Associations of pathogenic mutations responsible for breast cancer risk with histology and immunohistochemistry in Romanian population

Open access

Abstract

Introduction: Breast cancer is the most common cancer in women worldwide, and Romania makes no exception from this trend. Genetic screening for Hereditary Breast and Ovarian Cancer began to be used on a larger scale after the introduction of Next Generation Sequencing. The aim of this study was to assess the association of deleterious mutations responsible for breast cancer with histopathological and immunohistochemical prognostic factors and to identify some genetic variants in the BRCA1 and BRCA2 genes. Method: 80 patients with breast cancer and negative genetic test or pathogenic variants on BRCA1/2, TP53, PALB2, CHEK2, ATM genes were included. All the cases had a prior histological diagnosis and complete immunohistochemical features. The genetic testing was conducted through a multigene panel. Results: 65% of patients had a deleterious mutation on BRCA genes. In 97.5% of cases the histology was invasive ductal carcinoma. Significant differences were identified between BRCA1 group and negative mutation group regarding estrogen receptor (ER) (p=0.0051), progesterone receptor (PR) (p=0.0004) and Ki67 (p=0.001). Seven breast cancer patients had BRCA1 c.3607C>T variant, which was statistically significantly associated with triple- negative breast cancer (p <0.0001). Of the 7 cases diagnosed with BRCA 2 mutations we identified the c.8755-1G>A variant in 3 cases and the c.9371A>T variant in 3 cases. Discussion and conclusion: Our study confirmed the association of BRCA1 mutations with negative ER, PR or triple negative breast cancer (TNBC). Description of BRCA1 c.3607C>T mutation for the first time in Romanian population and its association with TNBC will need further investigation.

1. 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; 49(6):1374-403. DOI: 10.1016/j.ejca.2012.12.027

2. Hall JM, Lee MK, Newman B, Morrow JE, Anderson LA, Huey B, et al. Linkage of early-onset familial breast cancer to chromosome 17q21. Science. 1990; 250(4988):1684-9. DOI: 10.1126/science.2270482

3. Wooster R, Neuhausen SL, Mangion J, Quirk Y, Ford D, Collins N, et al. Localization of a breast cancer susceptibility gene, BRCA2, to chromosome 13q12-13. Science. 1994; 265(5181):2088-90. DOI: 10.1126/science.8091231

4. Kurian AW, Kingham KE, Ford JM. Next-generation sequencing for hereditary breast and gynecologic cancer risk assessment. Curr Opin Obstet Gynecol. 2015; 27(1):23-33. DOI: 10.1097/GCO.0000000000000141

5. Hilbers FS, Vreeswijk MP, van Asperen CJ, Devilee P. The impact of next generation sequencing on the analysis of breast cancer susceptibility: a role for extremely rare genetic variation? Clin Genet. 2013; 84(5):407-14. DOI: 10.1111/cge.12256

6. Sharma P, Klemp JR, Kimler BF, Mahnken JD, Geier LJ, Khan QJ, et al. Germline BRCA mutation evaluation in a prospective triple-negative breast cancer registry: implications for hereditary breast and/or ovarian cancer syndrome testing. Breast Cancer Res Treat. 2014; 145(3):707-14. DOI: 10.1007/s10549-014-2980-0

7. Mavaddat N, Peock S, Frost D, Ellis S, Platte R, Fineberg E, et al. Cancer risks for BRCA1 and BRCA2 mutation carriers: results from prospective analysis of EMBRACE. J Natl Cancer Inst. 2013; 105(11):812-22. DOI: 10.1093/jnci/djt095

8. Zaky SS, Lund M, May KA, Godette KD, Beitler JJ, Holmes LR, et al. The negative effect of triple-negative breast cancer on outcome after breast-conserving therapy. Ann Surg Oncol. 2011; 18(10):2858-65. DOI: 10.1245/s10434-011-1669-4

9. Domagala P, Jakubowska A, Jaworska-Bieniek K, Kaczmarek K, Durda K, Kurlapska A, et al. Prevalence of Germline Mutations in Genes Engaged in DNA Damage Repair by Homologous Recombination in Patients with Triple-Negative and Hereditary Non-Triple-Negative Breast Cancers. PLoS One. 2015; 10(6):e0130393. DOI: 10.1371/journal.pone.0130393

10. Morris JL, Gordon OK. Positive results : making the best decisions when you’re at high risk for breast or ovarian cancer. Amherst, N.Y.: Prometheus Books; 2010. 395 p. p.

11. Daly MB, Pilarski R, Axilbund JE, Berry M, Buys SS, Crawford B, et al. Genetic/Familial High-Risk Assessment: Breast and Ovarian, Version 2.2015. J Natl Compr Canc Netw. 2016; 14(2):153-62. DOI: 10.6004/jnccn.2016.0018

12. Chennagiri N, White EJ, Frieden A, Lopez E, Lieber DS, Nikiforov A, et al. Orthogonal NGS for High Throughput Clinical Diagnostics. Sci Rep. 2016; 6:24650. DOI: 10.1038/srep24650

13. Unger MA, Nathanson KL, Calzone K, Antin-Ozerkis D, Shih HA, Martin AM, et al. Screening for genomic rearrangements in families with breast and ovarian cancer identifies BRCA1 mutations previously missed by conformation-sensitive gel electrophoresis or sequencing. Am J Hum Genet. 2000; 67(4):841-50. DOI: 10.1086/303076

14. Weissgerber TL, Milic NM, Winham SJ, Garovic VD. Beyond bar and line graphs: time for a new data presentation paradigm. PLoS Biol. 2015; 13(4):e1002128. DOI: 10.1371/journal.pbio.1002128

15. Kwong A, Chen JW, Shin VY. A new paradigm of genetic testing for hereditary breast/ovarian cancers. Hong Kong Med J. 2016; 22(2):171-7.

