panel of brca1/brca2 gene mutations — eastern european ... · (luminex). 2.2 brief description of...

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Panel of BRCA1/BRCA2 Gene Mutations — Eastern European Population

(Reference 2014.01.001)

Notice of Assessment

June 2014

1

1 GENERAL INFORMATION

1.1 Requester: Jewish General Hospital

1.2 Application for Review Submitted to MSSS: March 4, 2013

1.3 Application Received by INESSS: March 1, 2014

1.4 Notice Issued: June 30, 2014

Note:

This notice is based on the scientific and commercial information submitted by the requester and on a complementary review of the literature according to the data available at the time that this test was assessed by INESSS.

2 TECHNOLOGY, COMPANY, AND LICENCE(S)

2.1 Name of the Technology

Qualitative analysis of a panel of eight mutations in the BRCA11/2 genes using a fluorescent liquid bead array or the multiplex PCR method and detection using a liquid microsphere array (Luminex).

2.2 Brief Description of the Technology, and Clinical and Technical Specifications

The requester uses xMAP®2 Technology by Luminex® for detection. This technology colour-codes microbeads (or microspheres) with various fluorescent dyes specific to the molecules to be assayed [Lehmann et al., 2009]. Each type of microsphere is coated with specific oligonucleotides that allow it to hybridize to the complementary amplicons generated by multiplex PCR. The microspheres, which allow the capture of up to 100 different analytes, are in suspension, therefore providing a greater surface area. The microsphere and amplicon groupings emit two types of fluorescence: one intrinsic to each type of bead, and one emitted by a reporter molecule following the oligonucleotide's hybridization to the PCR product. The type of groups (and, consequently, genotype) present is determined with Luminex following the excitation of fluorophores and the detection and quantification of fluorescence.3

The requester expects eight mutations to be tested, six in the BRCA1 gene and two in the BRCA2 gene (Table 1).

1 BRCA: BReast CAncer gene. 2 x designates a biomarker or panel to be tested; MAP stands for multi-analyte profiling. 3 Technical details concerning xMAP® by Luminex® are available in the document published by the company [Angeloni et al., 2013; Lehmann et al., 2009].

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Table 1: Mutations in BRCA proposed by the requester

MUTATIONS ACCORDING TO DIFFERENT NOMENCLATURES

BRCA1 1 c.68_69delAG 185delAG 187delAG

2 c.181T>G 300T>G C61G

3 c.1016dupA 1135insA p.Val340fs

4 c.3700_3704del5 3819del5

5 c.4054delA 4153delA 4154delA

6 c.5266dupC 5382insC 5385insC

Gln1756fs

BRCA2 1 c.7913_7917del5 8141del5

2 c.8537_8538del2 8765delAG

2.3 Company or Developer: In-house protocol; use of xMAP® Technology by Luminex®.

2.4 Licence(s): Not applicable.

2.5 Patent, If Any

The US company Myriad Genetics has held patents on the BRCA genes since the mid-1990s. In 2013, the Supreme Court of the United States invalidated these patents, arguing that DNA is a product of nature and that only human inventions can be patented. The Court also ruled that DNA4 could no longer be patented in the United States. In Canada, it seems that patents are not always respected.

2.6 Approval Status (Health Canada, FDA): Not applicable.

2.7 Weighted Value: 188.50

3 CLINICAL INDICATIONS, PRACTICE SETTINGS, AND TESTING PROCEDURES

3.1 Targeted Patient Group

According to the requester, the targeted patients are of Eastern European ancestry and have hereditary breast or ovarian cancer.

The National Comprehensive Cancer Network (NCCN) [2014] guidelines for hereditary breast and ovarian cancer list the criteria that patients and their family must meet to undergo genetic testing. These include:

Breast cancer diagnosed at age 50 or under;

Multifocal primary breast cancer in the same breast or in the contralateral breast;

Breast and ovarian cancer in the same individual;

4 Lecrubier A. Aux États-Unis, la Cour Suprême interdit le brevetage des gènes [website]. Medscape, June 19, 2013. Available at: http://www.medscape.fr/voirarticle/3553687.

