Breast Cancer Risk Associated With BRCA1 and BRCA2 in Diverse Populations

James D. Fackenthal; Olufunmilayo I. Olopade

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Founder Mutations

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. The concept of a founder effect was described by Ernst Mayr[63] to explain the reduced genetic variability of some small populations relative to their parent populations. He proposed that, in cases where the small population was founded by a small number of individuals, they would carry only a small subset of the genetic variability of the parent population. Such a geographically isolated subpopulation (or parent population that suffers a dramatic decrease or bottleneck) could then give rise to larger populations with a conspicuous lack of overall genetic diversity, regained as new variants occur spontaneously or migrate in from other populations.[64,65]

The founder effect has been used to explain the high frequencies of disease-associated mutations in specific human populations. Classic examples include the high frequencies of the Tay-Sachs mutation in Jewish populations from eastern Europe (Ashkenazi Jews).[66] It has been estimated that the average individual carries four recessive-lethal mutations in the heterozygous state,[67] so a founder population of 40 individuals isolated from a larger parent population would be expected to carry over 100 deleterious mutations.[66] Likewise, a mutation that immigrated or arose de novo within a small population would be likely to have a higher frequency among descendants than if it had occurred in a larger population. Such founder mutations would therefore appear as high-frequency, deleterious mutations in unrelated families from closed populations that exhibit overall low genetic diversity.

When describing a recurring mutation as a potential founder mutation, it is important to show the mutation occurred only once in history. There are several examples of recurring mutations in BRCA1 and BRCA2 that arose multiple times in different populations because their particular local DNA-sequence environments create mutational hot spots. Such recurring mutations do not represent founder mutations. To make the distinction between single and multiple historical occurrences of the same mutation, it is necessary to look at genetic marker variants that are close enough to the mutation to remain associated through numerous generations, with little or no separation by meiotic recombination. Useful markers include single nucleotide polymorphisms and microsatellite markers, also known as short tandem repeats. A series of nearby markers that segregate together as a unit through generations constitutes a haplotype. 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.

Although founder populations in general are especially useful for gene discovery, founder mutations in BRCA1 and BRCA2 have been useful in defining mutation-associated risks in specific populations (see "Sidebar: Using Founder Mutations to Identify Disease-associated Genes"). Three of the best-characterized BRCA1 and BRCA2 founder mutations are found in Ashkenazi Jewish populations ( Table 3 ). The Ashkenazim are European Jews, historically separated from other major groups in Africa and the Middle East, though they generally trace their origins to the Near East before the Roman exile.[68] Ashkenazi Jewish populations have an unusually high prevalence of more than 20 known recessive disease-associated mutations, and genetic evidence suggests this reflects a founder effect resulting from a population bottleneck within the last millennium that resulted in a low number of maternal ancestors.[69,70] The mutations BRCA1 185delAG, BRCA1 5382insC, and BRCA2 6174delT have been identified in 0.8-1%, 0.1-0.4% and 1-1.5%, respectively, of Ashkenazi Jewish populations.[71,72] Among Ashkenazi breast cancer cases, these three founder mutations combined account for 6.7-11.7% of all patients,[73,74] 59% of patients from high-risk breast cancer families,[75] 30% of cases diagnosed under the age of 40 years,[76] and 24-62% of ovarian cancer cases occurring in patients that have not been selected on the basis of family history.[75,76,77] Although these three founder mutations are not identified in all high-risk breast and/or ovarian cancer families, they do represent the majority of germline BRCA1 and BRCA2 mutations found in Ashkenazi Jewish populations.[78,79] Indeed, one study has found only 16 out of 74 (21%) BRCA1 and BRCA2 mutations identified in an Ashkenazi population were non-founder BRCA1 and BRCA2 mutations.[80]

It is worth noting that BRCA1 185delAG is not found exclusively in Ashkenazi patients. This mutation has been found in patients of Spanish ancestry as well as other ethnic groups, sometimes with frequencies similar to those in Ashkenazi populations,[81,82,83] suggesting that this mutation may have existed before the Jewish diaspora. That is, because of the history of the Ashkenazi Jews, it is to be expected that this founder mutation may be identified in populations that do not identify themselves as historically Ashkenazi. That this variant has been found in patients of Spanish ancestry is probably because many Sephardic Jews were forced to convert to Roman Catholicism, and it is probably a marker for Jewish ancestry among Spaniards. Additionally, it has been suggested that microsatellite markers flanking 185delAG are consistent with it having arisen independently in at least two populations or subpopulations,[83] but these results have not been tested further with higher-resolution assays.

Another well-studied founder mutation is the Icelandic founder mutation BRCA2 999del5. Genetic evidence, in accordance with demographic data, suggests the Icelandic population was subject to a greater level of genetic drift than other European populations, resulting in reduced genetic variation. The founder effect is evident from the comparatively small number of mitochondrial lineages, mostly originating from Scandinavia and the British Isles.[84] The BRCA2 999del5 mutation, the sole high-frequency founder mutation in Iceland, was found in 0.4-0.6% of unaffected Icelanders, 7.7- 8.5% of breast cancer cases that had not been selected on the basis of family history or age of onset, 6-7.9% of ovarian cancer cases[85,86,87] and 40% of breast cancers occurring in males.[88]

The Ashkenazi founder mutations (BRCA1 mutations 185delAG and 5382insC, and BRCA2 mutation 6174delT) and the Icelandic founder mutation (BRCA2 999del5) have been used for penetrance analysis. In addition to the increased likelihood of finding a statistically useable number of BRCA1 and/or BRCA2 mutations in these populations, these founder mutations also allow examination of penetrance in a minimally heterogeneous genetic background, providing insights into potential genetic and/or environmental modifiers of BRCA1 and BRCA2 mutation-associated cancer risks. In most studies, cancer risks in carriers of these founder mutations are indeed lower when patients are not selected for family history, although the range of penetrance estimations in different studies is broad. Some show age-specific cumulative risks for breast cancer in these carriers to be 26-60%,[74,75,89,90,91,92,93] whereas others found higher risks, up to 80%.[43,44,85,93] These four founder mutations are associated with a similarly broad range of ovarian cancer risks (12-40%) by the age of 70 years.[44,89,93,94]

Such population-specific genetic risk assessments already affect the clinical testing options available to high-risk families. For example, individuals of Ashkenazi Jewish ancestry may be advised to seek genetic testing for only three high-frequency BRCA1 and BRCA2 founder mutations before considering the more expensive complete sequence analysis of both genes.[95,96] The efficiency of this strategy has prompted numerous hunts for similar high-frequency mutations in other ethnic groups, with some success.

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