Clinical criteria for genetic testing of genes other than BRCA1/2 in epithelial ovarian cancer (EOC) still do not exist. We assessed the frequency and predictors of deleterious mutations in 19 cancer predisposition genes in high-grade serous ovarian cancer (HGSOC) in Serbia. Next-generation sequencing was used to identify germline mutations in the whole coding regions of a gene panel. Patients’ characteristics and sequencing data were summarized with descriptive statistics and compared using chi-square test. Among 131 HGSOC patients, 23 had BRCA1 (17.6%) while 5 had BRCA2 (3.8%) mutation. In addition, 9 (6.9%) pathogenic mutations were detected in other genes including BRIP1 (n = 2;1.5%), CHEK2 (n = 2;1.5%), NBN (n = 3;2.3%) and RAD51C (n = 2;1.5%). Factors that predicted for BRCA1/2 mutations were: breast and ovarian cancers in the same patient (p = 0.031), young age of EOC (p = 0.029), menstrual status (p = 0.004) and family history of cancer (p < 0.0001). However, these factors did not predict for mutations in other cancer susceptibility genes. Applying established referral criteria for genetic testing in Serbia will help identify BRCA1/2 mutation carriers but will not help identify mutations in other cancer susceptibility genes. Until better predictors emerge we should be performing wider genetic testing of EOC in order to identify all mutation carriers.
Subscribe to Journal
Get full journal access for 1 year
only $37.50 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Roett MA, Evans P. Ovarian cancer: an overview. Am Fam Physician. 2009;80:609–16.
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68:7–30.
Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ. Cancer statistics, 2009. CA Cancer J Clin. 2009;59:225–49.
Toss A, Tomasello C, Razzaboni E, Contu G, Grandi G, Cagnacci A, et al. Hereditary ovarian cancer: not only BRCA 1 and 2 genes. Biomed Res Int. 2015;2015:341723.
Arts-De Jong M, De Bock GH, Van Asperen CJ, Mourits MJE, De Hullu JA, Kets CM. Germline BRCA1/2 mutation testing is indicated in every patient with epithelial ovarian cancer: a systematic review. Eur J Cancer. 2016;61:137–45.
Aljoša Mandić, László Thurzó, Dejan Ninčić, Milica Živaljević, Tihomir Dugandžija, Róbert Berkecz. Epidemiological data of ovarian cancer in Vojvodina and South Great Plain region in Hungary in 2007-2012 period: CrossBiomark IPA PROJECT HUSRB/1203/214/091. Arch Oncol. 2013;21:97–100.
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;41:1619–27.
Walsh T, Casadei S, Lee MK, Pennil CC, Nord AS, Thornton AM, et al. Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing. Proc Natl Acad Sci. 2011;108:18032–7.
Ramus SJ, Song H, Dicks E, Tyrer JP, Rosenthal AN, Intermaggio MP, et al. Germline mutations in the BRIP1, BARD1, PALB2, and NBN genes in women with ovarian cancer. J Natl Cancer Inst. 2015;107:1–8.
Berry DA, Iversen ES, 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;20:2701–12.
Antoniou AC, Pharoah PPD, Smith P, Easton DF. The BOADICEA model of genetic susceptibility to breast and ovarian cancer. Br J Cancer. 2004;91:1580–90.
Evans DGR, Eccles DM, Rahman N, Young K, Bulman M, Amir E, et al. A new scoring system for the chances of identifying a BRCA1/2 mutation outperforms existing models including BRCAPRO. J Med Genet. 2004;41:474–80.
Malander S, Ridderheim M, Måsbäck A, Loman N, Kristoffersson U, Olsson H, et al. One in 10 ovarian cancer patients carry germ line BRCA1 or BRCA2 mutations: results of a prospective study in Southern Sweden. Eur J Cancer. 2004;40:422–8.