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Breast cancer and more than 1 close relative diagnosed with breast cancer before the age of 50, or more than 1 close relative diagnosed with ovarian cancer at any age, or 3 or more close relatives diagnosed with breast cancer at any age;

Breast or ovarian cancer at any age and Ashkenazi Jewish ancestry;

Triple-negative breast cancer (estrogen and progesterone receptor-negative and HER2/neu5 negative);

Breast cancer in men;

Ovarian cancer and family history of breast or ovarian cancer.

This application focuses primarily on individuals and families from Easter European countries.

The requester expects to perform 50 tests per year.

3.2 Targeted Disease(s)

Breast cancer is the most common cancer among women. In 2013,6 an estimated 6,000 women in Quebec were diagnosed with breast cancer. Ovarian cancer is a rarer form of cancer. Most breast and ovarian cancer is sporadic. However, in 5% to 10% of cases, a family predisposition linked to a genetic mutation is observed.

Most patients with hereditary breast and ovarian cancer have a pathogenic mutation in the BRCA1 (located in chromosome 17: 17q21.31) or BRCA2 (located in chromosome 13: 13q13.1) genes. In a review of recent literature on hereditary cancers, Ballinger [2012] reports that 80% of families with cases of breast and ovarian cancer have mutations in the BRCA1 gene.

Mutations in the BRCA genes are inherited in an autosomal dominant manner; therefore, carriers have a 50% chance of passing on the mutation to each of their offspring. The presence of one of these mutations is linked to a lifetime risk of developing breast cancer. The penetrance or cumulative risk is 50% to 85% for breast cancer and somewhat lower, from 20% to 60%, for ovarian cancer [Ballinger, 2012].

The rate of mutations in BRCA1 and 2 in the general population is estimated at 1 in 300 to 1 in 800. However, the rate of founder mutations7 in target populations can be much higher. For example, in people of Eastern European Jewish origin (Ashkenazi), two founder mutations in BRCA1 (c.68_69delAG or 185delAG ; c.5266dupC or 5382insC) and 1 mutation in BRCA2 (c.5946delT or 6174delT) account for more than 90% of the mutations detected [Ballinger, 2012; Janavičius, 2010]. In this population, the prevalence of these three mutations is ten time higher than in an unselected population, or between 1.9% and 2.7% [AETMIS, 2006].

When a pathogenic mutation is discovered in BRCA1 or 2, several primary preventive measures, such as surgery (preventive mastectomy or oophorectomy) or hormone therapy can be taken [Petrucelli et al., 2013]. Close monitoring (annual screening, self-examination, etc.) is also recommended.

5 HER2/neu: human epidermal growth factor receptor 2. 6 Canadian Cancer Society (CCS). Canadian Cancer Statistics publication [website]. Available at: http://www.cancer.ca/en/cancer-information/cancer-101/canadian-cancer-statistics-publication/?region=qc. 7 Founder mutations occur more frequently in descendants with a common ancestry as a result of their geographic or ethnic isolation (founder populations) [AETMIS, 2006].

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3.3 Number of Patients Targeted: 50 tests per year.

3.4 Medical Specialties and Other Professions Involved

Oncology, genetics, oncogenetics, and genetic counselling.

3.5 Testing Procedure

In addition to the usual sampling procedures, risk assessment and pre- and post-test genetic counselling are an integral part of the genetic diagnostic procedure for hereditary cancers [Ballinger, 2012].

Various models are used to assess the risk of hereditary breast and ovarian cancer and to help identify individuals who might benefit from genetic testing. Petrucelli et al. [2013] present some of these models, as well as their advantages and limitations, and state that risk assessment is an art, and that probability models therefore cannot replace clinical judgment.

4 TECHNOLOGY BACKGROUND

4.1 Nature of the Diagnostic Technology

New test, complementary to others listed in the Index (codes 50039, 50040 and 50041). Could eventually replace test 50041.

