title: Germline variations of apurinic/apyrimidinic endonuclease 1 (APEX1) detected in female breast cancer patients.
abstract: 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) werecalculated 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.
authors.affiliation: Department of Biosciences, COMSATS Institute of Information and Technology, Islamabad, Pakistan E-mail : mkayani@comsats.edu.pk.
authors.forename: Kashif
authors.initials: K
authors.lastname: Ali
authors.forename: Ishrat
authors.initials: I
authors.lastname: Mahjabeen
authors.forename: Maimoona
authors.initials: M
authors.lastname: Sabir
authors.forename: Ruqia Mehmood
authors.initials: RM
authors.lastname: Baig
authors.forename: Maryam
authors.initials: M
authors.lastname: Zafeer
authors.forename: Muhammad
authors.initials: M
authors.lastname: Faheem
authors.forename: Mahmood Akhtar
authors.initials: MA
authors.lastname: Kayani
mesh_terms: D020121:5' Untranslated Regions / Q000235:genetics; D000328:Adult; D001943:Breast Neoplasms / Q000175:diagnosis / Q000235:genetics*; D016022:Case-Control Studies; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation / Q000235:genetics*; D006801:Humans; D008875:Middle Aged; D009367:Neoplasm Staging; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011379:Prognosis
chemical_list: D020121:5' Untranslated Regions; C085108:APEX1 protein, human; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase