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

Apurinic/apyrimidinic endonuclease 1 (APEX1) is a multifunctional protein which plays a central role inthe BER pathway. APEX1 gene being highly polymorphic in cancer patients and has been indicated to havea contributive role in Apurinic/apyrimidinic (AP) site accumulation in DNA and consequently an increasedrisk of cancer development. In this case-control study, all exons of the APEX1 gene and its exon/intronboundaries were amplified in 530 breast cancer patients and 395 matched healthy controls and then analyzedby single-stranded conformational polymorphism followed by sequencing. Sequence analysis revealed fourteenheterozygous mutations, seven 5’UTR, one 3´UTR, two intronic and four missense. Among identified mutationsone 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’UTRregion, 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 APEX1mutations 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 missensemutations [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 familyhistory and with early menopause. In conclusion, our study demonstrates a significant association between germline APEX1 mutations and breast cancer patients in the Pakistani population.