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Complexities of BRCA genes December 4, 2007

Posted by ramunas in breast cancer, cancer genetics, familial cancer, genetic testing, hereditary cancer, ovarian cancer, sporadic cancer.

There are some exciting news in cancer genetics. An extremely informative article about BRCA 1/2 genes mutations in different populations was published recently in Nature Reviews Cancer, which highlighted the complexity of BRCA mutation data and interpretation problems.

Inherited mutations in the BRCA1 and BRCA2 tumour-suppressor genes are the strongest indicators of breast and/or ovarian cancer risk. Prevalence of BRCA1 and BRCA2 mutations among high-risk cancer patients may vary by ethnicity, study inclusion criteria and mutation detection techniques.

In general, germline mutations in known breast cancer risk genes account for ~20% of breast cancers associated with family history. Aproximately 1-29% of such families will have mutations in BRCA1 gene and 1,5-25% in BRCA2 gene (ref.). As you’ve already noticed, there is wide variance, which is dependent on selection criteria, studied populations and technology used.

Moreover, there is a huge variation in penetrance (i.e. a proportion of persons who carry mutation and will develop disease). Studies show that the penetrance of deleterious BRCA1 and BRCA2 mutations is lower overall in a general population than in high-risk families, but the variability is broad and the confidence intervals are wide. One of the reason of such variability may be family-specific genetics and/or environment modifiers (the evidence for that is RAD51 polymorphism, which modify penetrance of BRCA2 (revied by GeneSherpa).

The most consistent and clearly written range I’ve found (and now use in practice) in a new edition of I.D.Young “Risk Calculation in Genetic Couseling“:

Cumulative risks for breast and ovarian cancer to age 70 years for BRCA1 mutation carriers average around 70-85% and 45-60%, respectively, for multiple-case (i.e. high risk) families, whereas average risks of 65% and 40% have been obtained for unselected (i.e. sporadic) cases. Comparable risks for BRCA2 carriers are 60-85% (breast) and 27%-31% (ovarian) for mulitple-case families and 45% (breast) and 11% (ovarian) for unselected cases.

As we approach the goal of personalized medicine, it is important to recognize the contribution of an individual patient’ s genotype to her (or his) breast cancer ovarian cancer syndromes include early age of cancer risk, as well as the gene–gene and gene–environment relationships that may modify mutation penetrance in each individual.

The results of sporadic breast/ovarian cancer studies suggest BRCA1 mutation frequencies ranging from 4 to 29% and BRCA2 mutation frequencies from 0.6 to 16% (ref.)

The important conclusion for clinicians is that it is likely most BRCA1 and BRCA2 mutations occurring in a clinical setting will be present in individuals with no family history of breast cancer.

Some BRCA1 and BRCA2 mutation carriers without family history of disease may have comparatively low (but still clinically significant) mutation-associated penetrance, whereas others may have uninformative family structures that do not reveal family history regardless of mutation penetrance, such as small size, few female relatives or patrilineal inheritance of the mutation (ref.).

One of the most useful ways to approach penetrance estimates is to examine founder mutations, or high frequency individual alleles that are particular to a specific population.

I’ve found very useful definition of founder mutation:

A recurrent mutation that occurs on a single haplotype in a population may be considered a founder mutation, while a mutation that occurs on more than one haplotype is considered to have occurred multiple times in the population history and is not a founder mutation (a haplotype is a set of nearby genetic markers that segregate together as a unit through generations) (ref.).

There is a schematic representation of most important known founder mutations:

And an excerpt from a table:

There are two common mutations of BRCA1 gene in Lithuania (the same as in Latvia and more or less in Poland, what reflect long coexistence of populations, although the origin is different – there are data of X and Y chromosome analysis in Baltic countries performed by my previous colleague), although I’ve found one protein truncating deletion not previously described anywhere (already submitted inquiry to BIC mutation database).



1. Steven Murphy MD - December 4, 2007

Great Stuff Ramunas. I do look forward to the day when we can detect the subtleties of these monster genes.
Great Post, thanks for the mention.

2. ramunas - December 4, 2007

Thank you, Steven! My dream is to make a simple array of tests (mutations, snp’s) to help better stratify patients for cancer risk and choose the best treatment. Today I would test BRCA+ patients for snp’s in RAD51 and CYP2D6 genes – you’ve already covered both of them on your cool site. And for a bunch of genes expression profile from tumor DNA..

3. Matt Mealiffe, M.D. - January 7, 2008

Nice post. Another very useful resource related to breast cancer genetics in the clinic is the online review at GeneTests, a frequently updated, peer-reviewed site that is useful for clinicians caring for these patients. It can be found in the “GeneReviews” section of the GeneTests website at http://www.genetests.org.
-Matt Mealiffe, M.D.

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