4.2 Brief Description of the Current Technological Context

At present, three tests in the Index concern mutations in the BRCA1 and 2 genes:

Breast and (or) ovarian cancer – BRCA1/BRCA2. Individual mutation with sequencing (code 50039; weighted value (WV): 134.0);

Breast and (or) ovarian cancer – BRCA1/BRCA2. French Canadian mutations (sequencing) (code 50040; WV: 485.0);

Breast and (or) ovarian cancer – BRCA1/BRCA2. Ashkenazi Jewish mutations (fragment analysis) (nucleic acid amplification test, or NAAT) (code 50041; WV: 174.0).

Moreover, 809 tests for BRCA1/BRCA2, with no indication of the mutations sought, were sent outside Quebec over the past year, for a total cost of $1.9 million or a mean cost of $2,348.60 per test.

4.3 Brief Description of the Advantages Cited for the New Technology

The technology will be used to test for eight founder mutations that predispose individuals of Eastern European ancestry to breast and ovarian cancer.

4.4 Cost of Technology and Options: Not assessed.

5 EVIDENCE

5.1 Clinical Relevance

5.1.1 Other Tests Replaced

The eight mutations proposed by the requester include the three mutations specific to populations of Ashkenazi Jewish ancestry. The analytical method is not the same as that set out in test 50041 (fragment analysis, NAAT). The diagnostic performance of the two techniques cannot be compared within the context of this notice.

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5.1.2 Diagnostic or Prognostic Value

Screening for mutations in BRCA1 or 2 is designed to identify carriers of the three mutations in order to provide them with prevention strategies. These strategies have proven to be effective in reducing the risk of cancer and associated mortality and morbidity rates. However, they do involve significant morbidity rates.

Morbidity and Mortality

Ballinger [2012] reviewed several studies and reported that the use of oral contraceptives by women with a BRCA mutation is associated with a 50% decrease in the risk of ovarian cancer. This decrease is even greater if the oral contraceptives are taken for longer than three years. The literature reports a possible increase in the risk of breast cancer with the use of oral contraceptives. However, a meta-analysis cited in the same review did not report an increased risk in women who are carriers of a BRCA mutation [Ballinger, 2012].

Several studies reviewed by Ballinger [2012] showed a lower risk of ovarian cancer and mortality in women who are carriers of a BRCA mutation who underwent preventive salpingo-oophorectomy. The risk is reduced by 85% to 95%, especially if the procedure is carried out before the age of 40.

Petrucelli et al. [2013] reviewed scientific literature on the consequences of preventive interventions in individuals without cancer but who have a confirmed mutation in BRCA1 or 2. Various studies report a significant decrease, of up to 90%, in the risk of cancer after a mastectomy or a preventive salpingo-oophorectomy. Moreover, a recent study of 1,619 women with breast cancer who are carriers of a BRCA1 and 2 mutation reported a survival advantage in those who underwent preventive surgery [Domchek et al., 2010].

Quality of Life and Adverse Effects

Preventive oophorectomy and hormone therapy with tamoxifen offered to women who are carriers of a BRCA mutation trigger surgical or treatment-induced menopause accompanied by side effects such as vasomotor symptoms, vaginal dryness, osteoporosis and increased risk of heart disease [Petrucelli et al., 2013]. Tamoxifen increases the risk of endometrial cancer and thromboembolic episodes, including pulmonary embolism.

Treatment Availability and Modifications Based on Test Results

The discovery of a mutation in BRCA1 or 2 does not alter treatment in individuals with breast or ovarian cancer. Treatment for hereditary breast and ovarian cancer is the same as that for sporadic cancer [Petrucelli et al., 2013]. However, according to NCCN guidelines, a bilateral mastectomy may be offered to individuals with breast cancer, as there is an increased risk of secondary malignancy in the same breast and in the other [NCCN, 2014].

Confirmation of the presence of a mutation can allow carriers of the mutation to be offered preventive clinical interventions, such as surgery (preventive salpingo-oophorectomy, preventive mastectomy), annual screening, or hormone therapy with tamoxifen, a partial estrogen antagonist.

5.1.3 Therapeutic Value: The test has prognostic value.

5.2 Clinical Validity

The clinical sensitivity of mutation tests is equal to the number of people who have the phenotype sought—in the present case, breast or ovarian cancer—or who will acquire the phenotype, in whom the test will be positive [AETMIS, 2006].

