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Founder BRCA1/2 mutations in the Europe: Italy July 30, 2010

Posted by ramunas in BRCA, breast cancer, cancer genetics, genetic testing, hereditary cancer, ovarian cancer.
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In Italy, 4–27% of the identified mutations recurred among apparently unrelated families, and significant regional founder effect has been demonstrated for few mutations [6366].

Four distinct BRCA1 founder mutations (c.3228_3229delAG (BIC: 3347delAG), c.3285delA (BIC: 3404delA), c.1380dupA (BIC: 1499insA), c.5062_5064del3 (BIC: 5181delGTT) accounted for a large fraction (73%) of BRCA1-attributable hereditary breast/ovarian cancer in families originating from Tuscany (Central Italy) area [47, 66].

The BRCA1 c.1380dupA mutation was reported in at least 14 families from Tuscany and originated here about 30 generations ago (∼750 years) [65].

In Sardinia, contribution of BRCA1/2 mutations to breast cancer predisposition has been reported for populations from the Northern part of the island [67], where founder BRCA2 c.8537_8538delAG (BIC: 8765delAG) mutation comprises 28% for BRCA1/2 positive families [68, 69]. The ratio of BRCA2 mutations to BRCA1 mutations is approximately 2:1, although BRCA1 being more prevalent in South-West area [68]. Conversely, previously regarded as another founder mutation, BRCA2 3950_3952delTAGinsAT was found instead running in families belonging to a single extended pedigree [68].

The BRCA1 c.4964_4982del19 (BIC: 5083del19) is a founder mutation from the southern region of Calabria and accounted for 23% of all BRCA1 mutations [60, 63]. It was also recurrently found at least four times in Sicilia [70, 71]. Another BRCA1 c.4724delC (BIC: 4843delC) mutation could be a possible Sicilian founder mutation, although present evidence is scarce [7173].

Using a number of independent approaches, Malacrida et al. [74] showed that previously reported BRCA1 c.5062_5064delGTT (BIC: 5181_5183delGTT/1688Val) variant of unknown significance (VUS) actually is a deleterious mutation with high frequency in North-East Italy [74]. The founder c.5062_5064delGTT mutation accounts for 15% (9/61) of families with small BRCA1 mutations.

My full review article: Janavicius R. Founder BRCA1/2 mutations in the Europe: implications for hereditary breast-ovarian cancer prevention and control

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Founder BRCA1/2 mutations in the Europe: Slovenia July 29, 2010

Posted by ramunas in BRCA, breast cancer, cancer genetics, genetic testing, hereditary cancer, ovarian cancer.
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In Slovenia five highly recurrent specific mutations were identified: four in the BRCA1 gene (c.1687C>T, c.181T>G, c.5266dupC, c.181T> (BIC: 300T>A)) and one in the BRCA2 gene (c.7806-2A>G (BIC: IVS16-2A>G) [43, 61, 62]. Respectively, they accounted for 26%, 18%, 13% and 11% of BRCA1 mutations and 56% of BRCA2 mutations. The c.7806-2A>G in the BRCA2 gene appears to be an unique founder mutation in the Slovenian population, found in 26% (10/38) of all BRCA1/2 mutations harboring families. These 5 mutations account for 67% of the BRCA1/2 positive families [43].

My full review article: Janavicius R. Founder BRCA1/2 mutations in the Europe: implications for hereditary breast-ovarian cancer prevention and control

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Founder BRCA1/2 mutations in the Europe: Austria July 28, 2010

Posted by ramunas in BRCA, breast cancer, cancer genetics, genetic testing, hereditary cancer, ovarian cancer.
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Austria

