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Breast cancer risk associated with BRCA1 and BRCA2 in diverse populations

Key Points

  • Inherited mutations in the BRCA1 and BRCA2 tumour-suppressor genes are the strongest indicators of breast and/or ovarian cancer risk.

  • Understanding the limitations of the various mutation ascertainment methods is crucial when assessing the literature reporting BRCA1 and BRCA2 mutation frequencies in different populations.

  • Prevalence of BRCA1 and BRCA2 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 and BRCA2 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 and BRCA2 mutations. The limited genetic variability in members of founder populations can help reduce the variability in penetrance of BRCA1 and BRCA2 mutations, providing a more reproducible assessment of true BRCA1 and BRCA2-associated cancer risk in these populations.

  • Clinicians who are interested in providing personalized cancer-risk counselling for patients should understand the contributions of BRCA1 and BRCA2 mutations in diverse populations, BRCA1 and BRCA2 mutation penetrance, and potential modifying factors that are particular to a patient's ethnicity, family history and environmental influences.

Abstract

Germline mutations in the BRCA1 or BRCA2 tumour-suppressor genes are strong predictors of breast and/or ovarian cancer development. The contribution of these mutations to breast cancer risk within any specific population is a function of both their prevalence and their penetrance. Mutation prevalence varies among ethnic groups and may be influenced by founder mutations. Penetrance can be influenced by mutation-specific phenotypes and the potential modifying effects of the patient's own genetic and environmental background. Although estimates of both mutation prevalence and mutation penetrance rates are inconsistent and occasionally controversial, understanding them is crucial for providing accurate risk information to each patient.

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Figure 1: Position of several founder mutations within BRCA1 (top) and BRCA2 (bottom).
Figure 2: Mercator projection of the Earth illustrating the “out of Africa” theory of early human migrations.

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Correspondence to Olufunmilayo I. Olopade.

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FURTHER INFORMATION

Breast cancer Information core

Glossary

Penetrance

A measure of the proportion of genetically similar individuals that show any phenotypic manifestation of a mutation that they have in common.

Protein truncation test

(PTT). A method of identifying truncating mutations from PCR-amplified cDNA or genomic exons using coupled in vitro transcription and translation followed by gel electrophoresis of labelled polypeptides.

High-risk patient

A patient from a high-risk family, or a family with multiple (especially first-degree) affected members. Such families with breast cancer may also be associated with ovarian cancer, bilateral breast cancer, male breast cancer and/or early-onset disease. These families are considered more likely than average to carry a high-penetrance (or high-risk) mutation in BRCA1 or BRCA2.

Heteroduplex analysis

(HA). A rapid method to detect mutations that relies on the fact that double-stranded DNA molecules with a single base-pair mismatch mutation migrate in gel electrophoresis to a different location compared with molecules that do not have a mismatch mutation.

Proband

The affected person that identifies a family for study.

Oophorectomy

Surgical removal of the ovaries.

Nonsense-mediated mRNA decay

(NMD). The process by which mRNA molecules carrying stop codons in any but the 5′- or 3′-most exon are degraded by a regulated pathway.

Tay–Sachs

A genetic disorder found in East European Jewish families. It is a lysosomal disease in which there is a deficiency of hexosaminidase A, an enzyme that degrades ganglioside GM2. The build-up of GM2 affects the brain and nerves leading to the death of affected children by 5 years of age.

Short tandem repeat

A chromosomal region containing variable tandem repeat numbers of single or short nucleotide repeat sequences.

Genetic drift

Random changes in allele frequencies over generations. This dynamic of random sampling has a greater effect in smaller populations.

Polygenic

A model of genetic determinism in which genetic variants of multiple genes function in combination to produce a phenotype.

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Fackenthal, J., Olopade, O. Breast cancer risk associated with BRCA1 and BRCA2 in diverse populations. Nat Rev Cancer 7, 937–948 (2007). https://doi.org/10.1038/nrc2054

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