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Kara J. Milliron, M.S.,
Sofia D. Merajver, M.D., Ph.D.
Associate Professor of Internal Medicine
Director, Breast and Ovarian Cancer Risk Evaluation Program
A woman's lifetime risk for developing breast cancer is estimated
to be one in eight (12.5%), with approximately 185,000 women
diagnosed with breast cancer each year (1). Research into
familial breast and ovarian cancer has so far led to the identification
of two main breast cancer susceptibility genes, BRCA1 and
BRCA2. Other genes, such as TP53, PTEN and ATM, also are known
to be involved in causing hereditary breast cancer. Families
with inherited mutations in BRCA1 or BRCA2 are likely to have
an apparent excess of cases of early onset breast and/or ovarian
cancer that follow an autosomal dominant pattern of inheritance.
It is estimated that one out of 300 individuals in the general
population carries a BRCA1 or BRCA2 mutation, one out of 40
Ashkenazic Jews carries a BRCA1 or BRCA2 mutation, and one
out of 2,500 Ashkenazic Jews carries two mutations.
Located on chromosome 17q21, BRCA1 is a tumor suppressor gene
that appears to be involved in the double-stranded DNA error
correction function. Mutations in BRCA1 are responsible for
approximately 50% of all inherited predisposition to breast
cancer. Current risk estimates for BRCA1 mutation is 55 to
85% lifetime risk for breast cancer and 20 to 40% lifetime
risk for ovarian cancer. Men who inherit a BRCA1 mutation
have a mildly elevated lifetime risk for prostate cancer.
BRCA1 mutation carriers may also have an elevated lifetime
risk for colon cancer.
BRCA2, located on chromosome 13q12, is also a tumor suppressor
gene, but little is known about its actual function. Mutations
in BRCA2 account for approximately 35% of the remaining hereditary
breast cancers. BRCA2 mutations appear to confer a similar
female breast cancer risk to that seen with BRCA1 mutations.
However, the risk of ovarian cancer for BRCA2 mutation carriers
appears to be lower, with up to a 27% lifetime risk for developing
ovarian cancer (2). Male breast cancer, a rare disease in
the general population, is much more common in the BRCA2 families.
Male BRCA2 mutation carriers have up to a 6% lifetime risk
for developing breast cancer (3). Detailed pedigree analyses
of BRCA2 families have identified other malignancies that
include: laryngeal, prostate, pancreatic and gastrointestinal
cancers, which may occur with increased frequency compared
to that of the general population (4).
DNA sequencing is the most sensitive for BRCA1 and BRCA2
mutation detection, as it determines the nucleotide sequence
of the coding regions of genes. It is estimated that sequencing
will uncover nearly 98% of all the mutations in the coding
regions of BRCA1 and BRCA2, but will consistently miss mutations
in non-coding regions of genes and large genomic deletions.
This phenomenon is evident, for example, in the Dutch population,
where 20 to 30% of individuals with a strong family history
of breast cancer will have a negative BRCA1 and BRCA2 sequencing
A test known as "The Ashkenazic Jewish panel" or the "multi-site
3 BRCAnalysis" tests for three specific mutations (185 delAG,
5382insC and 6174delT) found in BRCA1 and BRCA2 that are common
among people of Ashkenazic Jewish descent. Since 1/2500 individuals
of Ashkenazic Jewish ethnicity will carry two of these "founder"
mutations, it is recommended that all Ashkenazic Jewish individuals
seeking BRCA1 and BRCA2 mutation testing receive testing for
all three founder mutations, even if a particular mutation
is already known in the family.
A mutation-specific test is used when a mutation has been
identified in an affected family member. This test looks only
for the one specific mutation previously identified in the
family. If the test result is negative, the risk for breast
cancer in that individual is not zero, but usually equivalent
to that of the general population. It is important that the
full family cancer history of both the paternal and maternal
lineages be known in detail before ordering this test for
a second or higher degree relative of a mutation carrier,
as additional types of tests may be indicated as well.
The outcomes of a genetic test for a cancer susceptibility
gene need to be interpreted in the context of the known mutations
and the individual's specific history. A positive test result
means that a known deleterious mutation has been found, which
correlates with an increased risk for developing cancer. An
inconclusive test result means that a mutation is found, but
it is unknown whether the mutation correlates with an increase
risk for developing cancer. This inconclusive test result
is called a variant of uncertain significance. Information
on these variants is available through a worldwide web-based
databank, the Breast Information Core (BIC). As more information
is gathered, these variants can be reclassified to known deleterious
mutations or polymorphisms. A negative test result means that
no mutation was found in the coding region of BRCA1 and BRCA2.
