家族性乳腺癌易感基因的作用,BRCA1和BRCA2在DNA双链断裂(DSB)修复的同源重组途径中表明,涉及DNADSB修复的机制在乳腺肿瘤发生过程中具有特别的病因学重要性。然而,目前没有证据表明乳腺癌与其他DSB修复途径之间存在关联,非同源末端连接(NHEJ)途径。有可能,因为这种DNA修复途径对于哺乳动物细胞维持基因组稳定性至关重要,任何严重的缺陷都会导致严重的后果,例如基因组不稳定和细胞死亡,并阻断随后的细胞生长和肿瘤形成。因此,只有低外显率等位基因产生的细微缺陷才能避免致死性积累的基本遗传变化,并与癌症形成有关,如果每个NHEJ基因的个体推定的高风险基因型共同作用,这些等位基因的致瘤作用将变得更加明显。此外,这种联合效应可能会被特定的环境因素所改变,我们假设雌激素暴露可能是这样一个因素,因为雌激素被认为会导致DNADSB,引发乳腺肿瘤发生。因为单核苷酸多态性(SNPs)是基因组中最微妙的遗传变异,为了检验这些假设,我们对所有五个NHEJ基因(Ku70,Ku80,DNA-PKcs,连接酶IV,和XRCC4)在254例原发性乳腺癌患者和379例健康对照中。这些假设的支持来自以下观察:(a)Ku70和XRCC4中的两个SNP与乳腺癌风险相关(P<0.05);(b)在具有更多NHEJ基因的推定高风险基因型的女性中发现了患乳腺癌风险增加的趋势(具有一个另外的推定高风险基因型的校正比值比为1.46;95%置信区间,1.19-1.80);(c)在被认为更易感雌激素的女性中,风险与推定的高风险基因型数量之间的这种关联更强,更显著,即,无足月妊娠史的患者;(d)足月妊娠史赋予的保护作用仅在NHEJ基因的推定高危基因型较低的女性中显著.基于全面的NHEJ基因谱,这项研究提供了新的见解,表明NHEJ途径在乳腺癌发展中的作用,并支持乳腺癌是由雌激素暴露引发的可能性,导致DNADSB。
The role of the familial breast cancer susceptibility genes, BRCA1 and BRCA2, in the homologous recombination pathway for DNA double-strand break (DSB) repair suggests that the mechanisms involved in DNA DSB repair are of particular etiological importance during breast tumorigenesis. However, there is currently no evidence for an association between breast cancer and the other DSB repair pathway, the nonhomologous end-joining (NHEJ) pathway. It is possible that, because this DNA repair pathway is so crucial for mammalian cells to maintain genomic stability, any severe defects in it would result in serious outcomes, such as genomic instability and cell death, and block subsequent cell outgrowth and tumor formation. Thus, only subtle defects arising from low-penetrance alleles would escape lethality accumulating essential genetic changes and be associated with cancer formation, and the tumorigenic contribution of these alleles would become more obvious if individual putative high-risk genotypes of each NHEJ gene act jointly. Furthermore, this joint effect might be modified by specific environmental factors, and we hypothesized that estrogen exposure might be one such factor because estrogen is suggested to cause DNA DSBs, triggering breast tumorigenesis. Because single nucleotide polymorphisms (SNPs) are the most subtle genetic variation in the genome, to examine these hypotheses, we have genotyped 30 SNPs in all five NHEJ genes (Ku70, Ku80, DNA-PKcs, Ligase IV, and XRCC4) in 254 primary breast cancer patients and 379 healthy controls. Support for these hypotheses came from the observations that (a) two SNPs in Ku70 and XRCC4 were associated with breast cancer risk (P < 0.05); (b) a trend toward increased risk of developing breast cancer was found in women harboring a greater number of putative high-risk genotypes of NHEJ genes (an adjusted odds ratio of 1.46 for having one additional putative high-risk genotype; 95% confidence interval, 1.19-1.80); (c) this association between risk and the number of putative high-risk genotypes was stronger and more significant in women thought to be more susceptible to estrogen, i.e., those with no history of full-term pregnancy; and (d) the protective effect conferred by a history of full-term pregnancy was only significant in women with a lower number of putative high-risk genotypes of NHEJ genes. Based on comprehensive NHEJ gene profiles, this
study provides new insights to suggest the role of the NHEJ pathway in breast cancer development and supports the possibility that breast cancer is initiated by estrogen exposure, which causes DNA DSBs.