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Evaluation of Genetic Variations in miRNA-Binding Sites of BRCA1 and BRCA2 Genes as Risk Factors for the Development of Early-Onset and/or Familial Breast Cancer

  • Erturk, Elif (Department of Medical Biology, Faculty of Medicine, Uludag University) ;
  • Cecener, Gulsah (Department of Medical Biology, Faculty of Medicine, Uludag University) ;
  • Polatkan, Volkan (Department of General Surgery, Faculty of Medicine, Uludag University) ;
  • Gokgoz, Sehsuvar (Department of General Surgery, Faculty of Medicine, Uludag University) ;
  • Egeli, Unal (Department of Medical Biology, Faculty of Medicine, Uludag University) ;
  • Tunca, Berrin (Department of Medical Biology, Faculty of Medicine, Uludag University) ;
  • Tezcan, Gulcin (Department of Medical Biology, Faculty of Medicine, Uludag University) ;
  • Demirdogen, Elif (Department of Medical Biology, Faculty of Medicine, Uludag University) ;
  • Ak, Secil (Department of Medical Biology, Faculty of Medicine, Uludag University) ;
  • Tasdelen, Ismet (Department of General Surgery, Faculty of Medicine, Uludag University)
  • Published : 2014.10.23

Abstract

Although genetic markers identifying women at an increased risk of developing breast cancer exist, the majority of inherited risk factors remain elusive. Mutations in the BRCA1/BRCA2 gene confer a substantial increase in breast cancer risk, yet routine clinical genetic screening is limited to the coding regions and intronexon boundaries, precluding the identification of mutations in noncoding and untranslated regions. Because 3' untranslated region (3'UTR) polymorphisms disrupting microRNA (miRNA) binding can be functional and can act as genetic markers of cancer risk, we aimed to determine genetic variation in the 3'UTR of BRCA1/BRCA2 in familial and early-onset breast cancer patients with and without mutations in the coding regions of BRCA1/BRCA2 and to identify specific 3'UTR variants that may be risk factors for cancer development. The 3'UTRs of the BRCA1 and BRCA2 genes were screened by heteroduplex analysis and DNA sequencing in 100 patients from 46 BRCA1/2 families, 54 non-BRCA1/2 families, and 47 geographically matched controls. Two polymorphisms were identified. SNPs $c.^*1287C$ >T (rs12516) (BRCA1) and $c.^*105A$ >C (rs15869) (BRCA2) were identified in 27% and 24% of patients, respectively. These 2 variants were also identified in controls with no family history of cancer (23.4% and 23.4%, respectively). In comparison to variations in the 3'UTR region of the BRCA1/2 genes and the BRCA1/2 mutational status in patients, there was a statistically significant relationship between the BRCA1 gene polymorphism $c.^*1287C$ >T (rs12516) and BRCA1 mutations (p=0.035) by Fisher's Exact Test. SNP $c.^*1287C$ >T (rs12516) of the BRCA1 gene may have potential use as a genetic marker of an increased risk of developing breast cancer and likely represents a non-coding sequence variation in BRCA1 that impacts BRCA1 function and leads to increased early-onset and/or familial breast cancer risk in the Turkish population.

