Hereditary predisposition to breast and ovarian cancer (HBOC) is diagnosed by molecular analysis of deleterious mutations in BRCA genes, allowing oncogenetic follow-up of patients and of their families. BRCA testing addresses only to HBOC families, using restrictive inclusion criteria based on familial history of cancer and age at diagnosis. Sporadic ovarian cancer has high incidence and mortality in Romania, with low median age of diagnosis and possibly a higher magnitude of hereditary contribution comparing to othe populations. However, sporadic ovarian cancers do not qualify for BRCA testing according to inclusion criteria, and a complete BRCA screening of all cancers is neither feasible nor recommended. Despite the large diversity of BRCA mutations worldwide, some recurrent mutations have higher frequencies in diverse populations. Precisely screening for recurrent mutations in a target population allows to rapidly identifying mutation carriers without sequencing the entire BRCA genes. In Romanian population and neighboring countries, several recurrent mutations have already been described. In a consecutive series of 50 sporadic ovarian cancer patients, not qualifying for BRCA complete testing, we screened for 9 most common BRCA mutations, by multiplex-PCR, RFLP and targeted Sanger sequencing. Our results revealed 6 different BRCA mutations in 8 unrelated patients, with a frequency of 16%, much higher than expected. We further recommend screening for the identified mutations in larger series of cancer patients. The results are highly beneficial to cancer patients, healthy relatives, and overall, considering prevention in cancer a priority, to public health system and future of oncogenetics in Romania
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1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018 Nov;68(6):394-424. DOI: 10.3322/caac.21492
2. Ferlay J, Colombet M, Soerjomataram I, Mathers C, Parkin DM, Pineros M, et al. Estimating the global cancer incidence and mortality in 2018: GLOBOCAN sources and methods. International journal of cancer. 2019 Apr 15;144(8):1941-53. DOI: 10.1002/ijc.31937
3. Ferlay J, Steliarova-Foucher E, Lortet-Tieulent J, Rosso S, Coebergh JW, Comber H, et al. Cancer incidence and mortality patterns in Europe: estimates for 40 countries in 2012. Eur J Cancer. 2013 Apr;49(6):1374-403. DOI: 10.1016/j.ejca.2012.12.027
4. Antoniou AC, Gayther SA, Stratton JF, Ponder BA, Easton DF. Risk models for familial ovarian and breast cancer. Genet Epidemiol. 2000 Feb;18(2):173-90. DOI: 10.1002/(SICI)1098-2272(200002)18:2<173::AIDGEPI6>3.0.CO;2-R
5. Muinao T, Pal M, Deka Boruah HP. Origins based clinical and molecular complexities of epithelial ovarian cancer. Int J Biol Macromol. 2018 Oct 15;118(Pt A):1326-45. DOI: 10.1016/j.ijbiomac.2018.06.036
6. King MC, Marks JH, Mandell JB. Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2. Science. 2003 Oct 24;302(5645):643-6. DOI: 10.1126/science.1088759
7. Doherty JA, Jensen A, Kelemen LE, Pearce CL, Poole E, Schildkraut JM, et al. Current Gaps in Ovarian Cancer Epidemiology: The Need for New Population-Based Research. J Natl Cancer Inst. 2017 Oct 1;109(10).
8. Andrews L, Mutch DG. Hereditary Ovarian Cancer and Risk Reduction. Best Pract Res Clin Obstet Gynaecol. 2017 May;41:31-48. DOI: 10.1016/j.bpobgyn.2016.10.017
9. Lai T, Kessel B, Ahn HJ, Terada KY. Ovarian cancer screening in menopausal females with a family history of breast or ovarian cancer. J Gynecol Oncol. 2016 Jul;27(4):e41. DOI: 10.3802/jgo.2016.27.e41
10. Yamauchi H, Takei J. Management of hereditary breast and ovarian cancer. Int J Clin Oncol. 2018 Feb;23(1):45-51. DOI: 10.1007/s10147-017-1208-9
11. Helder-Woolderink JM, Blok EA, Vasen HF, Hollema H, Mourits MJ, De Bock GH. Ovarian cancer in Lynch syndrome; a systematic review. Eur J Cancer. 2016 Mar;55:65-73. DOI: 10.1016/j.ejca.2015.12.005
12. Ramus SJ, Antoniou AC, Kuchenbaecker KB, Soucy P, Beesley J, Chen X, et al. Ovarian cancer susceptibility alleles and risk of ovarian cancer in BRCA1 and BRCA2 mutation carriers. Hum Mutat. 2012 Apr;33(4):690-702.
