Thesis: The purpose of this paper is to review thediscovery and current understanding of how an individual’s chance of developingcancer can be determined by a genetically inheritable mutation in the BRCAgene. Introduction: Breast Cancer has always been known to becaused by damaged DNA. This damage can arise randomly, after direct exposure toUV rays or smoking, and it can even arise as a result of genetic influence. Butit was not until the 1990s did scientists realize that an individual’s chancesof developing any kind of cancer could be determined by genes.
While it wastraditionally thought that a genetically inheritable disease could definitelybe caused by a mutated gene, cancer was so versatile and specific it seemedhighly unlikely that a gene could cause someone to develop it. However, Dr.Marie-Claire King, a young woman who had just received her doctorate ingenetics with an undergraduate background in mathematics, observed how breastcancer seemed to “run in families.” Some families would have high incidences ofreoccurring breast cancer, as if they were passing cancer from one generationto the next. Dr. King wondered if the underlying cause of this breast cancertrend was a genetic component and sought out to find if there was in fact agenetic culprit that could impact a person’s chance of developing breastcancer. This line of thought would lead to a “great race” in search of the BRCA(BReast CAncer) gene until both forms, BRCA1 and BRCA2, were ultimatelydiscovered by scientist from Myriad Genetics in 1994.
Body: The first observations of a familial breastcancer trend were found in extensive family pedigrees: a record of an individual’srelatives over generations. A pedigree also records the presence of ailmentsand diseases within a family, including breast cancer. Dr. King knew that inorder to effectively investigate the genetics of breast cancer, she would haveto construct pedigrees with data from families affected by breast cancer.
Sheconducted interviews with individuals who gave their permission to use theirfamily history information for constructing pedigrees. One example of thisapproach is in a 1986 study where pedigrees were constructed to analyze thechance of an individual developing breast cancer if their sister developedbreast cancer at age 50 years or younger or at 40 years or younger. Patientdata was collected through the Los Angeles County Cancer Surveillance Programwhich records cancer diagnoses in Los Angeles County. Patients were asked bytheir physicians to interview them about their familial history of breastcancer, and if permission was granted, their data was used in the studiespedigrees. This study used statistical analysis to assessa person’s chance of developing breast cancer and reported it as relative risk.In thecontext of this study, a relative risk of 1 suggests there is little to no riskof developing breast cancer and greater than 1 would suggest there is an increasedrisk of developing breast cancer. RL1 A woman whose sisterdeveloped bilateral cancer at 50 years of age or younger had a significant riskof developing cancer with a relative risk score of 5.5.
The risk would drasticallyincrease if an individual’s sister was diagnosed with bilateral cancer at 40years of age or younger with a relative risk score of 10.5 (Ottman et al., 1986). RL2 Overall, this studyfound that the age an individual developed breast cancer combined with theirfamily history of breast cancer significantly impacted their chances ofdeveloping breast cancer later in life.Another notable database that was used for pedigreedata in other studies is the Utah Genealogy Database kept by the church of theLatter-Day Saints. This database is unique in the fact that in order to beincluded, an individual must have at least one relative that died or was bornon the Mormon Pioneer Trail of 1846-1868.
The database contains the familyhistory of over one million individuals and is so extensive it can span backseven generations for a single family. One 1993 study coupled this databasewith the Utah Cancer Registry: a population-based database that records cancer occurrencesand tumor information for the state of Utah. The purpose of this study was todetermine the impact of an individual’s family history on their chances ofdeveloping breast cancer later in life by creating comprehensive familiarpedigrees from multiple databases. This study found that women who had an extensive family history ofbreast cancer had the highest risk of developing breast cancer later in life.The risk would increase if a direct relative of an individual develops breastcancer such as an aunt. The risk was the highest if this direct relative was thebiological mother (Slattery and Kerber, 1993).
These results showed that an individuals familyhistory could calculate an individual’s chances of developing breast cancerlater in life because of the definite trends. While there was a clear correlation betweenfamily history of breast cancer risk observed in genetic pedigrees, this wasnot sufficient evidence to prove that there was a gene that was impacting an individual’schance of developing breast cancer. These pedigrees could not accurately recordif an individual was a carrier of a gene that impacted their breast cancer. Amore molecular approach would have to be used to find the elusive BRCA gene.Body #2: Backtrackinga while back – proposed “marker” method to widdle down search There was one majorobstacle that prevented scientists from finding the BRCA gene: pinpointing thelocation of a specific gene was not possible at the time. Scientists were onlyable to detect the linkage of individual traits, but could not map thelocations of genes within the human genome. But in 1980, a method to create agenetic linkage map was proposed in a study by Dr.
David Botstein, Dr. RaymondWhite, Dr. Mark Skolnick, and Dr. Ronald Davis. They proposed for the usage of RestrictionFragment Length Polymorphisms (RFLPs) as genetic markers to create a geneticlinkage map. A RFLP is formed when DNA restriction enzymes recognize specificDNA sequences and catalyze cleavage at endonuclease sites, creating fragmentsof DNA. The many forms of these fragments, polymorphisms, are unique to anindividual’s DNA.
The uniqueness of RFLPs can be seen in agarose electrophoresisgels as they create distinct band patterns in a gel. Electrophoresis gels havebeen used to track individual traits, the paternity of a child, and much more. One of the main benefitsof using RFLPs to create a genetic linkage map is how broad the search for agene can be. Previous studies have used RFLPs with a gene that has already beenisolated (cite?). But this was not possible with the BRCA gene because it hadnot been found.
The authors of this paper wanted to use RFLPs in a broadersense that did not require specific gene isolation. They wanted to use abroader approach to create a genetic linkage map, arguing this would besufficient enough to identify genetic linkage in the human genome and commonlinkages between individuals. In the context of searching for the BRCA gene, theauthors hoped to use this approach to determine if there was genetic linkage inpatients who had developed breast cancer or individuals who had an extensivefamily history of breast cancer. This study also utilized extensive family pedigrees forpatient data.
Using RFLP probes, the fingerprint from each individual would beanalyzed for gene linkage and other markers identified in the individual’schromosomes. Body#3: Narrowing and eventually finding BRCA gene Eventually, with the use of RFLP markers, thelocation of both forms of the BRCA gene were found. In 1994, a study waspublished detailing the locations of both BRCA1 and BRCA2, the methods used tolocate them, their functions, and how each gene impacts an individuals chanceof developing breast cancer. The authors mapped BRCA1 on the 17th chromosome(17q) and hypothesized that it encodes for a tumor suppressor protein. If this geneis mutated, the protein is not produced which significantly increases thechance of unregulated cell division which would ultimately lead to cancer. BRCA2was mapped on the 13th chromosome and was hypothesized to be responsiblefor early-onset breast cancer in individuals who possessed the mutated form of thegene. There are two types of mutations that have been identified for the BRCA gene.
(Miki et al., 1994).The discovery of BRCA1 and BRCA2s location motivatedfamilies to actively research their breast cancer risk. A 1995 study focused ondiagnostic testing for the BRCA genes and risk assessment of individuals with afamily history of breast cancer.
(Shattuck-Eidens et a., 1995). Conclusion:An incredible amount of effort was put intodiscovering the location of the BRCA1 and BRCA2 genes. This new-found methodologiesand knowledge is being used to help countless families who have been sufferingfrom breast cancer for generations. While the search for this specific gene isover, the same approach used to find the BRCA genes is currently being used tosearch for more cancer-causing genes.
Further implications of the technologyused to find the BRCA gene involves adding to the ever-growing list of knowncancer-causing genes, their functions in the human genome, and how to betterinform families about their risk of developing different kinds of cancers.