Table_1_Comprehensive Profiling of Gene Copy Number Alterations Predicts Patient Prognosis in Resected Stages I–III Lung Adenocarcinoma.XLSX

Background: Lung adenocarcinoma (LUAD) possesses a poor prognosis with a low 5-year survival rate even for stages I-III resected patients, it is thus critical to understand the determinants that affect the survival and discover new potentially prognostic biomarkers. Somatic copy number alterations (CNAs) are major source of genomic variations driving tumor evolution, CNAs screening may identify prognostic biomarkers.Methods: Oncoscan MIP array was used to analyze the patterns of CNAs on formalin fixed paraffin embedded(FFPE) tumor specimens from 163 consecutive stage I-III resected LUAD patients, 145 out of which received platinum-based adjuvant chemotherapy.Results: Of the 163 patients, 91(55.8%) were recurred within 3 years after surgery. The most common aberrations in our cohort were 1q, 5p, 5q, 7p, 8q, 14p, 16p, 17q, 20q for copy number gains and 8p, 9p, 13p, 16q, 18q for losses. The GISTIC2 analysis produced 45 amplification peaks and 40 deletion peaks, involving some reported genes TERT, EGFR, MYC, CCND1, CDK4, MDM2, ERBB2, NKX2-1, CCNE1, and CDKN2A, most of which were consistent with TCGA database. The amplifications of 12p12.1 (CMAS, GOLT1B, YS2, LDHB, RECQL, ETNK1, IAPP, PYROXD1, KRAS) and KDM5A were correlated with worse prognosis in our cohort, this result was further validated in 506 LUAD patients from TCGA. In addition, 163 patients could be well-classified into five groups, and the clinical outcomes were significantly different based on threshold copy number at reoccurring alteration peaks. Among the 145 patients who received adjuvant chemotherapy, focal amplification of ERBB2 and deletion of 4q34.3 were found to be specific in relapsed patients, this result was validated in an independent group of Imielinski et al., demonstrating these two CNAs may contribute to resected LUAD recurrence after adjuvant chemotherapy.Conclusion: This study suggests that CNAs profiling may be a potential prognostic classifier in resected LAUD patients. Amplifications of 12p12.1 and KDM5A might be prognostic biomarkers for LUAD, and amplification of ERBB2 and deletion of 4q34.3 predicted early relapse after adjuvant chemotherapy. These novel findings may provide implication for better implementation of precision therapy for lung cancer patients.

背景：肺腺癌（LUAD）预后较差，即便对于I-III期切除患者，其5年生存率亦较低，因此，理解影响患者生存的决定因素并发现新的潜在预后生物标志物至关重要。体细胞拷贝数改变（CNAs）是驱动肿瘤进化的基因组变异的主要来源，CNAs的筛查可能识别出预后生物标志物。方法：本研究采用Oncoscan MIP阵列分析163名连续I-III期切除的LUAD患者的石蜡包埋（FFPE）肿瘤标本中的CNAs模式，其中145名患者接受了基于铂的辅助化疗。结果：在163名患者中，91名（55.8%）在术后3年内出现复发。我们队列中最常见的异常包括1q、5p、5q、7p、8q、14p、16p、17q、20q的拷贝数增加和8p、9p、13p、16q、18q的拷贝数减少。GISTIC2分析产生了45个扩增峰和40个删除峰，涉及一些已报道的基因，如TERT、EGFR、MYC、CCND1、CDK4、MDM2、ERBB2、NKX2-1、CCNE1和CDKN2A，其中大部分与TCGA数据库一致。12p12.1（CMAS、GOLT1B、YS2、LDHB、RECQL、ETNK1、IAPP、PYROXD1、KRAS）和KDM5A的扩增与队列中较差的预后相关，这一结果在TCGA的506名LUAD患者中得到进一步验证。此外，163名患者可以根据复发改变峰的阈值拷贝数被良好地分为五组，临床结果基于这些阈值拷贝数存在显著差异。在145名接受辅助化疗的患者中，ERBB2的局部扩增和4q34.3的删除在复发患者中具有特异性，这一结果在Imielinski等人的独立组中得到验证，表明这两种CNAs可能参与辅助化疗后切除的LUAD复发。结论：本研究表明，CNAs分析可能成为切除性LAUD患者潜在的预后分类器。12p12.1和KDM5A的扩增可能是LUAD的预后生物标志物，而ERBB2的扩增和4q34.3的删除预示着辅助化疗后早期复发。这些新颖的发现可能对肺癌患者实施精准治疗具有启示意义。