Ali Kashif, Mahjabeen Ishrat, Sabir Maimoona, Baig Ruqia Mehmood, Zafeer Maryam, Faheem Muhammad, Kayani Mahmood Akhtar
Department of Biosciences, COMSATS Institute of Information and Technology, Islamabad, Pakistan E-mail :
Asian Pac J Cancer Prev. 2014;15(18):7589-95. doi: 10.7314/apjcp.2014.15.18.7589.
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) and5 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.
脱嘌呤/脱嘧啶内切酶1（APEX1）是一种多功能蛋白，在碱基切除修复（BER）途径中起核心作用。APEX1基因在癌症患者中具有高度多态性，并且已表明其在DNA中脱嘌呤/脱嘧啶（AP）位点积累中起促进作用，因此增加了癌症发生的风险。在这项病例对照研究中，对530例乳腺癌患者和395例匹配的健康对照者的APEX1基因的所有外显子及其外显子/内含子边界进行了扩增，然后通过单链构象多态性分析，随后进行测序。序列分析揭示了14个杂合突变，其中7个在5'非翻译区（UTR），1个在3'UTR，2个在内含子，4个为错义突变。在已鉴定的突变中，一个5'UTR（rs41561214）、一个3'UTR（rs17112002）和一个错义突变（Ser129Arg，Mahjabeen等人，2013年）已经被报道，而其余11个突变。在5'UTR区域观察到6个新突变（g.20923366T>G、g.20923435G>A、g.20923462G>A、g.20923516G>A、20923539G>A、g.20923529C>T），在内含子1中观察到2个（g.20923585T>G、g.20923589T>G），在外显子4中观察到3个错义突变（Glu101Lys、Ala121Pro、Ser123Trp）。5'UTR突变g.20923366T>G、g.20923435G>A和3'UTR（rs17112002）的频率分别计算为0.13、0.1和0.1。而错义突变Glu101Lys、Ser123Trp和Ser129Arg的频率计算为0.05。观察到APEX1突变与乳腺癌增加之间存在显著关联，g.20923435G>A（5'UTR）使乳腺癌风险增加约9倍（OR=8.68，95%CI=2.64至28.5），g.20923539G>A（5'UTR）使乳腺癌风险增加约13倍（OR=12.6，95%CI=3.01至53.0），三个错义突变[Glu101Lys（OR=4.82，95%CI=1.97至11.80）、Ser123Trp（OR=4.62，95%CI=1.7至12.19）、Ser129Arg（OR=4.86，95%CI=1.43至16.53）]使乳腺癌风险增加约5倍。观察到的突变发生率在有家族病史和早绝经的患者中更高。总之，我们的研究表明在巴基斯坦人群中，种系APEX1突变与乳腺癌患者之间存在显著关联。