13. Antoniou AC, Rookus M, Andrieu N, Brohet R, Chang-Claude J, Peock S, et al. Reproductive and hormonal factors, and ovarian cancer risk for BRCA1 and BRCA2 mutation carriers: results from the International BRCA1/2 Carrier Cohort Study. Cancer Epidemiol Biomarkers Prev. 2009 Feb;18(2):601-10. DOI: 10.1158/1055-9965.EPI-08-0546
14. Antoniou A, Pharoah PD, Narod S, Risch HA, Eyfjord JE, Hopper JL, et al. 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. 2003 May;72(5):1117-30. DOI: 10.1086/375033
15. Eccles DM, Balmana J, Clune J, Ehlken B, Gohlke A, Hirst C, et al. Selecting Patients with Ovarian Cancer for Germline BRCA Mutation Testing: Findings from Guidelines and a Systematic Literature Review. Adv Ther. 2016 Feb;33(2):129-50. DOI: 10.1007/s12325-016-0281-1
16. Feunteun J. Hereditary predisposition to cancer. Bull Acad Natl Med. 2005 May;189(5):797-800. DOI: 10.1016/S0001-4079(19)33506-X
17. Berry DA, Iversen ES, Jr., Gudbjartsson DF, Hiller EH, Garber JE, Peshkin BN, et al. BRCAPRO validation, sensitivity of genetic testing of BRCA1/BRCA2, and prevalence of other breast cancer susceptibility genes. J Clin Oncol. 2002 Jun 1;20(11):2701-12. DOI: 10.1200/JCO.2002.05.121
18. Antoniou AC, Pharoah PP, Smith P, Easton DF. The BOADICEA model of genetic susceptibility to breast and ovarian cancer. Br J Cancer. 2004 Oct 18;91(8):1580-90. DOI: 10.1038/sj.bjc.6602175
19. Kast K, Schmutzler RK, Rhiem K, Kiechle M, Fischer C, Niederacher D, et al. Validation of the Manchester scoring system for predicting BRCA1/2 mutations in 9,390 families suspected of having hereditary breast and ovarian cancer. International journal of cancer. 2014 Nov 15;135(10):2352-61. DOI: 10.1002/ijc.28875
20. Eisinger F, Bressac B, Castaigne D, Cottu PH, Lansac J, Lefranc JP, et al. [Identification and management of hereditary predisposition to cancer of the breast and the ovary (update 2004)]. Bull Cancer. 2004 Mar;91(3):219-37.
21. Negura L, Uhrhammer N, Negura A, Artenie V, Carasevici E, Bignon YJ. Complete BRCA mutation screening in breast and ovarian cancer predisposition families from a North-Eastern Romanian population. Fam Cancer. 2010 Dec;9(4):519-23. DOI: 10.1007/s10689-010-9361-6
22. Negura L, Dusa CP, Balmus MI, Azoicai D, Negura AM, Marinca MV, et al. BRCA1 5382insC founder mutation has not a significative recurrent presence in Northeastern Romanian cancer patients. Rom J Morphol Embryo. 2015;56(2):379-85.
23. Moller P, Hagen AI, Apold J, Maehle L, Clark N, Fiane B, et al. Genetic epidemiology of BRCA mutations--family history detects less than 50% of the mutation carriers. Eur J Cancer. 2007 Jul;43(11):1713-7. DOI: 10.1016/j.ejca.2007.04.023
24. Gayther SA, Mangion J, Russell P, Seal S, Barfoot R, Ponder BA, et al. Variation of risks of breast and ovarian cancer associated with different germline mutations of the BRCA2 gene. Nat Genet. 1997 Jan;15(1):103-5. DOI: 10.1038/ng0197-103
25. Negura L, Carasevici E, Negura A, Uhrhammer N, Bignon YJ. Identification of a recurrent BRCA1 mutation in two breast/ovarian cancer predisposition families with distinct phenotypes, by using allele-specific multiplex-PCR. Rev Romana Med Lab. 2010 Jun;18(2):53-61.
26. Negura L, Azoicai D, Matei M, Popoiu G, Negura A. Screening of a novel BRCA2 mutation by rapid in-house PCR-RFLP. Rev Romana Med Lab. 2011 Dec;19(4):333-9.