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The tables provided in the appendix show the prevalence of the mutations based on different categories and various ethnic groups from Eastern European countries as well as the results of two literature reviews that qualified the mutations according to their founder effect. Six of the eight mutations proposed by the requester are represented in these data and strongly linked to breast and ovarian cancer. No information was found on the other two.

5.3 Analytical (or Technical) Validity

A literature search did not identify any studies that assessed the technical performance of the method proposed by the requester—multiplex PCR and liquid microsphere suspension arrays—to detect mutations in BRCA.

The local validation data provided by the requester confirm the technology's performance for all the mutations (unpublished data).

5.4 Recommendations from Other Organizations

The 2010 European Society for Medical Oncology (ESMO) clinical practice guidelines recommend testing for mutations in BRCA for people at risk and their families [Balmaña et al., 2010]. Recommendations regarding preventive and therapeutic interventions for carriers of the mutations and their families are also provided.

Isaacs et al. reviewed the literature on genetic testing for hereditary breast and ovarian cancer syndrome (UpToDate, last update February 2014). The authors' conclusions and recommendations include the targeted testing of mutations specific to certain ethnic groups, such as people of Ashkenazi Jewish ancestry, for whom founder mutations have been described [Isaacs et al., 2014].

In 2014, the NCCN published the latest update of its clinical practice guidelines concerning the genetic assessment of breast and ovarian cancers. Clinical algorithms are provided for the treatment, preventive interventions and monitoring of patients and individuals who are carriers of BRCA mutations, as well as their families.

6 ANTICIPATED OUTCOMES OF INTRODUCING THE TEST

6.1 Impact on Material and Human Resources: Not assessed.

6.2 Economic Consequences of Introducing Test Into Quebec's Health Care and Social Services System

The economic consequences of introducing the test into Quebec's health care and social services system have not been assessed. However, tests for mutations and several targeted panels are already being performed in Quebec. In cases of suspected hereditary breast–ovarian cancer syndrome, more thorough sequencing tests are currently being sent outside Quebec at a cost that largely exceeds the weighted value calculated by the requester for this mutation panel. Implementing and conducting these tests in Quebec would certainly be cost-effective for the province.

For information purposes, Table 2 shows the number of tests for BRCA1 and 2 that were included in the Index and conducted in Quebec over the past two years.

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Table 2: Number of tests for BRCA1 and BRCA2 conducted in Quebec over the past two years

CODE TEST NUMBER OF TESTS WV

2012–2013 2013–2014

50039 Individual mutations (sequencing) 1,502 1,110 134

50040 French Canadian mutations (sequencing) 608 812 485

50041 Ashkenazi Jewish mutations (fragment analysis) (NAAT) 123 71 174

6.3 Main Organizational, Ethical, and Other (Social, Legal, Political) Issues

Patent issues concern BRCA gene testing in general. Also, ethical issues and issues concerning the availability of preventive interventions in cases of positive results apply to BRCA gene testing in general and are not specific to the panel targeting individuals of Eastern European ancestry.

7 IN BRIEF

7.1 Clinical Relevance

Tests for mutations in the BRCA1 and 2 genes have prognostic value. They can be used to identify carriers of the mutations who could benefit from close monitoring (more frequent clinical examinations, mammograms, ultrasound, MRI) and preventive surgical or pharmacological (hormone therapy) interventions. These interventions can reduce the risk of cancer and associated morbidity and mortality, but they are not without side effects that can affect quality of life. Genetic counselling before and after testing is essential.

7.2 Clinical Validity

Five of the eight mutations included in the requester's panel have been reported as having a founder effect in Eastern European populations. Two more have been identified as common in the same populations. One of the mutations is often reported in people of Scandinavian ancestry and sometimes in Eastern European populations.

7.3 Analytical Validity

No published validation studies on the method proposed by the requester to test for mutations in BRCA were found. However, local validation results confirm the performance of the method used.

