Fonville Natalie C, Vaksman Zalman, McIver Lauren J, Garner Harold R
Virginia Bioinformatics Institute, Virginia Tech, Blacksburg, VA 24061, USA.
Oncotarget. 2015 May 10;6(13):11407-20. doi: 10.18632/oncotarget.2933.
Ovarian cancer (OV) ranks fifth in cancer deaths among women, yet there remain few informative biomarkers for this disease. Microsatellites are repetitive genomic regions which we hypothesize could be a source of novel biomarkers for OV and have traditionally been under-appreciated relative to Single Nucleotide Polymorphisms (SNPs). In this study, we explore microsatellite variation as a potential novel source of genomic variation associated with OV. Exomes from 305 OV patient germline samples and 54 tumors, sequenced as part of The Cancer Genome Atlas, were analyzed for microsatellite variation and compared to healthy females sequenced as part of the 1,000 Genomes Project. We identified a subset of 60 microsatellite loci with genotypes that varied significantly between the OV and healthy female populations. Using these loci as a signature set, we classified germline genomes as 'at risk' for OV with a sensitivity of 90.1% and a specificity of 87.6%. Cross-analysis with a similar set of breast cancer associated loci identified individuals 'at risk' for both diseases. This study revealed a genotype-based microsatellite signature present in the germlines of individuals diagnosed with OV, and provides the basis for a potential novel risk assessment diagnostic for OV and new personal genomics targets in tumors.
卵巢癌（OV）在女性癌症死亡原因中位列第五，但针对该疾病的信息丰富的生物标志物仍然很少。微卫星是基因组中的重复区域，我们推测其可能是OV新型生物标志物的来源，并且相对于单核苷酸多态性（SNP）而言，传统上一直未得到充分重视。在本研究中，我们探索微卫星变异作为与OV相关的潜在新型基因组变异来源。对作为癌症基因组图谱一部分进行测序的305份OV患者种系样本和54份肿瘤的外显子组进行微卫星变异分析，并与作为千人基因组计划一部分进行测序的健康女性进行比较。我们鉴定出60个微卫星位点的一个子集，其基因型在OV和健康女性群体之间存在显著差异。使用这些位点作为特征集，我们将种系基因组分类为OV“高危”，灵敏度为90.1%，特异性为87.6%。与一组类似的乳腺癌相关位点进行交叉分析，确定了同时患有两种疾病的“高危”个体。这项研究揭示了在被诊断为OV的个体种系中存在基于基因型的微卫星特征，并为OV潜在的新型风险评估诊断和肿瘤新的个人基因组学靶点提供了基础。
