and Ovarian Cancer
| Breast and Ovarian Cancer in the Ashkenazi
MS, CGC and Jill
By Beth Crawford,
link between BRCA1 and BRCA2
and breast and ovarian cancer
was discovered in 1994. Later, additional studies conducted
samples originally donated for Tay Sachs disease research
revealed that people of Ashkenazi (Eastern
European) Jewish heritage are
more likely to have mutations in these genes
than members of the general population. Furthermore,
researchers have discovered that three specific mutations
in the BRCA1 and BRCA2 genes account for approximately
90 percent of the BRCA1 and BRCA2 mutations identified
in Ashkenazi Jews. This is in contrast to the hundreds
of unique BRCA1 and BRCA2 mutations that genetic testing
has turned up in people who are not of Ashkenazi Jewish
Debate Over Singling Out Certain Populations for
the shadow of the holocaust and the eugenics movement,
many people fear that identifying certain groups
as being at "high risk" for some diseases
could lead to discrimination. In the United States,
for example, insurance discrimination is of particular
and growing concern.
any such worries must be weighed against individual's
rights to information about their cancer risk,
which means that if scientists have discovered
that certain ethnic groups are at above-average
risk for a disease, it would be unethical to keep
that information silent.
Why Some Diseases Are More Prevalent in Certain
have long known that some inherited
diseases occur more commonly in certain ethnic groups
than they do in the general population. (Examples include
sickle cell anemia in people of African descent, and cystic
fibrosis in people of Northern European descent.) They
attribute this phenomenon to the "founder effect,"
which is seen in populations that have been isolated for
religious, cultural, or geographical reason and have originated
from a small group of common ancestors. In such populations,
disease-associated mutations get passed down with greater
frequency because any mutations present in the founders
become common in the resulting population. Researchers
believe the BRCA1 and BRCA2 mutations that today occur
with a relatively high degree of frequency in Ashkenazi
Jews originated in common ancestors approximately 600
hundred years ago.
Mutations and Their Frequency
1 in 40 Ashkenazi Jewish individuals carries one
of three BRCA1 or BRCA2 mutations, while approximately
1 in 500 members of the general population carry
any BRCA1 or BRCA2 mutation.
the three mutations that account for the vast majority
of BRCA1 and BRCA2 mutations in Ashkenazi Jews, two
occur on the BRCA1 gene and one occurs on the BRCA2
This mutation located is on the BRCA1 gene and was
the first to be linked to Ashkenazi Jews. It is found
in approximately one percent of the Ashkenazi Jewish
Also located on BRCA1, this mutation is less common
than the 185delAG mutation and is found in approximately
0.15 percent of individuals of Ashkenazi Jewish descent.
This mutation is located on the BRCA2 gene and is
the most common of the BRCA1 and BRCA2 mutations
found in the Ashkenazi Jewish population, occurring
in approximately 1.5 percent of such individuals
Do the Names Mean?
(and thus genes) are made up of different sequences
of just four individual molecules, called bases,
that scientists abbreviate with the letters A, C,
G, and T. Mutations can cause extra bases to be
added into the gene, or cause needed bases to be
deleted (among other possibilities).
names of the particular BRCA1 and BRCA2 mutations
in the Ashkenazi Jewish population are abbreviations
for the way the genes are mutated. For example,
185delAG, means that at the 185th base in the
gene, an A and a G are missing; and 5382insC means
that at the 5382nd base in the gene there is an
extra C. These types of gene mutations are often
referred to as spelling errors.
these percentages may sound low, when counted together
they take on more significance. Approximately 2.65 percent
of the Ashkenazi Jewish population has one of these
three mutations; a number far higher than the 0.2 percent
of the general population that carries a BRCA1 or BRCA2
the chances that a person of Ashkenazi Jewish descent
has one of these mutations rises dramatically if he
or she has a personal or family medical history of breast
or ovarian cancer. Consider, for example, the following
of Ashkenazi Jews who have been diagnosed with breast
cancer before the age of 40 have a BRCA1 mutation.
of Ashkenazi Jews with a family history of two or
more breast cancers carry one of these mutations.
of Ashkenazi Jews with a family history that includes
two or more cases of breast cancer and at least one
case of ovarian cancer carry one of these mutations.
course the bottom line in any discussion of cancer risk
is not how many people are carriers of a specific genetic
mutation, but how many of those carriers will actually
develop the associated disease. In the case of Ashkenazi
Jews with BRCA1 and BRCA2 mutations, a recent population-based
study suggests that 56 percent of such individuals will
develop breast cancer over the course of their lives,
and 16 percent will develop ovarian cancer by age 70.
In addition, this study showed that these two genes
increase the risk of prostate cancer in men who carry
mutations. Sixteen percent will develop the disease
by age 70. To see how these risk statistics stack up
against those of the general population, see the following
of General Population That Will Develop the Disease
of Ashkenazi Jewish Mutation Carriers That Will
Develop the Disease
are population-based studies so powerful?
Studies that start
with a large and diverse population can help avoid
biases that might be present, but not obvious, in
studies that start with a more narrow population.
most recent population-based study also cast great doubt
on earlier studies that linked these specific BRCA1
and BRCA2 mutations to an increase in colon cancer risk.
In addition, the risk estimates from the population-based
study are lower than those from earlier studies that
looked at cancer risk only in mutation carriers. It
is not clear whether this difference is because the
cancer risk is lower when an individual has these three
particular mutations than if they had other BRCA1 and
BRCA2 mutations, or whether the cancer risk is lower
because this was a population-based study that could
give more accurate risk estimates than could the earlier
researchers have been able to pinpoint three mutations
that account for the majority
of BRCA1 and BRCA2 defects in Ashkenazi Jews, genetic
testing is simpler for this population
than it is for the population at large. This is because
DNA testing can begin with just these three mutations,
making the tests less expensive and often easier to
interpret than the full-sequence genetic testing that's
required to identify the hundreds of BRCA1- and BRCA2-associated
mutations that can arise in members of the general population.
The rationale for the three mutation test is that 90
percent of the time in an Ashkenazi Jewish family, if
there is a mutation it will be one of these three. If
this test is negative it may be necessary to go on to
the full sequence test for BRCA1 and BRCA2 to rule out
a mutation as the cause for the family history.
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