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Positive book for all with positive results April 9, 2011

Posted by ramunas in BRCA, breast cancer, cancer genetics, genetic testing, hereditary cancer, ovarian cancer.
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An amazing book written by BRCA2 positive cancer survivor and clinical geneticist: “Positive Results: Making the Best Decisions When You’re at High Risk for Breast or Ovarian Cancer”,which is now in my hands and hungry eyes.

This is very informative and up-to-date single reference for all (women and men) who are at increased genetic risk due to BRCA1/2 mutations, as well as clinicians dealing with these patients.

This source i’ll definitely now include in my recommendations for high risk women, along with FORCE and a free gift of Liv Breast Self-Exam Kit kindly provided by Association for Hereditary Cancer (PVAS).

Founder BRCA1/2 mutations in the Europe: Belgium August 7, 2010

Posted by ramunas in BRCA, breast cancer, cancer genetics, genetic testing, hereditary cancer, ovarian cancer.
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Claes et al. [91] in a 49 BRCA1/2 positive families found six major recurrent founder mutations (three BRCA1 c.212+3A> (BIC: IVS5+3A>G), c.2359dupG (BIC: 2478insG), c.3661G>T (BIC: 3780G>T) and three BRCA2 c.516+1G>A (BIC: IVS6+1G>A), c.6275_6276delTT (BIC: 6503_6504delTT), c.8904delC (BIC: 9132delC) alterations), which accounted for nearly 60% of all mutations identified. BRCA1 c.212+3A>G was previously reported as Belgian founder mutation [92, 93], later also found in a few German, Dutch and French families [91]. BRCA1 c.2359dupG and BRCA2 c.516+1G>A have not yet been reported in other populations.

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: Portugal August 6, 2010

Posted by ramunas in BRCA, breast cancer, cancer genetics, genetic testing, hereditary cancer, ovarian cancer.
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An Alu sequence insertion in BRCA2 exon 3 (c.156_157insAlu (BIC: 384insAlu)) is a founder mutation of Portuguese origin and accounts for more than one-fourth of deleterious BRCA1/2 mutations in breast/ovarian cancer families in Northern/Central Portugal. This mutation creates BRCA2 exon 3 skipping and is the most frequent large BRCA2 rearrangement described to date [89, 90].

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: Spain August 5, 2010

Posted by ramunas in BRCA, breast cancer, cancer genetics, genetic testing, hereditary cancer, ovarian cancer.
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In Spain, five mutations in BRCA1 and other five in BRCA2 genes account for approximately half of the mutations detected in Spanish families. Specific mutations differ significantly in their frequencies and geographic distribution.

A compilation of BRCA test results from different laboratories shows that five mutations in the BRCA1 gene (c.68_69delAG, c.211A>G (BIC: 330A>G), c.5117G>A (BIC: 5236G>A), c.5123C>A (BIC: 5242C>A), c.470_471delCT (BIC: 589_590delCT) account for 46.6% of BRCA1 mutations and four mutations in BRCA2 (c.2808_2811del4 (BIC: 3036_3039del4), c.6629_6630delAA (BIC: c.6857delAA), c.9026_9030del5 (BIC: 9254-9258del5), c.9310_9311delAA (BIC: 9538delAA)) account for 56.6% of the BRCA2 mutations [79].

Diez et al., [80] have reviewed the frequency of BRCA1 and BRCA2 recurrent mutations reported in seven geographic areas of Spain.

The founder mutation BRCA1 c.211A>G, that leads to aberrant splicing of the transcript, originates from North Western Spain (Galicia) and accounts up to 50% of all mutations in this region [81]. It was also found in French and British families of Spanish origin [82].

The BRCA1 c.68_69delAG and BRCA2 c.9026_9030del5 mutations accounted for the 30.4% (7/23) of the BRCA1 mutations and for the 18.5% (5/27) of the BRCA2 positive families respectively and were specific only to the Mediterranean areas. Indeed, haplotype studies indicated a common origin of c.68_69delAG mutation in Spanish (Sephardic Jewish) and Ashkenazi Jewish populations [83]. Some data indicate an unique origin of reported BRCA2 exon 23 mutation BRCA2 c.9026_9030del5 in Catalan families (North-East Spain) [84]. Likewise, the BRCA2 c.2808_2811del4 mutation was predominant only in the Castilla-Leon region (Central Spain), but it also has been described worldwide in many populations and is the second recurrent pathological mutation in the BIC database ranking with a presumable multiple different origins [85, 86].

Splicing mutation c.5153-1G>A (BIC: 5272-1G>A) of BRCA1 and frameshift mutation c.5146_5149del4 (BIC: 5374delTATG) of BRCA2 are also prevalent founder mutations in the Central Spain region, accounting for 18.4% and 13.6% of BRCA1 and BRCA2 positive families, respectively [80, 85, 87]. Such knowledge of the spectrum of mutations and their geographical distribution can allow a more effective detection strategy in countries with large Spanish population.

Conversely, in the Basque population, only 1.2% (1/81) of early onset breast cancer women unselected for family history had pathological mutations; no founder mutation was identified [88].

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: France August 4, 2010

Posted by ramunas in BRCA, breast cancer, cancer genetics, genetic testing, hereditary cancer, ovarian cancer.
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In France geographical clustering in North-Eastern part is evident for two recurrent BRCA1 mutations, suggesting a founder effect. The c.3481_3491del11 (BIC: 3600del11) in exon 11 accounts for 37% and the nonsense mutation c.5128G>T (BIC: 5247G>T/Gly1710X) in exon 18 for 15% of all BRCA1/2 mutations in that region (overall 52%) [4, 75].

The haplotype analysis of the families carrying the mutation c.3481_3491del11, all originating from Alsace–Lorraine, revealed the presence of a common allele, indicating a founder effect [75]. Although this mutation is found in many different geographical areas, it is more common in France. The BRCA1 mutation c.5128G>T would appear to be specific to the France, but the analysis of its haplotype is less conclusive and needs further confirmation [6].

The BRCA1 c.5030_5033delCTAA (BIC: 5149delCTAA) [76] and c.3839_3843delinsAGGC (BIC: 3958delCTCAGinsAGGC) [77] mutations were reported in at least three independent families from France.

Well-described founder mutations are identified in French-Canadians population in Quebec, which originated from France during 17–18th century settlement period. In this region 4 BRCA1 gene mutations (c.4327C>T (BIC: 4446C>T/Arg1443X), c.3756_3759del4 (BIC: 3875delGTCT), c.962G>A (BIC: 1081G>A), c.2834_2836delinsC (BIC: 2953delGTA/insC) and 3 BRCA2 mutations (c.3170_3174del5 (BIC: 3398del5), c.5857G>T (BIC: 6085G>T), c.8537_8538delAG (BIC: 8765delAG)) are now routinely included in early onset breast/ovarian cancer screening assays and represent up to 84% of the total BRCA1/2 mutations in the French-Canadian population in Quebec [78]. Among these, the most common founder mutations are BRCA1 c.4327C>T and BRCA2 c.8537_8538delAG and c.3170_3174del5, which are found in 1.7% of women affected by breast cancer diagnosed before age 41 and in 1.3% of women with ovarian cancer [6].

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: 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 #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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