Thesis: as a result of genetic influence. But it



The purpose of this paper is to review the
discovery and current understanding of how an individual’s chance of developing
cancer can be determined by a genetically inheritable mutation in the BRCA

We Will Write a Custom Essay Specifically
For You For Only $13.90/page!

order now




Breast Cancer has always been known to be
caused by damaged DNA. This damage can arise randomly, after direct exposure to
UV rays or smoking, and it can even arise as a result of genetic influence. But
it was not until the 1990s did scientists realize that an individual’s chances
of developing any kind of cancer could be determined by genes. While it was
traditionally thought that a genetically inheritable disease could definitely
be caused by a mutated gene, cancer was so versatile and specific it seemed
highly unlikely that a gene could cause someone to develop it. However, Dr.
Marie-Claire King, a young woman who had just received her doctorate in
genetics with an undergraduate background in mathematics, observed how breast
cancer seemed to “run in families.” Some families would have high incidences of
reoccurring breast cancer, as if they were passing cancer from one generation
to the next. Dr. King wondered if the underlying cause of this breast cancer
trend was a genetic component and sought out to find if there was in fact a
genetic culprit that could impact a person’s chance of developing breast
cancer. 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 ultimately
discovered by scientist from Myriad Genetics in 1994.



The first observations of a familial breast
cancer trend were found in extensive family pedigrees: a record of an individual’s
relatives over generations. A pedigree also records the presence of ailments
and diseases within a family, including breast cancer. Dr. King knew that in
order to effectively investigate the genetics of breast cancer, she would have
to construct pedigrees with data from families affected by breast cancer. She
conducted interviews with individuals who gave their permission to use their
family history information for constructing pedigrees. One example of this
approach is in a 1986 study where pedigrees were constructed to analyze the
chance of an individual developing breast cancer if their sister developed
breast cancer at age 50 years or younger or at 40 years or younger. Patient
data was collected through the Los Angeles County Cancer Surveillance Program
which records cancer diagnoses in Los Angeles County. Patients were asked by
their physicians to interview them about their familial history of breast
cancer, and if permission was granted, their data was used in the studies


This study used statistical analysis to assess
a person’s chance of developing breast cancer and reported it as relative risk.
In the
context of this study, a relative risk of 1 suggests there is little to no risk
of developing breast cancer and greater than 1 would suggest there is an increased
risk of developing breast cancer. RL1 A woman whose sister
developed bilateral cancer at 50 years of age or younger had a significant risk
of developing cancer with a relative risk score of 5.5. The risk would drastically
increase if an individual’s sister was diagnosed with bilateral cancer at 40
years of age or younger with a relative risk score of 10.5 (Ottman et al., 1986). RL2 Overall, this study
found that the age an individual developed breast cancer combined with their
family history of breast cancer significantly impacted their chances of
developing breast cancer later in life.

Another notable database that was used for pedigree
data in other studies is the Utah Genealogy Database kept by the church of the
Latter-Day Saints. This database is unique in the fact that in order to be
included, an individual must have at least one relative that died or was born
on the Mormon Pioneer Trail of 1846-1868. The database contains the family
history of over one million individuals and is so extensive it can span back
seven generations for a single family. One 1993 study coupled this database
with the Utah Cancer Registry: a population-based database that records cancer occurrences
and tumor information for the state of Utah. The purpose of this study was to
determine the impact of an individual’s family history on their chances of
developing breast cancer later in life by creating comprehensive familiar
pedigrees from multiple databases. This study found that women who had an extensive family history of
breast cancer had the highest risk of developing breast cancer later in life.
The risk would increase if a direct relative of an individual develops breast
cancer such as an aunt. The risk was the highest if this direct relative was the
biological mother (Slattery and Kerber, 1993). These results showed that an individuals family
history could calculate an individual’s chances of developing breast cancer
later in life because of the definite trends.


While there was a clear correlation between
family history of breast cancer risk observed in genetic pedigrees, this was
not sufficient evidence to prove that there was a gene that was impacting an individual’s
chance of developing breast cancer. These pedigrees could not accurately record
if an individual was a carrier of a gene that impacted their breast cancer. A
more molecular approach would have to be used to find the elusive BRCA gene.

Body #2: Backtracking
a while back – proposed “marker” method to widdle down search


There was one major
obstacle that prevented scientists from finding the BRCA gene: pinpointing the
location of a specific gene was not possible at the time. Scientists were only
able to detect the linkage of individual traits, but could not map the
locations of genes within the human genome. But in 1980, a method to create a
genetic linkage map was proposed in a study by Dr. David Botstein, Dr. Raymond
White, Dr. Mark Skolnick, and Dr. Ronald Davis. They proposed for the usage of Restriction
Fragment Length Polymorphisms (RFLPs) as genetic markers to create a genetic
linkage map. A RFLP is formed when DNA restriction enzymes recognize specific
DNA sequences and catalyze cleavage at endonuclease sites, creating fragments
of DNA. The many forms of these fragments, polymorphisms, are unique to an
individual’s DNA. The uniqueness of RFLPs can be seen in agarose electrophoresis
gels as they create distinct band patterns in a gel. Electrophoresis gels have
been used to track individual traits, the paternity of a child, and much more.

One of the main benefits
of using RFLPs to create a genetic linkage map is how broad the search for a
gene can be. Previous studies have used RFLPs with a gene that has already been
isolated (cite?). But this was not possible with the BRCA gene because it had
not been found. The authors of this paper wanted to use RFLPs in a broader
sense that did not require specific gene isolation. They wanted to use a
broader approach to create a genetic linkage map, arguing this would be
sufficient enough to identify genetic linkage in the human genome and common
linkages between individuals. In the context of searching for the BRCA gene, the
authors hoped to use this approach to determine if there was genetic linkage in
patients who had developed breast cancer or individuals who had an extensive
family history of breast cancer.

This study also utilized extensive family pedigrees for
patient data. Using RFLP probes, the fingerprint from each individual would be
analyzed for gene linkage and other markers identified in the individual’s

#3: Narrowing and eventually finding BRCA gene


Eventually, with the use of RFLP markers, the
location of both forms of the BRCA gene were found. In 1994, a study was
published detailing the locations of both BRCA1 and BRCA2, the methods used to
locate them, their functions, and how each gene impacts an individuals chance
of developing breast cancer. The authors mapped BRCA1 on the 17th chromosome
(17q) and hypothesized that it encodes for a tumor suppressor protein. If this gene
is mutated, the protein is not produced which significantly increases the
chance of unregulated cell division which would ultimately lead to cancer. BRCA2
was mapped on the 13th chromosome and was hypothesized to be responsible
for early-onset breast cancer in individuals who possessed the mutated form of the
gene. 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 motivated
families to actively research their breast cancer risk. A 1995 study focused on
diagnostic testing for the BRCA genes and risk assessment of individuals with a
family history of breast cancer. (Shattuck-Eidens et a., 1995).


An incredible amount of effort was put into
discovering the location of the BRCA1 and BRCA2 genes. This new-found methodologies
and knowledge is being used to help countless families who have been suffering
from breast cancer for generations. While the search for this specific gene is
over, the same approach used to find the BRCA genes is currently being used to
search for more cancer-causing genes. Further implications of the technology
used to find the BRCA gene involves adding to the ever-growing list of known
cancer-causing genes, their functions in the human genome, and how to better
inform families about their risk of developing different kinds of cancers.