Breast cancer risk associated with genotypic polymorphism of the nonhomologous end-joining genes: a multigenic study on cancer susceptibility.
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.
Fu
Yi-Ping
YP
Institute of Biomedical Sciences, Academia Sinica, Taipei, 11529, Taiwan.
Yu
Jyh-Cherng
JC
Cheng
Ting-Chih
TC
Lou
M Ann
MA
Hsu
Giu-Cheng
GC
Wu
Chia-Yun
CY
Chen
Sou-Tong
ST
Wu
Hurng-Sheng
HS
Wu
Pei-Ei
PE
Shen
Chen-Yang
CY
D034961:Antigens, Nuclear / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics*; D016022:Case-Control Studies; D004249:DNA Damage; D004265:DNA Helicases; D000072481:DNA Ligase ATP; D011088:DNA Ligases / Q000235:genetics; D004260:DNA Repair / Q000235:genetics*; D051747:DNA-Activated Protein Kinase; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D000072200:Ku Autoantigen; D009687:Nuclear Proteins; D011110:Polymorphism, Genetic; D017346:Protein Serine-Threonine Kinases / Q000235:genetics
D034961:Antigens, Nuclear; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C101467:XRCC4 protein, human; D051747:DNA-Activated Protein Kinase; C497263:PRKDC protein, human; D017346:Protein Serine-Threonine Kinases; D004265:DNA Helicases; C106893:XRCC5 protein, human; C000606509:Xrcc6 protein, human; D000072200:Ku Autoantigen; D011088:DNA Ligases; D000072481:DNA Ligase ATP