7.4 Recommendations from Other Organizations

Recent guidelines for the diagnosis of hereditary breast and ovarian cancer include testing for mutations in BRCA in the algorithm.

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8 INESSS NOTICE IN BRIEF

Panel of BRCA1/BRCA2 gene mutations – Eastern European population

Status of the Diagnostic Technology:

Established

Innovative

Experimental (for research purposes only)

Replacement for technology: which becomes obsolete

INESSS Recommendation:

Include test in the Index conditional upon the implementation of an external quality control mechanism

Do not include test in the Index

Reassess test

Additional Recommendation:

Draw connection with listing of drugs, if companion test

Produce an optimal use manual

Identify indicators, when monitoring is required

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REFERENCES

Agence d’évaluation des technologies et des modes d’intervention en santé (AETMIS). Contribution des analyses moléculaires des gènes BRCA 1/2 à l’évaluation du risque de prédisposition au cancer du sein ou de l’ovaire : rapport sommaire. Rapport préparé par Julie Tranchemontagne, Lucy Boothroyd et Ingeborg Blancquaert. Montréal, Qc : AETMIS; 2006.

Angeloni S, Cordes R, Dunbar S, Garcia C, Gibson G, Martin C, Stone V. xMAP Cookbook. A collection of methods and protocols for developing multiplex assays with xMAP Technology. 1st Edition. Austin, TX : Luminex; 2013. Available at: http://cdn2.hubspot.net/hub/128032/file-213083097-pdf/Luninex-xMap_Cookbook.pdf.

Armaou S, Pertesi M, Fostira F, Thodi G, Athanasopoulos PS, Kamakari S, et al. Contribution of BRCA1 germ-line mutations to breast cancer in Greece : A hospital-based study of 987 unselected breast cancer cases. Br J Cancer 2009;101(1):32-7.

Ballinger LL. Hereditary gynecologic cancers: Risk assessment, counseling, testing and management. Obstet Gynecol Clin N Am 2012;39(2):165-81.

Balmaña J, Diez O, Rubio I, Castiglione M, ESMO Guidelines Working Group. BRCA in breast cancer: ESMO clinical practice guidelines. Ann Oncol 2010;21(Suppl 5):v20-v22.

Bogdanova NV, Antonenkova NN, Rogov YI, Karstens JH, Hillemanns P, Dörk T. High frequency and allele-specific differences of BRCA1 founder mutations in breast cancer and ovarian cancer patients from Belarus. Clin Genet 2010;78(4):364-72.

Brozek I, Ratajska M, Piatkowska M, Kluska A, Balabas A, Dabrowska M, et al. Limited significance of family history for presence of BRCA1 gene mutation in Polish breast and ovarian cancer cases. Fam Cancer 2012;11(3):351-4.

Brozek I, Cybulska C, Ratajska M, Piatkowska M, Kluska A, Balabas A, et al. Prevalence of the most frequent BRCA1 mutations in Polish population. J Appl Genet 2011;52(3):325-30.

Dobričić J, Krivokuća A, Brotto K, Mališić E, Radulović S, Branković-Magić M. Serbian high-risk families: Extensive results on BRCA mutation spectra and frequency. J Hum Genet 2013;58(8):501-7.

Domchek SM, Friebel TM, Singer CF, Evans DG, Lynch HT, Isaacs C, et al. Association of risk-reducing surgery in BRCA1 or BRCA2 mutation carriers with cancer risk and mortality. JAMA 2010;304(9):967-75.

Fostira F, Tsitlaidou M, Papadimitriou C, Pertesi M, Timotheadou E, Stavropoulou AV, et al. Prevalence of BRCA1 mutations among 403 women with triple-negative breast cancer: Implications for genetic screening selection criteria: A Hellenic Cooperative Oncology Group Study. Breast Cancer Res Treat 2012;134(1):353-62.

Gaj P, Kluska A, Nowakowska D, Bałabas A, Piatkowska M, Dabrowska M, et al. High frequency of BRCA1 founder mutations in Polish women with nonfamilial breast cancer. Fam Cancer 2012;11(4):623-8.

