Germline Variations of Apurinic/Apyrimidinic Endonuclease 1 (APEX1) Detected in Female Breast Cancer Patients

  • Ali, Kashif (Department of Biosciences, COMSATS Institute of Information and Technology) ;
  • Mahjabeen, Ishrat (Department of Biosciences, COMSATS Institute of Information and Technology) ;
  • Sabir, Maimoona (Department of Biosciences, COMSATS Institute of Information and Technology) ;
  • Baig, Ruqia Mehmood (Department of Biosciences, COMSATS Institute of Information and Technology) ;
  • Zafeer, Maryam (Department of Biosciences, COMSATS Institute of Information and Technology) ;
  • Faheem, Muhammad (Nuclear Medicine, Oncology and Radiotherapy Institute) ;
  • Kayani, Mahmood Akhtar (Department of Biosciences, COMSATS Institute of Information and Technology)
  • Published : 2014.10.11


Apurinic/apyrimidinic endonuclease 1 (APEX1) is a multifunctional protein which plays a central role in the BER pathway. APEX1 gene being highly polymorphic in cancer patients and has been indicated to have a contributive role in Apurinic/apyrimidinic (AP) site accumulation in DNA and consequently an increased risk of cancer development. In this case-control study, all exons of the APEX1 gene and its exon/intron boundaries were amplified in 530 breast cancer patients and 395 matched healthy controls and then analyzed by single-stranded conformational polymorphism followed by sequencing. Sequence analysis revealed fourteen heterozygous mutations, seven 5'UTR, one 3'UTR, two intronic and four missense. Among identified mutations one 5'UTR (rs41561214), one 3'UTR (rs17112002) and one missense mutation (Ser129Arg, Mahjabeen et al., 2013) had already been reported while the remaining eleven mutations. Six novel mutations (g.20923366T>G, g.20923435G>A, g.20923462G>A, g.20923516G>A, 20923539G>A, g.20923529C>T) were observed in 5'UTR region, two (g.20923585T>G, g.20923589T>G) in intron1 and three missense (Glu101Lys, Ala121Pro, Ser123Trp) in exon 4. Frequencues of 5'UTR mutations; g.20923366T>G, g.20923435G>A and 3'UTR (rs17112002) were calculated as 0.13, 0.1 and 0.1 respectively. Whereas, the frequency of missense mutations Glu101Lys, Ser123Trp and Ser129Arg was calculated as 0.05. A significant association was observed between APEX1 mutations and increased breast cancer by ~9 fold (OR=8.68, 95%CI=2.64 to 28.5) with g.20923435G>A (5'UTR), ~13 fold (OR= 12.6, 95%CI=3.01 to 53.0) with g.20923539G>A (5'UTR) and~5 fold increase with three missense mutations [Glu101Lys (OR=4.82, 95%CI=1.97 to 11.80), Ser123Trp (OR=4.62, 95%CI=1.7 to 12.19), Ser129Arg (OR=4.86, 95%CI=1.43 to 16.53)]. The incidence of observed mutations was found higher in patients with family history and with early menopause. In conclusion, our study demonstrates a significant association between germ line APEX1 mutations and breast cancer patients in the Pakistani population.


