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01-04-2018 | Epidemiology

High prevalence of deleterious BRCA1 and BRCA2 germline mutations in arab breast and ovarian cancer patients

Authors: Al-Joharah Alhuqail, Areej Alzahrani, Hannah Almubarak, Sarah Al-Qadheeb, Lamyaa Alghofaili, Nisreen Almoghrabi, Hamed Alhussaini, Ben Ho Park, Dilek Colak, Bedri Karakas

Published in: Breast Cancer Research and Treatment | Issue 3/2018

Abstract

Purpose

The BRCA1 and BRCA2 (BRCA) genes are heavily involved in mammalian cell DNA repair processes. Germline pathogenic mutations in BRCA increase the lifetime risk of developing breast and/or ovarian cancer in women. In the Arabian Peninsula, most breast and ovarian cancers are diagnosed as early-onset cases, some of which may be due to germline variants in BRCA genes. To identify the BRCA germline mutation frequency and spectrum in the Arab breast and ovarian cancers, we have sequenced the protein-coding exons of these genes.

Methods

All BRCA coding exons were sequenced using genomic DNA isolated from lymphocytes in 173 Arab breast and ovarian cancer patients by a massively parallel sequencing technology and verified by Sanger sequencing.

Results

We identified a total of 17 distinct pathogenic mutations, of which four were novel, in 28 patients; nine out of 108 breast (8.3%) and 19 out of 65 ovarian cancer (29.2%) patients. Thirteen of the 17 mutations were detected in BRCA1 and four mutations were found in BRCA2 gene. Four pathogenic BRCA1 mutations (c.1140dupG, c.4136_4137delCT, c.5095C>T, and c.5530delC) accounted for 54% of all the mutations detected in our patient cohort. Additionally, we identified a likely pathogenic BRCA1 missense variant in two of 108 breast (1.9%) and a BRCA2 missense variant in one of 65 ovarian cancer (1.5%) patients.

Conclusions

The overall frequencies of the BRCA germline mutations were 10.2% in breast and 30.7% in ovarian cancer patients. These data shed new light into the prevalence of BRCA mutations in the Arab women population.

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Ferlay J, Soerjomataram I, Dikshit R et al (2015) Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 136:E359–E386. https://doi.org/10.1002/ijc.29210 CrossRefPubMed

Claus EB, Schildkraut JM, Thompson WD, Risch NJ (1996) The genetic attributable risk of breast and ovarian cancer. Cancer 77:2318–2324. https://doi.org/10.1002/(SICI)1097-0142(19960601)77:11<2318:AID-CNCR21>3.0.CO;2-Z CrossRefPubMed

King M-C, Marks JH, Mandell JB, New York Breast Cancer Study Group (2003) Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2. Science 302:643–646. https://doi.org/10.1126/science.1088759 CrossRef

Antoniou A, Pharoah PDP, Narod S et al (2003) Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case series unselected for family history: a combined analysis of 22 studies. Am J Hum Genet 72:1117–1130. https://doi.org/10.1086/375033 CrossRefPubMedPubMedCentral

Ford D, Easton DF, Stratton M et al (1998) Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. The breast cancer linkage consortium. Am J Hum Genet 62:676–689CrossRefPubMedPubMedCentral

Risch HA, McLaughlin JR, Cole DE et al (2001) Prevalence and penetrance of germline BRCA1 and BRCA2 mutations in a population series of 649 women with ovarian cancer. Am J Hum Genet 68:700–710. https://doi.org/10.1086/318787 CrossRefPubMedPubMedCentral

Yurgelun MB, Hiller E, Garber JE (2015) Population-wide screening for germline BRCA1 and BRCA2 mutations: too much of a good thing? J Clin Oncol 33:3092–3095. https://doi.org/10.1200/JCO.2015.60.8596 CrossRefPubMed

Levy-Lahad E, Friedman E (2007) Cancer risks among BRCA1 and BRCA2 mutation carriers. Br J Cancer 96:11–15. https://doi.org/10.1038/sj.bjc.6603535 CrossRefPubMedPubMedCentral

Kuchenbaecker KB, Hopper JL, Barnes DR et al (2017) Risks of breast, ovarian, and contralateral breast cancer for BRCA1 and BRCA2 mutation carriers. JAMA 317:2402–2416. https://doi.org/10.1001/jama.2017.7112 CrossRefPubMed

10.

Al-Eid HS (2014) Cancer Incidence Report, Saudi Arabia. pp 1–108. http://www.chs.gov.sa/Ar/mediacenter/NewsLetter/2010%20Report%20(1).pdf

11.

Al-Kuraya K, Schraml P, Sheikh S et al (2005) Predominance of high-grade pathway in breast cancer development of Middle East women. Mod Pathol 18:891–897. https://doi.org/10.1038/modpathol.3800408 CrossRefPubMed

12.

Underhill C, Toulmonde M, Bonnefoi H (2011) A review of PARP inhibitors: from bench to bedside. Ann Oncol 22:268–279. https://doi.org/10.1093/annonc/mdq322 CrossRefPubMed

13.