Soegaard M, Kjaer SK, Cox M, Wozniak E, Hogdall E, Hogdall C, et al. BRCA1 and BRCA2 mutation prevalence and clinical characteristics of a population-based series of ovarian cancer cases from denmark. Clin Cancer Res. 2008;14:3761–7.
Eccles DM, Balmaña 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;33:129–50.
NCCN. Evidence-based cancer guidelines, oncology drug compendium, oncology continuing medical education. https://www.nccn.org/. Accessed 10 Jul 2018.
Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J., et al. 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. 2015;17:405–24.
Krivokuca A, Dragos VS, Stamatovic L, Blatnik A, Boljevic I, Stegel V., et al. Novel BRCA1 splice-site mutation in ovarian cancer patients of Slavic origin. Fam Cancer. 2017;17:179–85.
Bolton KL, Chenevix-Trench G, Goh C, Sadetzki S, Ramus SJ, Karlan BY, et al. Association between BRCA1 and BRCA2 mutations and survival in women with invasive epithelial ovarian cancer. JAMA. 2012;307:382.
Candido-dos-Reis FJ, Song H, Goode EL, Cunningham JM, Fridley BL, Larson MC, et al. Germline mutation in BRCA1 or BRCA2 and ten-year survival for women diagnosed with epithelial ovarian cancer. Clin Cancer Res. 2015;21:652–7.
George A, Kaye S, Banerjee S. Delivering widespread BRCA testing and PARP inhibition to patients with ovarian cancer. Nat Rev Clin Oncol. 2017;14:284–96.
Alsop K, Fereday S, Meldrum C, deFazio A, Emmanuel C, George J, et al. BRCA mutation frequency and patterns of treatment response in brca mutation–positive women with ovarian cancer: a report from the Australian Ovarian Cancer Study Group. J Clin Oncol. 2012;30:2654–63.
Ledermann J, Harter P, Gourley C, Friedlander M, Vergote I, Rustin G, et al. Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer: a preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial. Lancet Oncol. 2014;15:852–61.
Fong PC, Yap TA, Boss DS, Carden CP, Mergui-Roelvink M, Gourley C, et al. Poly(ADP)-ribose polymerase inhibition: frequent durable responses in BRCA carrier ovarian cancer correlating with platinum-free interval. J Clin Oncol. 2010;28:2512–9.
Norquist BM, Harrell MI, Brady MF, Walsh T, Lee MK, Gulsuner S, et al. Inherited mutations in women with ovarian carcinoma. JAMA Oncol. 2016;2:482.
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;121:353–7.
Bell D, Berchuck A, Birrer M, Chien J, Cramer DW, Dao F, et al. Integrated genomic analyses of ovarian carcinoma. Nature. 2011;474:609–15.
Minion LE, Dolinsky JS, Chase DM, Dunlop CL, Chao EC, Monk BJ. Hereditary predisposition to ovarian cancer, looking beyond BRCA1/BRCA2. Gynecol Oncol. 2015;137:86–92.
Ziółkowska I, Mosor M, Nowak J. Regional distribution of heterozygous 657del5 mutation carriers of theNBS1 gene in Wielkopolska province (Poland). J Appl Genet. 2006;47:269–72.
Górski B, Dębniak T, Masojć B, Mierzejewski M, Mędrek K, Cybulski C, et al. Germline 657del5 mutation in the NBS1 gene in breast cancer patients. Int J Cancer. 2003;106:379–81.
Coulet F, Fajac A, Colas C, Eyries M, Dion-Minière A, Rouzier R, et al. Germline RAD51C mutations in ovarian cancer susceptibility. Clin Genet. 2013;83:332–6.
Krivokuca A, Yanowski K, Rakobradovic J, Benitez J, Brankovic-Magic M. RAD51C mutation screening in high-risk patients from Serbian hereditary breast/ovarian cancer families. Cancer Biomark. 2015;15:775–81.
Baysal BE, DeLoia JA, Willett-Brozick JE, Goodman MT, Brady MF, Modugno F, et al. Analysis of CHEK2 gene for ovarian cancer susceptibility. Gynecol Oncol. 2004;95:62–9.