In Austria the ratio of BRCA1 mutations to BRCA2 mutations is 2:1 (Rappaport, personal communication). There were initial reports for several apparently founder BRCA1 mutations in Austria [58, 59], although they (c.181T>G (BIC: 300T>G/C61G), c.5266dupC, c.1687C>T (BIC: 1806C>T)) represent common mutations prevalent in other European countries. In Austria these alterations represent 15%, 10% and 6% of the BRCA1 mutation families, respectively (Rappaport, personal communication). Of note, c.1687C>T is also frequent in Slovenia [43] and Sweden (BIC database). Haplotype analysis revealed a common ancestor for the Austrian and Swedish families, which may indicate Austrian origin of this mutation [59], although its even more common in Slovenia (26% of the BRCA1 mutation families) [43]. Another common mutation is BRCA1 c.3016_3019del4 (BIC: 3135del4) (8% of the BRCA1 mutation families), which was also found in Italy [60]. One BRCA1 mutation c.2676_2679del4 (BIC: 2795del4) was reported at least in three unrelated families in Austria only, what may represent founder effect [58, 59], however this mutation is uncommon. The most prevalent BRCA2 mutations are c.8363G>A (BIC: 8591G>A/W2788X), c.8754+1G>A (BIC: IVS21-1G>A) and c.3860delA (BIC: 4088delA), representing 9%, 7% and 6% of the BRCA2 mutation families respectively (Rappaport, personal communication).

My full review article: Janavicius R. Founder BRCA1/2 mutations in the Europe: implications for hereditary breast-ovarian cancer prevention and control

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Founder BRCA1/2 mutations in the Europe: Ashkenazi Jews July 20, 2010

Posted by ramunas in BRCA, breast cancer, cancer genetics, genetic testing, hereditary cancer, ovarian cancer.
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The BRCA1/2 founder effect in Ashkenazi Jews population is very well described. About 10 millions Ashkenazi people living worldwide are descendants of ancestors from Eastern and Central Europe, such as Poland, Lithuania, Belarus, Germany, Hungary, Ukraine and Russia. The most well characterized three founder mutations are two in BRCA1 gene c.68_69delAG (BIC: 185delAG) and c.5266dupC (BIC: 5382insC) and one in BRCA2 c.5946delT (BIC: 6174delT) [3133]. Screening for these three founder mutations alone is now part of routine clinical practice for Ashkenazi Jewish individuals.

These 3 mutations (BRCA1 c.68_69delAG, c.5266dupC and BRCA2 c.5946delT) account for 98–99% of identified mutations and are carried by about 2.6% (1/40) of the Ashkenazi Jewish population (1%, 0.13% and 1.52% respectively) [3436]. There are differences between particular mutations and breast/ovarian cancer risk [37]. The average risk of breast cancer by the age of 70 years is similar for carriers of the BRCA1 c.68_69delAG and c.5266dupC mutations (64% and 67% respectively), however is much lower for the c.5946delT mutation (43%). The corresponding values for ovarian cancer lifetime risk is respectively of 14%, 33% and 20% in carriers, respectively [6, 37, 38].

It is worth noting that BRCA1 c.68_69delAG and c.5266dupC are not found exclusively in Ashkenazi patients. The c.68_69delAG mutation has been found in patients of Spanish ancestry (i.e. Hispanic) as well as other non-Ashkenazi ethnic groups, sometimes with frequencies similar to those in Ashkenazi populations [3], suggesting a common ancient ancestor or two independent mutational events [39].

The c.5266dupC mutation in BRCA1 exon 20 is the second most frequently reported mutation in the BIC database, being very prevalent in Central and Eastern Europe. This single mutation is found in a various frequency in high risk breast and/or ovarian cancer families from Poland (34%) [40], Russia (14%) [41], Hungary (14%) [42], Slovenia (13%) [43], Ashkenazi Jews (10%) [44], Greece (8%) [45], Germany (4%) [46], Italy (3%) [47]. It is virtually absent in Spain and Portugal and is found at low frequency in the Netherlands, Belgium and Scandinavian countries [6]. In Russia, Belarus, Poland, Latvia, Czech Republic, Greece and Lithuania this mutation accounts for respectively 94% [48], 73% [49], 60% [40], 55% [50], 37–52% [51, 52], 46% [45], 34% [53, 54] of all BRCA1 mutations.

