Findlay J M, Middleton M R, Tomlinson I
Molecular and Population Genetics, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford; Oxford OesophagoGastric Centre.
NIHR Oxford Biomedical Research Centre, Churchill Hospital, Oxford, UK.
Ann Oncol. 2015 Apr;26(4):624-644. doi: 10.1093/annonc/mdu449. Epub 2014 Sep 11.
There is an urgent need for biomarkers to help predict prognosis and guide management of esophageal cancer. This review identifies, evaluates and meta-analyses the evidence for reported somatic and germline DNA sequence biomarkers of outcome and stage.
A systematic review was carried out of the PubMed, EMBASE and Cochrane databases (20 August 2014), in conjunction with the ASCO Level of Evidence scale for biomarker research. Meta-analyses were carried out for all reported markers associated with outcome measures by more than one study.
Four thousand and four articles were identified, 762 retrieved and 182 studies included. There were 65 reported markers of survival or recurrence 12 (18.5%) were excluded due to multiple comparisons. Following meta-analysis, significant associations were seen for six tumor variants (mutant TP53 and PIK3CA, copy number gain of ERBB2/HER2, CCND1 and FGF3, and chromosomal instability/ploidy) and seven germline polymorphisms: ERCC1 rs3212986, ERCC2 rs1799793, TP53 rs1042522, MDM2 rs2279744, TYMS rs34743033, ABCB1 rs1045642 and MTHFR rs1801133. Twelve germline markers of treatment complications were reported; 10 were excluded. Two tumor and 15 germline markers (11 excluded) of chemo (radio)therapy response were reported. Following meta-analysis, associations were demonstrated for mutant TP53, ERCC1 rs11615 and XRCC1 rs25487. There were 41 tumor/germline reported markers of stage; 27 (65.9%) were excluded.
Numerous DNA markers of outcome and stage have been reported, yet few are backed by high-quality evidence. Despite this, a small number of variants appear reliable. These merit evaluation in prospective trials, within the context of high-throughput sequencing and gene expression.
迫切需要生物标志物来帮助预测食管癌的预后并指导其治疗。本综述对已报道的与预后和分期相关的体细胞和种系DNA序列生物标志物的证据进行识别、评估和荟萃分析。
结合美国临床肿瘤学会（ASCO）生物标志物研究证据等级量表，对PubMed、EMBASE和Cochrane数据库（2014年8月20日）进行系统综述。对多项研究报道的与预后指标相关的所有标志物进行荟萃分析。
共识别出4004篇文章，检索到762篇，纳入182项研究。有65个已报道的生存或复发标志物，其中12个（18.5%）因多重比较被排除。经过荟萃分析，发现6种肿瘤变异（突变型TP53和PIK3CA、ERBB2/HER2、CCND1和FGF3的拷贝数增加以及染色体不稳定/倍性）和7种种系多态性存在显著关联：ERCC1 rs3212986、ERCC2 rs1799793、TP53 rs1042522、MDM2 rs2279744、TYMS rs34743033、ABCB1 rs1045642和MTHFR rs1801133。报道了12种治疗并发症的种系标志物；10种被排除。报道了2种肿瘤和15种（11种被排除）化疗（放疗）反应的种系标志物。经过荟萃分析，发现突变型TP53、ERCC1 rs11615和XRCC1 rs25487存在关联。有41种已报道的肿瘤/种系分期标志物；27种（65.9%）被排除。
已报道了许多与预后和分期相关的DNA标志物，但很少有得到高质量证据支持的。尽管如此，少数变异似乎是可靠的。这些值得在前瞻性试验中，在高通量测序和基因表达的背景下进行评估。