Lawrenson K, Iversen ES, Tyrer J, Weber RP, Concannon P, Hazelett DJ, et al. Common variants at the CHEK2 gene locus and risk of epithelial ovarian cancer. Carcinogenesis. 2015;36:1341–53.
Cybulski C, Górski B, Huzarski T, Byrski T, Gronwald J, Debniak T, et al. Effect of CHEK2 missense variant I157T on the risk of breast cancer in carriers of other CHEK2 or BRCA1 mutations. J Med Genet. 2009;46:132–5.
Bogdanova N, Enβen-Dubrowinskaja N, Feshchenko S, Lazjuk GI, Rogov YI, Dammann O, et al. Association of two mutations in theCHEK2 gene with breast cancer. Int J Cancer. 2005;116:263–6.
Szymanska-Pasternak J, Szymanska A, Medrek K, Imyanitov EN, Cybulski C, Gorski B, et al. CHEK2 variants predispose to benign, borderline and low-grade invasive ovarian tumors. Gynecol Oncol. 2006;102:429–31. S
Vicus D, Finch A, Cass I, Rosen B, Murphy J, Fan I, et al. Prevalence of BRCA1 and BRCA2 germ line mutations among women with carcinoma of the fallopian tube. Gynecol Oncol. 2010;118:299–302.
Pal T, Permuth-Wey J, Betts JA, Krischer JP, Fiorica J, Arango H, et al. BRCA1 and BRCA2 mutations account for a large proportion of ovarian carcinoma cases. Cancer . 2005;104:2807–16.
Alsop K, Fereday S, Meldrum C, deFazio A, Emmanuel C, George J, et al. BRCA mutation frequency and patterns of treatment response in BRCA mutation-positive women with ovarian cancer: a report from the Australian Ovarian Cancer Study Group. J Clin Oncol. 2012;30:2654–63.
Janavičius R. Founder BRCA1/2 mutations in theEurope: implications for hereditary breast-ovarian cancer prevention and control. EPMA . 2010;1:397–412.
Song H, Cicek MS, Dicks E, Harrington P, Ramus SJ, Cunningham JM, et al. The contribution of deleterious germline mutations in BRCA1, BRCA2 and the mismatch repair genes to ovarian cancer in the population. Hum Mol Genet. 2014;23:4703–9.
Loveday C, Turnbull C, Ramsay E, Hughes D, Ruark E, Frankum JR, et al. Germline mutations in RAD51D confer susceptibility to ovarian cancer. Nat Genet. 2011;43:879–82.
Bonadona V, Bonaïti B, Olschwang S, Grandjouan S, Huiart L, Longy M, et al. Cancer Risks Associated With Germline Mutations in MLH1, MSH2, and MSH6 Genes in Lynch Syndrome. JAMA. 2011;305:2304.
Hearle N, Schumacher V, Menko FH, Olschwang S, Boardman LA, Gille JJP, et al. Frequency and Spectrum of Cancers in the Peutz-Jeghers Syndrome. Clin Cancer Res. 2006;12:3209–15.
Mai PL, Best AF, Peters JA, DeCastro RM, Khincha PP, Loud JT, et al. Risks of first and subsequent cancers among TP53 mutation carriers in the National Cancer Institute Li-Fraumeni syndrome cohort. Cancer. 2016;122:3673–81.
This study was supported by a grant from the Ministry of Education, Science and Technological development of the Republic of Serbia (Grant number 41026)
Conflict of interest
The authors declare that they have no conflict of interest.
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Krivokuca, A., Boljevic, I., Jovandic, S. et al. Germline mutations in cancer susceptibility genes in high grade serous ovarian cancer in Serbia. J Hum Genet 64, 281–290 (2019) doi:10.1038/s10038-019-0562-z
Drug Discovery Today: Disease Models (2018)