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Hartwig M, Janiszewska H, Bąk A, Pilarska M, Heise M, Junkiert-Czarnecka A, et al. Prevalence of the BRCA1 c.68_69delAG (BIC: 185delAG) mutation in women with breast cancer from north-central Poland and a review of the literature on other regions of the country. Contemp Oncol (Pozn) 2013;17(1):34-7.

Isaacs C, Fletcher SW, Peshkin BN. Genetic testing for hereditary breast and ovarian cancer syndrome. Waltham, MA : Wolters Kluwer Health; Available at: http://www.uptodate.com.

Janavičius R. Founder BRCA1/2 mutations in the Europe: Implications for hereditary breast-ovarian cancer prevention and control. EPMA J 2010;1(3):397-412.

Karami F and Mehdipour P. A comprehensive focus on global spectrum of BRCA1 and BRCA2 mutations in breast cancer. Biomed Res Int 2013;2013:928562.

Konecny M, Milly M, Zavodna K, Weismanova E, Gregorova J, Mlkva I, et al. Comprehensive genetic characterization of hereditary breast/ovarian cancer families from Slovakia. Breast Cancer Res Treat 2011;126(1):119-30.

Lehmann S, Dupuy A, Beaudeux JL, Lizard G. Méthodes d’analyses moléculaires multiplexes sur supports solides ou en milieu liquide pour l’identification de biomarqueurs protéiques dans les fluides biologiques et les extraits cellulaires ou tissulaires. Ann Biol Clin 2009;67(4):381-93.

Machackova E, Foretova L, Lukesova M, Vasickova P, Navratilova M, Coene I, et al. Spectrum and characterisation of BRCA1 and BRCA2 deleterious mutations in high-risk Czech patients with breast and/or ovarian cancer. BMC Cancer 2008;8:140.

National Comprehensive Cancer Network (NCCN). Clinical practice guidelines in oncology. Genetic/familial high-risk assessment: Breast and ovarian. Version I.2014. Fort Washington, PA : NCCN; 2014. Available at: http://www.nccn.org/.

Novaković S, Milatović M, Cerkovnik P, Stegel V, Krajc M, Hočevar M, et al. Novel BRCA1 and BRCA2 pathogenic mutations in Slovene hereditary breast and ovarian cancer families. Int J Oncol 2012;41(5):1619-27.

Petrucelli N, Daly MB, Feldman GL. BRCA1 and BRCA2 hereditary breast and ovarian cancer. Dans : Pagon RA, Adam MP, Ardinger HH, et al., réd. GeneReviews® [Internet]. Seattle, WA : University of Washington; 2013. Available at: http://www.ncbi.nlm.nih.gov/books/NBK1247/.

Pohlreich P, Zikan M, Stribrna J, Kleibl Z, Janatova M, Kotlas J, et al. High proportion of recurrent germline mutations in the BRCA1 gene in breast and ovarian cancer patients from the Prague area. Breast Cancer Res 2005;7(5):R728-36.

Ratajska M, Brozek I, Senkus-Konefka E, Jassem J, Stepnowska M, Palomba G, et al. BRCA1 and BRCA2 point mutations and large rearrangements in breast and ovarian cancer families in Northern Poland. Oncol Rep 2008;19(1):263-8.

Van del Looij M, Szabo C, Besznyak I, Liszka G, Csokay B, Pulay T, et al. Prevalence of founder BRCA1 and BRCA2 mutations among breast and ovarian cancer patients in Hungary. Int J Cancer 2000;86(5):737-40.

http://www.ncbi.nlm.nih.gov/pubmed/16168118



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APPENDIX A Prevalence of Mutations by Category and Ethnic Group from Eastern European Countries

