Breast Cancer Susceptibility Genes and Risk Reduction.
Olufunmilayo I. Olopade
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Abstract
•
Inherited mutations in the BRCA1 and BRCA2 tumor suppressor genes are the
strongest indicators of breast and/or ovarian cancer risk.
•
Understanding the limitations of the various mutation ascertainment methods is
critical when assessing of the literature reporting BRCA1/2 mutation frequencies in
different populations.
•
Prevalence of BRCA1/2 mutations among high-risk cancer patients may vary by
ethnicity, study inclusion criteria, and mutation detection techniques.
•
Many studies focus on the prevalence of BRCA1/2 mutations in different ethnic
populations. However, the cancer risks associated with these mutations are a function of
mutation penetrance.
•
Founder mutations in some populations may affect the prevalence of inherited
BRCA1/2 mutations. The limited genetic variability in members of founder populations
can help reduce the variability in penetrance of BRCA1/2 mutations, providing a more
reproducible assessment of true BRCA1/2-associated cancer risk in these populations.
•
Clinicians interested in providing personalized cancer-risk counseling for patients
should understand the contributions of BRCA1/2 mutations in diverse populations,
BRCA1/2 mutation penetrance, and potential modifying factors particular to patients’
ethnicity, family history, and environmental influences.
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Introduction
Numerous epidemiological factors affect the likelihood of developing breast and
ovarian cancer, but no other predictor is as powerful as an inherited mutation in the tumor
suppressor genes BRCA1 or BRCA2. Even though hereditary breast cancer accounts for
only 5-10% of all breast cancer cases, individuals carrying mutations in one of these
genes have a 40-80% chance of developing breast cancer, making these mutations the
strongest breast cancer predictors known 1-3.
BRCA1 and BRCA2 were molecularly identified in 1994 and 1995, respectively, and
since then patients with strong personal and/or family history of breast and/or ovarian
cancer have been counseled to seek molecular genetic testing for germline mutations in
these genes 4,5. In the context of this review, the term ‘mutation’ will be used to refer to a
disease and/or risk-associated deleterious genetic lesion. Indicators of inherited breast
and/or ovarian cancer syndromes include early age of cancer onset, multiple affected
individuals within a family (especially multiple first-degree relatives), the development
of bilateral disease and males with breast cancer. It has been estimated that 0.7-29% of
such families are accounted for by mutations in BRCA1, and 1.5-25% are accounted for
by mutations in BRCA2 6-9. Although these reports represent a very wide range of
population proportions, the majority of evidence suggests that, in general, germline
mutations in known breast cancer risk genes account for about 20% of breast cancers
associated with family history 10,11 (previously reviewed by Szabo and King, 1997 12). It
is therefore critical to understand the contribution of BRCA1/2 mutation-associated risks
to these breast cancer populations.
Studies of BRCA1/2 mutation frequencies have revealed great differences in populations
from different geographic regions and ethnicities. For example, 34% of Swedish highrisk families carry deleterious BRCA1 mutations, and 69% of these are a single mutation.
However, only 2% carried mutations in BRCA2 13. By contrast, 32% of similarly highrisk Sardinian families carry one of two common BRCA2 mutations, and 11% carry a
single BRCA1 mutation 14. In Poland, 64% of high-risk families carry a BRCA1 mutation
(one of nine recurring mutations), but rarely any BRCA2 mutations 15 (similar ranges are
reviewed by Szabo and King 12). As we approach the goal of personalized medicine, it is
important to recognize the role of an individual patient’s genotype to her breast cancer
risk, as well as the gene-gene and gene-environment relationships that may modify
mutation penetrance in each individual.
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