Liu Li, Huang Jiao, Wang Ke, Li Li, Li Yangkai, Yuan Jingsong, Wei Sheng
Department of Epidemiology and Biostatistics, and the Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China.
Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China.
Oncotarget. 2015 Nov 10;6(35):38016-28. doi: 10.18632/oncotarget.5697.
In conjunction with clinical characteristics, prognostic biomarkers are essential for choosing optimal therapies to lower the mortality of lung adenocarcinoma. Whole genome sequencing (WGS) of 7 cancerous-noncancerous tissue pairs was performed to explore the comparative copy number variations (CNVs) associated with lung adenocarcinoma. The frequencies of top ranked CNVs were verified in an independent set of 114 patients and then the roles of target CNVs in disease prognosis were assessed in 313 patients. The WGS yielded 2604 CNVs. After frequency validation and biological function screening of top 10 CNVs, 9 mutant driver genes from 7 CNVs were further analyzed for an association with survival. Compared with the PBXIP1 amplified copy number, unamplified carriers had a 0.62-fold (95%CI = 0.43-0.91) decreased risk of death. Compared with an amplified TERT, those with an unamplified TERT had a 35% reduction (95% CI = 3%-56%) in risk of lung adenocarcinoma progression. Cases with both unamplified PBXIP1 and TERT had a median 34.32-month extension of overall survival and 34.55-month delay in disease progression when compared with both amplified CNVs. This study demonstrates that CNVs of TERT and PBXIP1 have the potential to translate into the clinic and be used to improve outcomes for patients with this fatal disease.
结合临床特征，预后生物标志物对于选择最佳治疗方案以降低肺腺癌死亡率至关重要。对7对癌组织与非癌组织进行全基因组测序（WGS），以探索与肺腺癌相关的比较拷贝数变异（CNV）。在一组独立的114例患者中验证了排名靠前的CNV的频率，然后在313例患者中评估目标CNV在疾病预后中的作用。WGS产生了2604个CNV。在对前10个CNV进行频率验证和生物学功能筛选后，对来自7个CNV的9个突变驱动基因与生存的相关性进行了进一步分析。与PBXIP1扩增拷贝数相比，未扩增携带者的死亡风险降低了0.62倍（95%CI = 0.43-0.91）。与TERT扩增相比，TERT未扩增者的肺腺癌进展风险降低了35%（95%CI = 3%-56%）。与两个CNV均扩增的病例相比，PBXIP1和TERT均未扩增的病例总生存期中位数延长了34.32个月，疾病进展延迟了34.55个月。本研究表明，TERT和PBXIP1的CNV有可能转化应用于临床，用于改善这种致命疾病患者的预后。