However, it is possible that there is a mutation in areas
of BRCA1 and BRCA2 that cannot be identified using current
methods, along with the possibility the cancers in the family
may be associated with a mutation in an uncharacterized cancer
susceptibility gene. Finally, regardless of a family's mutation
status, it is possible that some of the cancers seen in the
family are sporadic or due to other causes.
Because their risk for developing breast cancer is increased
over that of the general population, tamoxifen has been offered
as a chemopreventive option for BRCA1 and BRCA2 mutation carriers.
However, as of this writing, the effect of tamoxifen as a
chemoprevention agent in BRCA mutation carriers is not completely
known. Studies are currently investigating the BRCA mutation
status of many participants from the original breast cancer
prevention trial. The expectation is that when the data are
analyzed, the results will prove efficacy.
One prevention option available to BRCA1 and/or BRCA2 mutation
carriers is prophylactic bilateral mastectomy. Researchers
from the Mayo Clinic published findings that prophylactic
mastectomy was associated with a reduction in breast cancer
incidence by approximately 90%, in women designated at high
risk for developing breast cancer (5). However, it is not
known how many of these women actually had a BRCA1 and/or
BRCA2 mutation. The inclusion criteria used to define their
"high-risk" women are very broad and include variables that
may not be associated with mutations in BRCA1 and BRCA2.
Prophylactic bilateral oophorectomy is considered a prevention
option for women at high risk for developing ovarian cancer.
This procedure significantly reduces the risk of ovarian cancer,
but does not completely eliminate the risk. Researchers have
shown that the failure rate of prophylactic bilateral oophorectomy
is between 2% and 11% (6) (7). The resulting cancer is peritoneal
carcinomatosis. It is unknown at this time whether the risks
of peritoneal carcinomatosis are increased for BRCA1 and BRCA2
mutation carriers. It is reasonable to screen for peritoneal
carcinomatosis by CA-125 blood tests.
Genetic testing and cancer risk management is a complex and
dynamic process. Even with our current ability to sequence
genes and study complex models of genetic abnormalities, the
science of genetic testing has limitations that must be adapted
to clinical applications. It should be noted that in some
high-risk women, drastic surgical measures do not always assuage
all cancer fears. Therefore, consistent protocols for counseling
must be in place to help manage cancer risk evaluation patients.
- Brody L, Biesecker B. Breast cancer susceptibility genes:
BRCA1 and BRCA2. Medicine 1998; 77(3):208-226.
- Ford D, Easton DF, Bishop DT, Narod SA, Goldgar DE. Risks
of cancer in BRCA1-mutation carriers. Breast Cancer Linkage
Consortium. Lancet 1994; 343:692-695.
- Easton DF, Steele L, Fields P, Ormistin W, Averill D,
Daly PA. Cancer risk in two large breast cancer families
linked to BRCA2 on chromosome 13q12-13. Am J Hum Genet 1997;
- Breast Cancer Linkage Consortium. Cancer risks in BRCA2
mutation carriers. JNCI 1999; 91:1310-1316.
- Hartman L, Schaid D, Woods J, et al. Efficacy of bilateral
prophylactic mastectomy in women with a family history of
breast cancer. N Eng J Med 1998; 340:77-84.
- Piver MS, Jishi MF, Tsukada Y. Primary peritoneal carcinoma
after prophylactic oophorectomy in women with a family history
of ovarian cancer. Cancer 1993; 71:2751-2755.
- Tobacman JK, Tucker MA, Kase R. Intra-abdominal carcinomatosis
after prophylactic oophorectomy in ovarian cancer prone
families. Lancet 1982; 795-797.
Ovarian Cancer Risk Evaluation Clinic
The Breast and Ovarian Cancer Risk Evaluation Program at the
University of Michigan Compre hensive Cancer Center provides
individuals with an accurate assessment of their personal
risk for developing breast and other related cancers, and
offers a comprehensive plan for follow-up and preventative
The program offers:
- review of family history, highlighting cancer occurrence
- education in basic genetic principles as applied to breast and ovarian cancer o discussion of individualized risk (based on family history and personal risk factors)
- instruction in proper breast self-examination technique
- discussion of behaviors thought to effect the risk of various cancers
- education regarding genetic testing and availability of research protocols
- presentation of an individualized plan for follow-up care
- recommendations with respect to lifestyle issues and choices
- written summary of the visit sent to your referring physician
- confidential patient summary letter that reviews the genetic counseling session
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