GENE AND MUTATIONS POPULATION NUMBER OF CASES/FAMILIES

% SAMPLE FOUNDER EFFECT

STUDY

BRCA1 c.5266dupC Belarusian 49/1,945 2.5 Women with BC Bogdanova et al., 2010

26/201 12.9 Women with OC

1/1,019 0.1 Healthy controls

Hungarian 7/500 1.4 Women with BC Van der Looij et al., 2000


1/350 0.3 Healthy controls

Serb 1/94 Probands (index case) Dobričić et al., 2013

Polish 29/16,849 0.17 NB, general population Brozek et al., 2012; 2011

35/1,845 1.9 Subgroup with BC

17/363 4.7 Subgroup with OC

Polish 114/906 12.6 Familial breast cancer Yes Gaj et al., 2012

51/675 7.6 Nonfamilial breast cancer

Polish 21/64 Families with BC Yes Ratajska et al., 2008

Greek 11/403 Breast cancer, ESR, PR, HER2- Yes Fostira et al., 2012

Greek 13/987 Patients with BC Armaou et al., 2009

Czech 75/1,010 Probands Machackova et al., 2008

Czech 13/96 Families with recurrent BOC Pohlreich et al., 2005

5/55 High risk without family history

Slovenian 9/379 Families with HBOC Novaković et al., 2012

Slovak

32/85 38 Families with HBC Konecny et al., 2011

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STUDY

c.181T>G Belarusian 20/1,945 1.0 Women with BC Bogdanova et al., 2010


2/1,019 0.2 Healthy controls

Hungarian 9/500 1.8 Women with BC Van der Looij et al., 2000


0/350 0 Healthy controls

Polish 11/13,462 0.08 NB, general population Brozek et al., 2012; 2011

18/1,486 1.2 Subgroup with BC

12/363 3.3 Subgroup with OC

Polish 38/906 4.2 Familial breast cancer Yes Gaj et al., 2012





1/55 High risk without family history

Slovenian 31/379 Families with HBOC Novaković et al., 2012

Slovak 14/85 17 Families with HBC Konecny et al., 2011

c.68_69delAG Hungarian 1/500 0.2 Women with BC Van der Looij et al., 2000



Polish 1/252 0.4 Women with BC Hartwig et al., 2013

1/69 1.4 With hereditary BC criteria


Polish 0/12,485 NB, general population Brozek et al., 2012; 2011

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STUDY

Polish 8/906 0.9 Familial breast cancer Gaj et al., 2012




Czech 1/55 High risk without family history Pohlreich et al., 2005


c.3700_3704del5 Polish 4/3,923 NB, general population Brozek et al., 2012; 2011

Polish 11/906 1.2 Familial breast cancer Gaj et al., 2012


Polish 4/64 Families with BC Ratajska et al., 2008




c.5256_5277+3179del3200 Greek 2/403 Breast cancer, ESR, PR, HER2 - Yes Fostira et al., 2012

c.5468-285_5592+4019del4429_insCACAG Greek 7/403 Breast cancer, ESR, PR, HER2 - Yes Fostira et al., 2012

BRCA2 c.7913_7917del5 Czech 15/1,010 Probands Machackova et al., 2008

c.8537_8538del2 Czech 14/1,010 Probands Machackova et al., 2008

Abbreviations: BC = breast cancer; BOC = breast and ovarian cancer; ESR = estrogen receptors; HBC = hereditary breast cancer; HBOC = hereditary breast and ovarian cancer; HER2 = human epidermal growth factor receptor 2; NB = newborn; OC = ovarian cancer; PR = progesterone receptors.

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Founder mutations based on two literature reviews

ORIGIN JANAVIČIUS 2010 KARAMI AND MEHDIPOUR 2013

BRCA1 BRCA2 BRCA1 BRCA2

Ashkenazi Jewish c.68_69delAG c.5266dupC

c.5946delT

Slovak c.7806-2A>G c.6589delA

Slovenian c.5266dupC c.7806-2A>G

Czech c.5266dupC c.7913_7917del5 c.8537_8538del2

Hungarian c.5266dupC c.181T>G

c.5946delT c.5266dupC c.68_69delAG

Polish c.5266dupC c.181T>G

c.5266dupC c.181T>G

Latvian c.4035delA c.5266dupC

Lithuanian c.4035delA

Belarusian c.5266dupC c.4035delA c.5266dupC

Russian c.5266dupC c.5266dupC

panel of brca1/brca2 gene mutations — eastern european ... · (luminex). 2.2 brief description of...

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