García-Closas Montserrat, Egan Kathleen M, Newcomb Polly A, Brinton Louise A, Titus-Ernstoff Linda, Chanock Stephen, Welch Robert, Lissowska Jolanta, Peplonska Beata, Szeszenia-Dabrowska Neonila, Zatonski Witold, Bardin-Mikolajczak Alicja, Struewing Jeffery P
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, 6120 Executive Boulevard, Room 7076, Rockville, MD 20952-7234, USA.
Hum Genet. 2006 May;119(4):376-88. doi: 10.1007/s00439-006-0135-z. Epub 2006 Feb 17.
The double-strand break DNA repair pathway has been implicated in breast carcinogenesis. We evaluated the association between 19 polymorphisms in seven genes in this pathway (XRCC2, XRCC3, BRCA2, ZNF350, BRIP1, XRCC4, LIG4) and breast cancer risk in two population-based studies in USA (3,368 cases and 2,880 controls) and Poland (1,995 cases and 2,296 controls). These data suggested weak associations with breast cancer risk for XRCC3 T241M and IVS7-14A>G (pooled odds ratio (95% confidence interval): 1.18 (1.04-1.34) and 0.85 (0.73-0.98) for homozygous variant vs wild-type genotypes, respectively), and for an uncommon variant in ZNF350 S472P (1.24 (1.05-1.48)), with no evidence for study heterogeneity. The remaining variants examined had no significant relationships to breast cancer risk. Meta-analyses of studies in Caucasian populations, including ours, provided some support for a weak association for homozygous variants for XRCC3 T241M (1.16 (1.04-1.30); total of 10,979 cases and 10,423 controls) and BRCA2 N372H (1.13 (1.10-1.28); total of 13,032 cases and 13,314 controls), and no support for XRCC2 R188H (1.06 (0.59-1.91); total of 8,394 cases and 8,404 controls). In conclusion, the genetic variants evaluated are unlikely to have a substantial overall association with breast cancer risk; however, weak associations are possible for XRCC3 (T241M and IVS7-14A>G), BRCA2 N372H, and ZNF350 S472P. Evaluation of potential underlying gene-gene interactions or associations in population subgroups will require even larger sample sizes.
双链断裂DNA修复途径与乳腺癌发生有关。我们在美国（3368例病例和2880例对照）和波兰（1995例病例和2296例对照）的两项基于人群的研究中，评估了该途径中七个基因（XRCC2、XRCC3、BRCA2、ZNF350、BRIP1、XRCC4、LIG4）的19个多态性与乳腺癌风险之间的关联。这些数据表明，XRCC3的T241M和IVS7-14A>G（纯合变异型与野生型基因型的合并比值比（95%置信区间）：分别为1.18（1.04 - 1.34）和0.85（0.73 - 0.98））以及ZNF350的S472P罕见变异型（1.24（1.05 - 1.48））与乳腺癌风险存在弱关联，且无研究异质性证据。所检测的其余变异型与乳腺癌风险无显著关系。对包括我们的研究在内的高加索人群研究进行的荟萃分析，为XRCC3的T241M纯合变异型（1.16（1.04 - 1.30）；共10979例病例和10423例对照）和BRCA2的N372H（1.13（1.10 - 1.28）；共13032例病例和13314例对照）的弱关联提供了一些支持，而对XRCC2的R188H（1.06（0.59 - 1.91）；共8394例病例和8404例对照）则无支持。总之，所评估的基因变异型不太可能与乳腺癌风险存在实质性的总体关联；然而，XRCC3（T241M和IVS7-14A>G）、BRCA2的N372H和ZNF350的S472P可能存在弱关联。评估人群亚组中潜在的基因-基因相互作用或关联需要更大的样本量。
