Breast Cancer Risk Assessment: Moving Beyond BRCA 1 and 2
Introduction
Breast cancer is the most common cancer in women worldwide, and in the United States alone, it is estimated that there would be more than 230,000 patients with invasive disease in 2015 with more than 40,000 deaths expected in 2015.1 The discovery that BRCA mutations are associated with an increased risk of breast cancer (as well as ovarian and other cancers) was a seminal event in cancer genetics. For the first time, genomic linkage analysis revealed the presence of deleterious mutations on chromosome 17q21 associated with breast and ovarian cancers in high-risk families.2 These gene mutations were discovered to be located on the BRCA1 gene. A subsequent discovery of families with high risk who were not found to have a BRCA1 mutation identified BRCA2 located on chromosome 13q12-13.3 Yet, although mutations in BRCA account for between 12% and 31% of breast cancer risk among high-risk families,4, 5 it is now recognized that other breast cancer susceptibility genes also exist.
Evidence-based testing guidelines, counseling, and risk-reducing interventions have been established for hereditary breast and ovarian cancer syndrome (BRCA1 and BRCA2) as well as other less common high-penetrance autosomal dominantly inherited breast cancer conditions, including Li-Fraumeni syndrome (TP53), hereditary diffuse gastric cancer (CDH1), Cowden׳s syndrome (PTEN), and Peutz-Jeghers syndrome (STK11).6 However, next-generation technology has enabled massively parallel sequencing at low cost, which has fostered the advent of multiplex genetic testing and the identification of other less penetrant genes carrying a predisposition to breast and other cancers.
Section snippets
TP53
Mutations involving p53 are inherited in an autosomal dominant fashion. The result is a familial predisposition to a diverse array of cancers, including breast cancer. Indeed, the estimated risk of breast cancer in women with this condition is roughly 49% by 60 years, and in several studies, up to one-third of those women diagnosed with breast cancers were diagnosed before 30 years.7, 8
STK11
Mutations in the serine-threonine kinase STK11 result in Peutz-Jeghers syndrome, which is associated with the
CHEK2
The CHEK2 gene is a member of the Fanconi Anemia (FA)-BRCA pathway and is involved in both checkpoint function and in BRCA1- and p53-mediated repair. Mutations in CHEK2, including 1100delC, have recently been associated with a 3- to 5-fold increase of breast cancer.12 In a large meta-analysis of 26,000 cases compared to as many controls, for example, the aggregated odds ratio of breast cancer in general, early-onset breast cancer, and familial breast cancer was 2.7, 2.6, and 4.8, respectively.
Moderately Penetrant Genes Not As Well Characterized
There are also a number of hereditary breast cancer genes that are not characterized very well at this time. Researchers are not certain of the risk they carry for breast and other cancers, and investigations are under way.
Approaching Risk Evaluation
In light of the evergrowing number of genes associated with an elevated risk for familial breast cancer, risk evaluation and counseling become even more important. There are a number of models available for estimation of familial breast cancer risk, as well as models that estimate BRCA carrier probability. Most experts agree that a BRCA carrier probability of 10% or higher is sufficient to warrant testing; however, meeting current national clinical criteria for BRCA testing and confirming
Claus Tables
The Claus tables are based only on family history characteristics to help estimate breast cancer risk for white unaffected women with 1-2 close female relatives with breast cancer (ie, first- or second-degree relatives) and in whom no known cancer-associated gene mutation has been identified.22
Gail Model
This model estimates a woman׳s lifetime risk for the development of breast cancer, as well as her risk over the next 5 years. The 5-year Gail calculation is often used to determine if a woman is eligible
BRCAPRO
The BRCAPRO model uses 6 predictive models for prediction of familial breast cancer. The end result is a program that can be used to construct a family history tree, which also calculates the individual׳s risk for breast (or ovarian) cancer and the probability of carrying a BRCA mutation. In a study that evaluated the validity of BRCAPRO to predict the presence of BRCA1 and BRCA2 mutations, it was found to have the highest c-statistic (0.82), suggesting that it was among the best predictors of
BRCA Mutation Testing
BRCA mutation analysis can range from straightforward to more complex testing because options include testing for a specified variant in either BRCA1 or BRCA2 (single-site analysis), full sequencing of the entire genes, and testing for gene rearrangements using polymerase chain reaction or comparative genomic hybridization.
For patients from certain ethnic backgrounds, specific mutations in BRCA are highly prevalent. Among the best characterized are 187delAG and 5385insC mutations of BRCA1 and
A Clinical Approach to Risk Testing
A reasonable algorithm for genetic testing is provided in the Figure. Genetic test results can be positive, negative (with the variable interpretation), or uncertain. A positive test result indicates the presence of a genetic alteration believed to be molecularly harmful and with evidence of associated increased cancer risks. The interpretation of a negative test result can be more challenging because the unaffected negative-result patient can either be completely relieved of cancer risk if a
References (35)
- et al.
Germline p53 mutations in a cohort with childhood sarcoma: Sex differences in cancer risk
Am J Hum Genet
(2003) - et al.
Very high risk of cancer in familial Peutz-Jeghers syndrome
Gastroenterology
(2000) - et al.
Genetic testing and cancer risk management recommendations by physicians for at-risk relatives
Genet Med
(2011) - et al.
Cancer statistics, 2015
CA Cancer J Clin
(2015) - et al.
Linkage of early-onset familial breast cancer to chromosome 17q21
Science
(1990) - et al.
Localization of a breast cancer susceptibility gene, BRCA2, to chromosome 13q12-13
Science
(1994) - et al.
Analysis of cancer risk and BRCA1 and BRCA2 mutation prevalence in the kConFab familial breast cancer resource
Breast Cancer Res
(2006) - et al.
The emerging landscape of breast cancer susceptibility
Nat Genet
(2008) - NCCN clinical practice guidelines in oncology: genetic/familial high-risk assessment: Breast and ovarian. Version 1;...
- et al.
Prevalence and diversity of constitutional mutations in the p53 gene among 21 Li-Fraumeni families
Cancer Res
(1994)
Peutz-Jeghers syndrome: A systematic review and recommendations for management
Gut
Lifetime cancer risks in individuals with germline PTEN mutations
Clin Cancer Res
CHEK2⁎1100delC genotyping for clinical assessment of breast cancer risk: Meta-analyses of 26,000 patient cases and 27,000 controls
J Clin Oncol
Low-penetrance susceptibility to breast cancer due to CHEK2(⁎)1100delC in noncarriers of BRCA1 or BRCA2 mutations
Nat Genet
Breast-cancer risk in families with mutations in PALB2
N Engl J Med
ATM mutations that cause ataxia-telangiectasia are breast cancer susceptibility alleles
Nat Genet
Truncating mutations in the Fanconi anemia J gene BRIP1 are low-penetrance breast cancer susceptibility alleles
Nat Genet
Cited by (0)
Conflict of interest: none.