27. Janavicius R. Founder BRCA1/2 mutations in the Europe: implications for hereditary breast-ovarian cancer prevention and control. Epma J. 2010 Sep;1(3):397-412. DOI: 10.1007/s13167-010-0037-y
28. Burcos T, Cimponeriu D, Ion DA, Spandole S, Apostol P, Toma M, et al. Analysis of several BRCA1 and BRCA2 mutations in a hospital-based series of unselected breast cancer cases. Chirurgia (Bucur). 2013 Jul-Aug;108(4):468-72.
29. Goidescu IG, Caracostea G, Eniu DT, Stamatian FV. Prevalence of deleterious mutations among patients with breast cancer referred for multigene panel testing in a Romanian population. Clujul Med. 2018;91(2):157-65. DOI: 10.15386/cjmed-894
30. Zhang S, Royer R, Li S, McLaughlin JR, Rosen B, Risch HA, et al. Frequencies of BRCA1 and BRCA2 mutations among 1,342 unselected patients with invasive ovarian cancer. Gynecol Oncol. 2011 May 1;121(2):353-7. DOI: 10.1016/j.ygyno.2011.01.020
31. Loginova AN, Pospekhova NI, Lyubchenko LN, Budilov AV, Zakhar’ev VM, Gar’kavtseva RF, et al. Spectrum of mutations in BRCA1 gene in hereditary forms of breast and ovarian cancer in Russian families. Bull Exp Biol Med. 2003 Sep;136(3):276-8. DOI: 10.1023/B:BEBM.0000008982.21806.9b
32. Van Der 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 Jun 1;86(5):737-40. DOI: 10.1002/(SICI)1097-0215(20000601)86:5<737::AID-IJC21>3.0.CO;2-1
33. Cybulski C, Kluzniak W, Huzarski T, Wokolorczyk D, Kashyap A, Rusak B, et al. The spectrum of mutations predisposing to familial breast cancer in Poland. International journal of cancer. 2019 Dec 15;145(12):3311-20. DOI: 10.1002/ijc.32492
34. Dodova RI, Mitkova AV, Dacheva DR, Hadjo LB, Vlahova AI, Hadjieva MS, et al. Spectrum and frequencies of BRCA1/2 mutations in Bulgarian high risk breast cancer patients. BMC Cancer. 2015;15:523. DOI: 10.1186/s12885-015-1516-2
35. Yazici H, Bitisik O, Akisik E, Cabioglu N, Saip P, Muslumanoglu M, et al. BRCA1 and BRCA2 mutations in Turkish breast/ovarian families and young breast cancer patients. Br J Cancer. 2000 Sep;83(6):737-42. DOI: 10.1054/bjoc.2000.1332
36. Tsigginou A, Vlachopoulos F, Arzimanoglou I, Zagouri F, Dimitrakakis C. Cumulative BRCA mutation analysis in the Greek population confirms that homogenous ethnic background facilitates genetic testing. Hered Cancer Clin Pract. 2015;13(1):17. DOI: 10.1186/s13053-015-0037-y
37. Ozolina S, Sinicka O, Jankevics E, Inashkina I, Lubinski J, Gorski B, et al. The 4154delA mutation carriers in the BRCA1 gene share a common ancestry. Fam Cancer. 2009;8(1):1-4. DOI: 10.1007/s10689-008-9224-6
38. Cecener G, Sabour Takanlou L, Sabour Takanlou M, Egeli U, Eskiler GG, Aksoy S, et al. Clinicopathologic features and genetic characteristics of the BRCA1/2 mutation in Turkish breast cancer patients. Cancer Genet. 2020 Jan;240:23-32. DOI: 10.1016/j.cancer-gen.2019.10.004
39. Bănescu C. Do we really need genetic tests in current clinical practice? Rev Romana Med Lab. 2019;27(1):9-14. DOI: 10.2478/rrlm-2019-0010
40. Bănescu C, Skrypnyk C. The Value of FLT3, NPM1 and DNMT3A Gene Mutation Analysis in Acute Myeloid Leukemia Diagnosis. Rev Romana Med Lab. 2019;27(3):239-43. DOI: 10.2478/rrlm-2019-0024
41. Goidescu IG, Eniu DT, Caracostea GV, Cruciat G, Stamatian F. Associations of pathogenic mutations responsible for breast cancer risk with histology and immunohistochemistry in Romanian population. Rev Romana Med Lab. 2018;26(2):165-75. DOI: 10.1515/rrlm-2017-0037