Haplotype analysis points to the Baltic origin of this mutation approximately 38 generations ago during the medieval period [55], with a gradual decrease thereafter from East to the West and nearly worldwide spread. A common ancestor for c.5266dupC mutation families reported from Europe, Brazil and North America is evident [46, 56, 57].

My full review article: Janavicius R. Founder BRCA1/2 mutations in the Europe: implications for hereditary breast-ovarian cancer prevention and control

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Founder BRCA1/2 mutations in the Europe #4 July 14, 2010

Posted by ramunas in cancer genetics.
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The purpose of this review is to summarize current evidence about the BRCA1/2 founder mutations diversity in European populations. For the current manuscript only the unequivocally deleterious mutations were considered, excluding as yet the unclassified variants that could not be clearly related with pathogenicity. For the consistency, the unequivocal term “founder” is used for those mutations where haplotype studies revealed shared polymorphic markers consistent with common ancestor, or when unrelated mutation carriers were repeatedly identified (at least 3 times). Some mutations previously described as founder mutations in one country, subsequently are found at a higher proportion in other countries/regions as true founders. These mutations in adjacent countries will likely reflect the gradient transition from the “epicenter” over the time due to historical co-existence of different populations in the same region. Mutations that do not segregate with the same alleles are referred as “recurrent”. They presumably occurred several times at unstable ‘mutational hot spots’ parts of the gene. The mutation nomenclature will be generally presented according to Human Genome Variation Society (HGVS) recommendations (http://www.hgvs.org/rec.html); only at the first mutation mention the older BIC database (http://research.nhgri.nih.gov/bic/) nomenclature will be used between the parentheses, where possible. BRCA1 is numbered by GeneBank U14680 reference sequence; BRCA2 is numbered by GeneBank U43746 reference sequence.

For the mutations distribution in other geographic regions or more detailed prevalence, penetrance and contribution to unselected for family history cancer cases, readers are referred to other review sources [3, 4, 6, 2730].

Full review article: Janavicius R. Founder BRCA1/2 mutations in the Europe: implications for hereditary breast-ovarian cancer prevention and control

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Founder BRCA1/2 mutations in the Europe #3 July 12, 2010

Posted by ramunas in BRCA, breast cancer, cancer genetics, genetic testing, ovarian cancer.
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Fortunately, recent advances in high-throughput mutation detection and screening techniques, such as high resolution melting (HRM) analysis [24] and conformation-sensitive capillary electrophoresis (CSCE) [25] are especially promising rapid, sensitive, cost-efficient and ammenable for automation screening approaches for the large genes, whereas decreased cost in genotyping methods offers affordable targeted testing option for predefined set of mutations.

Massively parallel next-generation sequencing platforms [26] provide another technological breakthrough, however they are still at a prohibited cost and complex data overload for routine use.

On the other hand, variation in the distribution of BRCA1 and BRCA2 mutations is well recognized worldwide [27] and several recent reviews already summarized the evidence, that in certain countries and ethnic communities the BRCA1/2 mutation spectrum is limited to a few founder mutations [3, 4, 6, 28]. Founder effects are most prominent in geographically, culturally or religiously isolated populations that undergo rapid expansion from a limited number of ancestors, when, as a consequence of low genetic diversity, some alleles become more frequent.