16. Weischer M, Bojesen SE, Tybjaerg-Hansen A, Axelsson CK, Nordestgaard BG. Increased risk of breast cancer associated with CHEK2*1100delC. J Clin Oncol. 2007; 25(1):57-63. DOI: 10.1200/JCO.2005.05.5160

17. Domagala P, Huzarski T, Lubinski J, Gugala K, Domagala W. Immunophenotypic predictive profiling of BRCA1-associated breast cancer. Virchows Arch. 2011; 458(1):55-64. DOI: 10.1007/s00428-010-0988-3

18. 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; 9(4):519-23. DOI: 10.1007/s10689-010-9361-6

19. 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;108(4):468-72.

20. 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 U S A. 2011; 108(44):18032-7. DOI: 10.1073/pnas.1115052108

21. 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. DOI: 10.1186/1471-2407-8-140

22. Wojcik P, Jasiowka M, Strycharz E, Sobol M, Hodorowicz- Zaniewska D, Skotnicki P, et al. Recurrent mutations of BRCA1, BRCA2 and PALB2 in the population of breast and ovarian cancer patients in Southern Poland. Hered Cancer Clin Pract. 2016; 14:5. DOI: 10.1186/s13053-016-0046-5

23. Cybulski C, Huzarski T, Byrski T, Gronwald J, Debniak T, Jakubowska A, et al. Estrogen receptor status in CHEK2-positive breast cancers: implications for chemoprevention. Clin Genet. 2009; 75(1):72-8. DOI: 10.1111/j.1399-0004.2008.01111.x

24. Liu C, Wang Y, Wang QS, Wang YJ. The CHEK2 I157T variant and breast cancer susceptibility: a systematic review and meta-analysis. Asian Pac J Cancer Prev. 2012; 13(4):1355-60. DOI: 10.7314/APJCP.2012.13.4.1355

25. Huszno J, Budryk M, Kolosza Z, Tecza K, Pamula Pilat J, Nowara E, et al. A Comparison between CHEK2*1100delC/I157T Mutation Carrier and Noncarrier Breast Cancer Patients: A Clinicopathological Analysis. Oncology. 2016; 90(4):193-8. DOI: 10.1159/000444326

26. Kriege M, Hollestelle A, Jager A, Huijts PE, Berns EM, Sieuwerts AM, et al. Survival and contralateral breast cancer in CHEK2 1100delC breast cancer patients: impact of adjuvant chemotherapy. Br J Cancer. 2014; 111(5):1004-13. DOI: 10.1038/bjc.2014.306

27. Cybulski C, Kluzniak W, Huzarski T, Wokolorczyk D, Kashyap A, Jakubowska A, et al. Clinical outcomes in women with breast cancer and a PALB2 mutation: a prospective cohort analysis. Lancet Oncol. 2015; 16(6):638-44. DOI: 10.1016/S1470-2045(15)70142-7

28. Heikkinen T, Karkkainen H, Aaltonen K, Milne RL, Heikkila P, Aittomaki K, et al. The breast cancer susceptibility mutation PALB2 1592delT is associated with an aggressive tumor phenotype. Clin Cancer Res. 2009; 15(9):3214-22. DOI: 10.1158/1078-0432.CCR-08-3128

29. Couch FJ, Hart SN, Sharma P, Toland AE, Wang X, Miron P, et al. Inherited mutations in 17 breast cancer susceptibility genes among a large triple-negative breast cancer cohort unselected for family history of breast cancer. J Clin Oncol. 2015; 33(4):304-11. DOI: 10.1200/JCO.2014.57.1414

30. Wilson JR, Bateman AC, Hanson H, An Q, Evans G, Rahman N, et al. A novel HER2-positive breast cancer phenotype arising from germline TP53 mutations.J Med Genet. 2010; 47(11):771-4. DOI: 10.1136/jmg.2010.078113

31. Bougeard G, Renaux-Petel M, Flaman JM, Charbonnier C, Fermey P, Belotti M, et al. Revisiting Li-Fraumeni Syndrome From TP53 Mutation Carriers. J Clin Oncol. 2015; 33(21):2345-52. DOI: 10.1200/JCO.2014.59.5728

32. Stagni V, Manni I, Oropallo V, Mottolese M, Di Benedetto A, Piaggio G, et al. ATM kinase sustains HER2 tumorigenicity in breast cancer. Nat Commun. 2015;6:6886. DOI: 10.1038/ncomms7886

33. Eccles DM, Li N, Handwerker R, Maishman T, Copson ER, Durcan LT, et al. Genetic testing in a cohort of young patients with HER2-amplified breast cancer. Ann Oncol. 2016; 27(3):467-73. DOI: 10.1093/annonc/mdv592

Revista Romana de Medicina de Laborator

Romanian Journal of Laboratory Medicine

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