Keywords

Breast cancer;BRCA1;BRCA2;3'UTR;SNP;early onset;Turkey

Acknowledgement

Supported by : Uludag University

References

  1. Barroso E, Pita G, Arias JI, et al (2009). The Fanconi anemia family of genes and its correlation with breast cancer susceptibility and breast cancer features. Breast Cancer Res Treat, 118, 655-60. https://doi.org/10.1007/s10549-009-0439-5
  2. Betel D, Koppal A, Agius P, Sander C, Leslie C (2010). Comprehensive modeling of microRNA targets predicts functional non-conserved and non-canonical sites. Genome Biol, 11, 8-11. https://doi.org/10.1186/gb-2010-11-s1-p8
  3. Chen Y, Lee W, Chew HK (1999). Emerging roles of BRCA1 in transcriptional regulation and DNA repair. J Cell Physiol, 181, 385-92. https://doi.org/10.1002/(SICI)1097-4652(199912)181:3<385::AID-JCP2>3.0.CO;2-4
  4. Brewster BL, Rossiello F, French JD, et al (2012). Identification of fifteen novel germline variants in the BRCA1 3'UTR reveals a variant in a breast cancer case that introduces a functional miR-103 target site. Hum Mutat, 33, 1665-75. https://doi.org/10.1002/humu.22159
  5. Cazzola M, Skoda RC (2000). Translational pathophysiology: a novel molecular mechanism of human disease. Blood, 95, 3280-88.
  6. Cecener G, Egeli U, Tunca B, et al (2014). BRCA1/2 germline mutations and their clinical importance in Turkish breast cancer patients. Cancer Invest, 1-13.
  7. Claus EB, Risch N, Thompson WD (1991). Genetic analysis of breast cancer in the cancer and steroid hormone study. Am J Hum Genet, 48, 232-42.
  8. Conne B, Stutz A, Vassalli JD (2000). The 3'-untranslated region of messenger RNA: a molecular "hot spot" for pathology? Nat Med, 6, 637-41. https://doi.org/10.1038/76211
  9. Downs-Holmes C, Silverman P (2011). Breast cancer: overview and updates. The Nurse Practitioner, 36, 20-6.
  10. Egeli U, Cecener G, Tunca B, Tasdelen I (2006). Novel germline BRCA1 and BRCA2 mutations in Turkish women with breast and/or ovarian cancer and their relatives. Cancer Invest, 24, 484-91. https://doi.org/10.1080/07357900600814706
  11. Erturk E, Cecener G, Egeli U, et al (2014). Expression status of let-7a and miR-335 among breast tumors in patients with and without germ-line BRCA mutations. Mol and Cell Biochem.
  12. Esquela-Kerscher A, Slack FJ (2006). Oncomirs-microRNAs with a role in cancer. Nat Rev Cancer, 6, 259-69. https://doi.org/10.1038/nrc1840
  13. Ferla R, Calo V (2007). Founder mutations in BRCA1 and BRCA2 genes. Ann Oncol, 18, 93-8.
  14. Hayashita Y, Osada H, Tatematsu Y, et al (2005). A polycistronic microRNA cluster, miR-17-92, is overexpressed in human lung cancers and enhances cell proliferation. Cancer Res, 65, 9628-32. https://doi.org/10.1158/0008-5472.CAN-05-2352
  15. 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, 676-89. https://doi.org/10.1086/301749
  16. Goto Y, Yue L, Yokoi A, et al (2001). A novel single-nucleotide polymorphism in the 3'-untranslated region of the human dihydrofolate reductase gene with enhanced expression. Clin Cancer Res, 7, 1952-6.
  17. Hafez MM, Hassan ZK, Zekri AR, et al (2012). MicroRNAs and metastasis-related gene expression in Egyptian breast cancer patients. Asian Pac J Cancer Prev, 13, 591-8. https://doi.org/10.7314/APJCP.2012.13.2.591
  18. He L, Thomson JM, Hemann MT, et al (2005). A microRNA polycistron as a potential human oncogene. Nature, 435, 828-33. https://doi.org/10.1038/nature03552
  19. Hennessy BT, Timms KM, Carey MS, et al (2010). Somatic mutations in BRCA1 and BRCA2 could expand the number of patients that benefit from poly (ADP ribose) polymerase inhibitors in ovarian cancer. J Clin Oncol, 28, 3570-6. https://doi.org/10.1200/JCO.2009.27.2997
  20. Jemal A, Bray F, Center MM, et al (2011). Global cancer statistics. CA Cancer J Clin, 61, 69-90. https://doi.org/10.3322/caac.20107
  21. Joseph S, Sellappa S, Prathyumnan S, Keyan KS (2011). A novel polymorphism in BRCA2 exon 8 and breast cancer risk in South India. Asian Pac J Cancer Prev, 12, 309-11.
  22. Jovanovic M, Hengartner MO (2006). miRNAs and apoptosis: RNAs to die for. Oncogene, 25, 6176-87. https://doi.org/10.1038/sj.onc.1209912