Full review article: Janavicius R. Founder BRCA1/2 mutations in the Europe: implications for hereditary breast-ovarian cancer prevention and control

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Founder BRCA1/2 mutations in the Europe #2 July 10, 2010

Posted by ramunas in BRCA, breast cancer, cancer genetics, hereditary cancer, ovarian cancer.
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Currently, in most countries clinical BRCA1/2 testing is offered after genetic counseling by clinical cancer geneticist (oncogeneticist) when mutation finding probability exceeds 10%, or even 20% (as in the UK) [18]. Various selection criteria, based on family history, age at onset and tumors clinicopathological features, as well as computational risk prediction models (Claus, BRCAPRO, BOADICEA, IBIS, Myriad and Manchester scoring system [19, 20]) are used. Unfortunately, these models often underestimate the probability of finding a mutation, are validated only in some countries, are not particularly helpful for daily use and no consensus exist regarding their common use [9, 21]. Moreover, familial history is also absent or unknown in at least half of all mutation possitive families [22] and mutation detection methods varies between most centers.

It is now evident, that in a near future the uptake and demand for rapid BRCA1/2 mutations testing will increase and more flexible genetic counseling strategies will be needed. As new targeted therapies become available, more individuals will request testing to get access to specific treatments (i.e., PARP inhibitors), regardless of their a priori low risk and clinicians will force laboratories towards rapid testing results. This tendency is already seen in the centers enroling patients for PARP inhibitors clinical trials (van Osterweik, personal communication) as well as during peridiagnostic (presurgical) testing for a newly diagnozed breast cancer patients [23].

However, a full BRCA1 and BRCA2 gene screening still remains labor and time consuming challenge due to large genes size, diverse mutations or variants of unknown significance (VUS) and complexity of large genomic rearangements (LGRs), requiring special technical approach. This procedure still remains too complex and expensive to cover a broader target (e.g. all breast or ovarian cancer patients and their first degree relatives) and cannot be routinely applied in less privileged countries.

My full review article: Janavicius R. Founder BRCA1/2 mutations in the Europe: implications for hereditary breast-ovarian cancer prevention and control

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Founder BRCA1/2 mutations in the Europe #1 July 8, 2010

Posted by ramunas in BRCA, breast cancer, cancer genetics, genetic testing, ovarian cancer.
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After a long silence, I’ll take my responsibility to provide readers with up to date information about founder BRCA1/2 mutations in the Europe from my review article which was just published in The EPMA Journal (International Reviews in Predictive, Preventive and Personalised Medicine, The Official Journal of the European Association for Predictive, Preventive and Personalised Medicine (PPPM) by Springer group.

Introduction.

The most significant and well characterized genetic risk factors for breast and/or ovarian cancer to date are germline mutations of the BRCA1 (MIM#113705; 17q chromosome; [1]) and BRCA2 (MIM#600185; 13q chromosome [2]) genes. In the general population, about 5–10% of all breast cancer and 10–15% of ovarian cancer cases can be attributed to these major genetic risk factors, which can explain around half of breast/ovarian cancer aggregation in some families [3, 4]. The prevalence of BRCA1/2 mutation carriers in the general population is around 0.2% (1/500) what accounts for BRCA1 mutation rate carriers of around 1/800 [5], however it can vary significantly among different countries or some ethnic groups due to founder effect [6].

The mutations in these high-penetrance genes confer a high life-time risk of breast and ovarian cancer. Women with an inherited BRCA1 mutation have a lifetime risk of 65–80% of developing breast cancer and 37–62% of developing ovarian cancer, while BRCA2 mutation carriers have a lifetime risk of 45–85% for breast cancer and 11–23% for ovarian cancer [7].

The identification of BRCA1 and BRCA2 mutation carriers and individualized risk assessment is an important procedure growing in clinical importance, since management protocols for mutation carriers become well established [810] and proven life-saving, risk-reducing preventive medical interventions exist [1113]. Once mutation is identified in a given family, a very informative predictive (or presymptomatic) oncogenetic test can be offered virtually to all adult family members. Moreover, oncogenetic testing is becoming the powerful therapeutical predictive tool, as new targeted therapeutic opportunities, such as poly(ADP-ribose) (PARP) inhibitors [14, 15], emerge and chemosensitivity to platinum based therapy is constantly reported [16, 17].

TBC.