Frankel Adam, Armour Nicola, Nancarrow Derek, Krause Lutz, Hayward Nicholas, Lampe Guy, Smithers B Mark, Barbour Andrew
Surgical Oncology Group, School of Medicine, The University of Queensland, Princess Alexandra Hospital, Woolloongabba, 4102 Brisbane, QLD 4006, Australia.
Genes Chromosomes Cancer. 2014 Apr;53(4):324-38. doi: 10.1002/gcc.22143. Epub 2014 Jan 21.
The incidence of esophageal adenocarcinoma (EAC) has been increasing rapidly for the past 3 decades in Western (Caucasian) populations. Curative treatment is based around esophagectomy, which has a major impact on quality of life. For those suitable for treatment with curative intent, 5-year survival is ∼30%. More accurate prognostic tools are therefore needed, and copy number aberrations (CNAs) may offer the ability to act as prospective biomarkers in this regard. We performed a genome-wide examination of CNAs in 54 samples of EAC using single-nucleotide polymorphism (SNP) arrays. Our aims were to describe frequent regions of CNA, to define driver CNAs, and to identify CNAs that correlated with survival. Regions of frequent amplification included oncogenes such as EGFR, MYC, KLF12, and ERBB2, while frequently deleted regions included tumor suppressor genes such as CDKN2A/B, PTPRD, FHIT, and SMAD4. The genomic identification of significant targets in cancer (GISTIC) algorithm identified 24 regions of gain and 28 regions of loss that were likely to contain driver changes. We discovered 61 genes in five regions that, when stratified by CNA type (gain or loss), correlated with a statistically significant difference in survival. Pathway analysis of the genes residing in both the GISTIC and prognostic regions showed they were significantly enriched for cancer-related networks. Finally, we discovered that copy-neutral loss of heterozygosity is a frequent mechanism of CNA in genes currently targetable by chemotherapy, potentially leading to under-reporting of cases suitable for such treatment.
在过去30年中，西方（高加索）人群中食管腺癌（EAC）的发病率一直在迅速上升。根治性治疗以食管切除术为基础，这对生活质量有重大影响。对于那些适合进行根治性治疗的患者，5年生存率约为30%。因此，需要更准确的预后工具，而拷贝数变异（CNA）在这方面可能具有作为前瞻性生物标志物的能力。我们使用单核苷酸多态性（SNP）阵列对54例EAC样本进行了全基因组CNA检测。我们的目的是描述CNA的常见区域，定义驱动CNA，并识别与生存相关的CNA。常见扩增区域包括EGFR、MYC、KLF12和ERBB2等癌基因，而常见缺失区域包括CDKN2A/B、PTPRD、FHIT和SMAD4等肿瘤抑制基因。癌症基因组识别重要靶点（GISTIC）算法确定了24个可能包含驱动变化的扩增区域和28个缺失区域。我们在五个区域发现了61个基因，根据CNA类型（扩增或缺失）进行分层时，这些基因与生存的统计学显著差异相关。对GISTIC区域和预后区域中的基因进行通路分析表明，它们在癌症相关网络中显著富集。最后，我们发现杂合性拷贝中性缺失是目前可通过化疗靶向的基因中CNA的常见机制，这可能导致适合此类治疗的病例报告不足。