  23. Kayani Mu, Kayani MA, Malik FA, Faryal R (2011). Role of miRNAs in breast cancer. Asian Pac J Cancer Prev, 12, 3175-80.
  24. Keen JC, Davidson NE (2003). The biology of breast carcinoma. Cancer, 97, 825-33. https://doi.org/10.1002/cncr.11126
  25. Kooshyar MM, Nassiri M, Mahdavi M, Doosti M, Parizadeh A (2013). Identification of germline BRCA1 mutations among breast cancer families in Northeastern Iran. Asian Pac J Cancer Prev, 14, 4339-45. https://doi.org/10.7314/APJCP.2013.14.7.4339
  26. Kenemans P, Verstraeten RA, Verheijen RH (2004). Oncogenic pathways in hereditary and sporadic breast cancer. Maturitas, 49, 34-43. https://doi.org/10.1016/j.maturitas.2004.06.005
  27. Khana KK, Jackson SP (2001). DNA double-strand breaks: signaling, repair and the cancer connection. Nat Genet, 27, 247-54. https://doi.org/10.1038/85798
  28. Kontorovich T, Levy A, Korostishevsky M, Nir U, Friedman E (2010). Single nucleotide polymorphisms in miRNA binding sites and miRNA genes as breast/ovarian cancer risk modifiers in Jewish high-risk women. Int J Cancer, 127, 589-97. https://doi.org/10.1002/ijc.25065
  29. Li JY, Jia S, Zhang WH, et al (2013). Differential distribution of microRNAs in breast cancer grouped by clinicopathological subtypes. Asian Pac J Cancer Prev, 14, 3197-203. https://doi.org/10.7314/APJCP.2013.14.5.3197
  30. Lu J, Getz G, Miska EA, et al (2005). MicroRNA expression profiles classify human cancers. Nature, 435, 834-8. https://doi.org/10.1038/nature03702
  31. Miki Y, Swensen J, Shattuck-Eidens D, et al (1994). A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science, 266, 66-71. https://doi.org/10.1126/science.7545954
  32. Nicoloso MS, Sun H, Spizzo R, et al (2010). Single-nucleotide polymorphisms inside microRNA target sites influence tumor susceptibility. Cancer Res, 70, 2789-98. https://doi.org/10.1158/0008-5472.CAN-09-3541
  33. Nilsen TW (2007). Mechanisms of microRNA-mediated gene regulation in animal cells. Trends Genet, 23, 243-9. https://doi.org/10.1016/j.tig.2007.02.011
  34. O'Donnell KA, Wentzel EA, Zeller KI, Dang CV, Mendell JT (2005). c-MYC regulated microRNAs modulate E2F-1 expression. Nature, 435, 839-43. https://doi.org/10.1038/nature03677
  35. Pelletier C, Speed WC, Paranjape T, et al (2011). Rare BRCA1 haplotypes including 3'UTR SNPs associated with breast cancer risk. Cell Cycle, 10, 90-9. https://doi.org/10.4161/cc.10.1.14359
  36. Sehl ME, Langer LR, Papp JC, et al (2009). Associations between single nucleotide polymorphisms in double-stranded DNA repair pathway genes and familial breast cancer. Clin Cancer Res, 15, 2192-203. https://doi.org/10.1158/1078-0432.CCR-08-1417
  37. Peto I, Collins N, Barfoot R, et al (1999). Prevalence of BRCA1 and BRCA2 gene mutations in patients with early-onset breast cancer. J Natl Cancer Inst, 91, 943-9. https://doi.org/10.1093/jnci/91.11.943
  38. Pongsavee M, Yamkamon V, Dakeng S, et al (2009). The BRCA1 3'-UTR: 5711?421T/T_5711?1286T/T genotype is a possible breast and ovarian cancer risk factor. Genet Test Mol Biomarkers, 13, 307-17. https://doi.org/10.1089/gtmb.2008.0127
  39. Scully R, Livingston DM (2000). In search of the tumoursuppressor functions of BRCA1 and BRCA2. Nature, 408, 429-32. https://doi.org/10.1038/35044000
  40. Szabo CI, King MC (1997). Population genetics of BRCA1 and BRCA2. Am J Hum Genet, 60, 1013-20.
  41. Wooster R, Bignell G, Lancaster J, et al (1995). Identification of the breast cancer susceptibility gene BRCA2. Nature, 378, 789-92. https://doi.org/10.1038/378789a0
  42. Wu W, Sun M, Zou GM, Chen J (2007). MicroRNA and cancer: current status and prospective. Int J Cancer, 120, 953-60.
  43. Venkitaraman AR (2002). Cancer susceptibility and the functions of BRCA1and BRCA2. Cell, 108, 171-82. https://doi.org/10.1016/S0092-8674(02)00615-3
  44. Zhang B, Pan X, Anderson TA (2006). MicroRNA: a new player in stem cells. J Cell Physiol, 209, 266-9. https://doi.org/10.1002/jcp.20713

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