  1. Alanazi M, Pathan AA, Shaik JP, Amri AA, Parine NR (2013). The C allele of a synonymous SNP (rs1805414, Ala284Ala) in PARP1 is a risk factor for susceptibility-breast cancer in Saudi patients. Asian Pac J Cancer Prev, 14, 3051-6.
  2. Adzhubei IA, Schmidt S, Peshkin L, et al (2010). A method and server for predicting damaging missense mutations. Nat Methods, 7, 248-9.
  3. Ahmed HG, Al-Adhraei MA, Al-Thobhani AK (2011). Correlations of hormone receptors (ER and PR), Her2/neu and p53 expression in breast ductal carcinoma among Yemeni women. Open Cancer Immunol J, 4, 1-9.
  4. Ahmed HG, Safi SH, Shumo AI, Abdulrazig M (2007). Expression of estrogen and progesterone receptors among Sudanese women with breast cancer: immunohistochemical study. Sudan J Medical Stud, 2, 5-6.
  5. Avery CL (2007). Genotype-by-smoking interaction and the risk of atherosclerosis and its clinical sequelae. PhD Thesis, Epidemiology Department, University of North Carolina at Chapel Hill, USA.
  6. Azizun-Nisa, Bhurgri Y, Raza F, Kayani N (2008). Comperison of ER, PR and HER-2/neu (C erb B2) reactivity pattern with histologic grade, tumor size and lymph node status in breast cancer. Asian Pac J Cancer Prev, 9, 553-6.
  7. Bhakat KK, Mantha AK, Mitra S (2009). Transcriptional regulatory functions of mammalian AP-endonuclease (APE1/Ref-1), an essential multifunctional protein. Antioxid Redox Signal, 11, 621-38.
  8. Dumitrescu RG, Cotarla I (2005). Understanding breast cancer risk-where do we stand in 2005? J Cell Mol Med, 9, 208-21.
  9. Dyrkheeva NS, Khodyreva SN, Lavrik OI (2007). Multifunctional human apurinic/apyrimidinic endonuclease 1: the role of additional functions. Mol Biol (Mosk), 41, 450-66.
  10. Hu JJ, Smith TR, Miller MS, et al (2001). Amino acid substitution variants of APE1 and XRCC1 genes associated with ionizing radiation sensitivity. Carcinogenesis, 22, 917-22.
  11. Fishel ML and Kelley MR (2007). The DNA base excision repair protein Ape1/Ref-1 as a therapeutic and chemopreventive target. Mol. Aspects Med, 28, 375-95.
  12. Grantham R (1974). Amino acid difference formula-help explain protein evolution. Science, 185, 862-4.
  13. Hedayati-Moghadam MR (2008). Correlation of HER2/neu overexpression, p53 protien accumulation and steroid receptor status with tumor characteristics: an Iranian study of breast cancer patients. Iranian J Publ Health, 37, 19-28.
  14. Kang H, Dai Z, Ma X, et al (2013). A genetic variant in the promoter of APE1 gene (-656 T>G) is associated with breast cancer risk and progression in a Chinese population. Gene, 15, 97-100.
  15. Karahalil B, Bohr VA, Wilson DM (2012). Impact of DNA polymorphisms in key DNA base excision repair proteins on cancer risk. Hum Exp Toxicol, 31, 981-1005.
  16. Kim KY, Han W, Noh DY, Kang D, Kwack K (2013). Impact of genetic polymorphisms in base excision repair genes on the risk of breast cancer in a Korean population, Gene, 15, 192-6.
  17. Kumar P, Henikoff S, Ng PC (2009). Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat Protoc, 4, 1073-81.
  18. Li Q, Wang JM, Peng Y, et al (2013). Association of DNA base excision repair XRCC1, OGG1 and APE1 gene polymorphisms with nasopharyngeal carcinoma susceptibility in a Chinese population. Asian Pac J Cancer Prev, 14, 5145-51.
  19. Li Z, Guan W, Li MX, et al (2011). Genetic polymorphism of DNA base-excision repair genes (APE1, OGG1 and XRCC1) and their correlation with risk of lung cancer in a Chinese population. Arch Med Res, 42, 226-34.
  20. Luo H, Li Z, Qing Y, et al (2014). Single nucleotide polymorphisms of DNA base excision repair genes (APE1, OGG1 and XRCC1) associated with breast cancer risk in a Chinese population. Asian Pac J Cancer Prev, 15, 1133-40.
  21. Lo YL, Jou YS, Hsiao CF, et al (2009). A polymorphism in the APE1 gene promoter is associated with lung cancer risk. Cancer Epidemiol Biomarkers Prev, 18, 223-9.
  22. Lodish, Havery (2004). Molecular Cell Biology. W.H. Freeman and Company, New York, p. 113. ISBN 0-7167-4366-3.
