 Aug 30.
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