El-Harith E-HA, Abdel-Hadi MS, Steinmann D, Dörk T (2002) BRCA1 and BRCA2 mutations in breast cancer patients from Saudi Arabia. Saudi Med J 23:700–704

14.

Abulkhair O (2014) BRCA 1 and BRCA 2 mutations in Saudi breast cancer patients (single institution). J Clin Oncol 32:10. https://doi.org/10.1200/jco.2014.32.26_suppl.10 CrossRef

15.

Merdad A, Gari MA, Hussein S et al (2015) Characterization of familial breast cancer in Saudi Arabia. BMC Genom 16(Suppl 1):S3. https://doi.org/10.1186/1471-2164-16-S1-S3 CrossRef

16.

Amemiya Y, Bacopulos S, Al-Shawarby M et al (2015) A comparative analysis of breast and ovarian cancer-related gene mutations in Canadian and Saudi Arabian patients with breast cancer. Anticancer Res 35:2601–2610PubMed

17.

Trujillano D, Weiss MER, Schneider J et al (2015) Next-generation sequencing of the BRCA1 and BRCA2 genes for the genetic diagnostics of hereditary breast and/or ovarian cancer. J Mol Diagn 17:162–170. https://doi.org/10.1016/j.jmoldx.2014.11.004 CrossRefPubMed

18.

Walter SD, Cook RJ (1991) A comparison of several point estimators of the odds ratio in a single 2 × 2 contingency table. Biometrics 47:795–811CrossRefPubMed

19.

Richards S, Aziz N, Bale S et al (2015) Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 17:405–423. https://doi.org/10.1038/gim.2015.30 CrossRefPubMedPubMedCentral

20.

Abouelhoda M, Faquih T, El-Kalioby M, Alkuraya FS (2016) Revisiting the morbid genome of Mendelian disorders. Genome Biol 17:e1004030–e1004037. https://doi.org/10.1186/s13059-016-1102-1 CrossRef

21.

Karakas B, Colak D, Kaya N et al (2013) Prevalence of PIK3CA mutations and the SNP rs17849079 in Arab breast cancer patients. Cancer Biol Ther 14:888–896. https://doi.org/10.4161/cbt.25945 CrossRefPubMedPubMedCentral

22.

Fackenthal JD, Olopade OI (2007) Breast cancer risk associated with BRCA1 and BRCA2 in diverse populations. Nat Rev Cancer 7:937–948. https://doi.org/10.1038/nrc2054 CrossRefPubMed

23.

Bu R, Siraj AK, Al-Obaisi KAS et al (2016) Identification of novel BRCA founder mutations in Middle Eastern breast cancer patients using capture and sanger sequencing analysis. Int J Cancer. https://doi.org/10.1002/ijc.30143 PubMedCentral

24.

Janavičius R (2010) Founder BRCA1/2 mutations in the Europe: implications for hereditary breast-ovarian cancer prevention and control. EPMA J 1:397–412. https://doi.org/10.1007/s13167-010-0037-y CrossRefPubMedPubMedCentral

25.

Kim H, Choi DH (2013) Distribution of BRCA1and BRCA2 mutations in Asian patients with breast cancer. J Breast Cancer 16:357–359. https://doi.org/10.4048/jbc.2013.16.4.357 CrossRefPubMedPubMedCentral

26.

Ferla R, Calo V, Cascio S et al (2007) Founder mutations in BRCA1 and BRCA2 genes. Ann Oncol 18:1–2. https://doi.org/10.1093/annonc/mdm234 CrossRef

27.

Finkelman BS, Rubinstein WS, Friedman S et al (2012) Breast and ovarian cancer risk and risk reduction in Jewish BRCA1/2 mutation carriers. J Clin Oncol 30:1321–1328. https://doi.org/10.1200/JCO.2011.37.8133 CrossRefPubMedPubMedCentral

28.

Rothberg JM, Hinz W, Rearick TM et al (2011) An integrated semiconductor device enabling non-optical genome sequencing. Nature 475:348–352. https://doi.org/10.1038/nature10242 CrossRefPubMed

29.

Simen BB, Yin L, Goswami CP et al (2015) Validation of a next-generation-sequencing cancer panel for use in the clinical laboratory. Arch Pathol Lab Med 139:508–517. https://doi.org/10.5858/arpa.2013-0710-OA CrossRefPubMed

30.

Machackova E, Foretova L, Lukesova M et al (2008) Spectrum and characterisation of BRCA1 and BRCA2 deleterious mutations in high-risk Czech patients with breast and/or ovarian cancer. BMC Cancer 8:3–11. https://doi.org/10.1186/1471-2407-8-140 CrossRef

Title: High prevalence of deleterious BRCA1 and BRCA2 germline mutations in arab breast and ovarian cancer patients
Authors: Al-Joharah Alhuqail
Areej Alzahrani
Hannah Almubarak
Sarah Al-Qadheeb
Lamyaa Alghofaili
Nisreen Almoghrabi
Hamed Alhussaini
Ben Ho Park
Dilek Colak
Bedri Karakas
Publication date: 01-04-2018
Publisher: Springer US
Published in: Breast Cancer Research and Treatment / Issue 3/2018
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI: https://doi.org/10.1007/s10549-017-4635-4

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