Barroso E, Milne R L, Fernández L P, Zamora P, Arias J I, Benítez J, Ribas G
Human Genetics Group, Human Cancer Genetics Programme, Spanish National Cancer Centre (CNIO), Madrid, Spain.
Carcinogenesis. 2006 Sep;27(9):1930-7. doi: 10.1093/carcin/bgl062. Epub 2006 May 5.
Several components of the Fanconi anaemia (FA) family of proteins allow the formation of the DNA repair complex foci formed by proteins such as BRCA1/2 and RAD51. Because the genes that participate in the DNA repair pathway have been described as low-penetrance breast cancer susceptibility genes, we postulated that variants in FA genes could also be associated with sporadic breast cancer risk. We studied seven SNPs in FANCA, FANCL and FANCD2 in a total of 897 consecutive and non-related sporadic breast cancer cases and 1033 unaffected controls from the Spanish population. We observed a statistically significant association with sporadic breast cancer for the variant rs2272125 (L1366L) located on FANCD2 (OR per allele=1.35; 95% C.I. 1.09-1.67; P=0.005). Both haplotype and diplotype analyses confirmed this association, where one haplotype and pooled diplotypes carrying it were associated with more than 4-fold risk (P=0.007 and P=0.006, respectively). Screening for potential causal variants in FANCD2 was performed, detecting one in the putative promoter region, which is located in a phylogenetically conserved motif with consensus binding sites for some transcriptional factors, suggesting a functional implication. Our data indicate that a relationship between FANCD2 and sporadic breast cancer risk may exist.
范可尼贫血（FA）蛋白家族的几个组分可促使由BRCA1/2和RAD51等蛋白形成DNA修复复合灶。由于参与DNA修复途径的基因已被描述为低外显率乳腺癌易感基因，我们推测FA基因中的变异也可能与散发性乳腺癌风险相关。我们研究了西班牙人群中897例连续且无亲缘关系的散发性乳腺癌病例及1033例未受影响对照中FANCA、FANCL和FANCD2基因中的7个单核苷酸多态性（SNP）。我们观察到位于FANCD2基因上的变异rs2272125（L1366L）与散发性乳腺癌存在统计学显著关联（每个等位基因的比值比=1.35；95%置信区间1.09 - 1.67；P = 0.005）。单倍型和双倍型分析均证实了这种关联，其中一种单倍型以及携带它的合并双倍型与超过4倍的风险相关（分别为P = 0.007和P = 0.006）。我们对FANCD2基因中潜在的因果变异进行了筛查，在假定的启动子区域检测到一个变异，该区域位于一个具有某些转录因子共有结合位点的系统发育保守基序中，提示其具有功能意义。我们的数据表明FANCD2与散发性乳腺癌风险之间可能存在关联。
