Abstract
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.
Highlights
Lung adenocarcinoma contributes to over 500,000 deaths annually and an average 5-year survival rate of less than 15% despite great advances in cancer therapy [1]
Seven male lung adenocarcinoma patients who were smokers and had no family history of cancer were recruited to participate in whole genome sequencing (WGS)
Samples from 114 patients with lung adenocarcinoma that had been diagnosed by histology were used to validate the frequencies of top 10 copy number variations (CNVs) by quantitative polymerase chain reaction
Summary
Lung adenocarcinoma contributes to over 500,000 deaths annually and an average 5-year survival rate of less than 15% despite great advances in cancer therapy [1]. Molecular biomarkers, especially single nucleotide polymorphisms (SNPs), assessing an individual’s genetic predisposition for diseases have shown potential for guiding clinical treatment of lung cancer [4,5,6]. Increasing evidence suggests that copy number variations (CNVs) may account for a large proportion of the heritability of lung cancer [7,8,9]. By whole genome sequencing (WGS) or target sequencing, some studies have demonstrated the prognostic prediction role www.impactjournals.com/oncotarget of high copy number alteration burden in the prostate cancer relapse [15], FGFR1 and PIK3CA amplifications in oral cavity squamous cell carcinoma [16], and MYC amplification in pancreatic adenosquamous carcinoma and lung adenocarcinomas [17, 18]
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