Human Genetics Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
Helleday Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden.
Mol Oncol. 2019 May;13(5):1110-1120. doi: 10.1002/1878-0261.12470. Epub 2019 Mar 1.
Single nucleotide polymorphisms (SNPs) in DNA glycosylase genes involved in the base excision repair (BER) pathway can modify breast and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers. We previously found that SNP rs34259 in the uracil-DNA glycosylase gene (UNG) might decrease ovarian cancer risk in BRCA2 mutation carriers. In the present study, we validated this finding in a larger series of familial breast and ovarian cancer patients to gain insights into how this UNG variant exerts its protective effect. We found that rs34259 is associated with significant UNG downregulation and with lower levels of DNA damage at telomeres. In addition, we found that this SNP is associated with significantly lower oxidative stress susceptibility and lower uracil accumulation at telomeres in BRCA2 mutation carriers. Our findings help to explain the association of this variant with a lower cancer risk in BRCA2 mutation carriers and highlight the importance of genetic changes in BER pathway genes as modifiers of cancer susceptibility for BRCA1 and BRCA2 mutation carriers.
DNA 糖基化酶基因中的单核苷酸多态性 (SNPs) 参与碱基切除修复 (BER) 途径，可改变 BRCA1 和 BRCA2 突变携带者的乳腺癌和卵巢癌风险。我们之前发现，UNG 基因中的 SNP rs34259 可能降低 BRCA2 突变携带者的卵巢癌风险。在本研究中，我们在更大系列的家族性乳腺癌和卵巢癌患者中验证了这一发现，以深入了解这种 UNG 变体如何发挥其保护作用。我们发现 rs34259 与 UNG 的显著下调以及端粒处 DNA 损伤水平降低有关。此外，我们发现该 SNP 与 BRCA2 突变携带者中端粒处的氧化应激易感性降低和尿嘧啶积累减少显著相关。我们的研究结果有助于解释该变体与 BRCA2 突变携带者中较低的癌症风险相关联，并强调了 BER 途径基因中的遗传变化作为 BRCA1 和 BRCA2 突变携带者癌症易感性修饰因子的重要性。