  23. Lu J, Zhang S, Chen D, et al (2009). Functional characterization of a promoter polymorphism in APE1/Ref-1 that contributesreduced lung cancer susceptibility. FASEB J, 23, 3459-69.
  24. Mahjabeen I, Baig RM, Sabir M, Kayani MA (2013). Genetic and expressional variations of APEX1 are associated with increased risk of head and neck cancer. Mutagenesis, 28, 213-8.
  25. Naeem M, Nasir A, Aman Z, Ahmad T, Samad A (2008). Frequency of HER2/neu receptor positivity and its association with other features of breast cancer. J Ayub Med Coll Abbottabad, 20, 23-6.
  26. Nosheen M, Ishrat M, Malik FA, Baig RM, Kayani MA (2010). Association of GSTM1 and GSTT1 gene deletions with risk of head and neck cancer in Pakistan: a case control study. Asian Pac J Cancer Prev, 11, 881-5.
  27. Pollard KS, Hubisz MJ, Rosenbloom KR, Siepel A (2010). Detection of non-neutral substitution rates on mammalian phylogenies. Genome Res, 20, 110-21.
  28. Popanda O, Seibold P, Nikolov I, et al (2013). Germline variants of base excision repair genes and breast cancer: a polymorphism in DNA polymerase gamma modified gene expression and breast cancer risk. Int J Cancer, 132, 55-62.
  29. Schultz PN, Klein MJ, Beck ML, Stava C, Sellin RV (2005). Breast cancer relationship between menopausal symptoms, physiologic health effects of cancer treatment and physical constraints on quality of life in long-term survivors. J Clin Nurs, 14, 204-11.
  30. Rampaul RS, Pinder SE, Elaston CW, Ellis IO (2001). Prognostic and predictive factors in primary breast cancer and their role in patient management; the Nottingham breast team. Eur J Surg Oncol, 27, 229-38.
  31. Retrieved May 20, 2014, from
  32. Rosenberg SM, Partridge AH (2013). Premature menopause in young breast cancer: effects on quality of life and treatment interventions. J Thorac Dis, 5, 55-61.
  33. Schwarz JM, Rodelsperger C, Schuelke M, Seelow D (2010). Mutation taster evaluates disease-causing potential of sequence alterations. Nat Methods, 7, 575-6.
  34. Shakeel S, Mahjabeen I, Mahmood Akhtar Kayani MA, Faryal R (2013). Association of SYK genetic variations with breast cancer pathogenesis. Asian Pac J Cancer Prev, 14, 3309-14.
  35. Sharif MA, Mamoon N, Mushtaq S, Khadim MT, Jamal S (2010). Steroid hormone receptor association with prognostic markers in breast carcinoma in Northern Pakistan. J Coll Physicians Surg Pak, 20, 181-5.
  36. Wang M, Chu H, Wang S, et al (2013). Genetic variant in APE1 gene promoter contributes-cervical cancer risk. Am J Obstet Gynecol, 360 1-7.
  37. Wang M, Qin C, Zhu J, et al (2010). Genetic variants of XRCC1, APE1, and ADPRT genes and risk of bladder cancer. DNA Cell Biol, 29, 303-11.
  38. Wong D, DeMott MS, Demple B (2003). Modulation of the 3'-->5'-exonuclease activity of human apurinic endonuclease (Ape1) by its 5'-incised Abasic DNA product. J Biol Chem, 278, 36242-9.
  39. Zhou K, Hu D, Lu J, et al (2011). A genetic variant in the APE1/Ref-1 gene promoter -141T/G may modulate risk of glioblastoma in a Chinese Han population. BMC Cancer, 23, 104-11.
  40. Zhang Y, Polly A. Newcomb, et al (2006). Genetic polymorphisms in base-excision repair pathway genes and risk of breast cancer. Cancer Epidemiol Biomarkers Prev, 15, 353-8.
  41. Zhang Y, Wang J (2010). Anticancer clinical utility of the apurinic/apyrimidinic endonuclease/redox factor-1 (APE/Ref-1). Chin J Cancer, 29, 333-9.
  42. Zhou B, Shan H, Su Y, et al (2011). The association of APE1 -656T>G and 1349 T>G polymorphisms and cancer risk: a meta-analysis based on 37 case-control studies. BMC Cancer, 11, 521-9.
  43. Zhou LP, Luan H, Dong XH, et al (2012). Association of functional polymorphisms of the XRCC4 gene with the risk of breast cancer: a meta-analysis. Asian Pac J Cancer Prev, 13, 3431-6.

Cited by

  1. MUFFINN: cancer gene discovery via network analysis of somatic mutation data vol.17, pp.1, 2016,
  2. LC-MS analysis of Hep-2 and Hek-293 cell lines treated with Brazilian red propolis reveals differences in protein expression vol.68, pp.8, 2016,