Genomic variations in paired normal controls for lung adenocarcinomas.

Li-Wei Qu,Gui-Zhen Wang,Guang-Biao Zhou,Bo Zhou,Ying Chen

doi:10.18632/oncotarget.22020

Abstract

Somatic genomic mutations in lung adenocarcinomas (LUADs) have been extensively dissected, but whether the counterpart normal lung tissues that are exposed to ambient air or tobacco smoke as the tumor tissues do, harbor genomic variations, remains unclear. Here, the genome of normal lung tissues and paired tumors of 11 patients with LUAD were sequenced, the genome sequences of counterpart normal controls (CNCs) and tumor tissues of 513 patients were downloaded from TCGA database and analyzed. In the initial screening, genomic alterations were identified in the “normal” lung tissues and verified by Sanger capillary sequencing. In CNCs of TCGA datasets, a mean of 0.2721 exonic variations/Mb and 5.2885 altered genes per sample were uncovered. The C:G→T:A transitions, a signature of tobacco carcinogen N-methyl-N-nitro-N-nitrosoguanidine, were the predominant nucleotide changes in CNCs. 16 genes had a variant rate of more than 2%, and CNC variations in MUC5B, ZXDB, PLIN4, CCDC144NL, CNTNAP3B, and CCDC180 were associated with poor prognosis whereas alterations in CHD3 and KRTAP5-5 were associated with favorable clinical outcome of the patients. This study identified the genomic alterations in CNC samples of LUADs, and further highlighted the DNA damage effect of tobacco on lung epithelial cells.

Highlights

Comprehensive sequencing efforts over the past decade have confirmed that cancer is a disease of the genome [1]
The C:G→T:A transitions, a signature of tobacco carcinogen N-methyl-N-nitro-N-nitrosoguanidine, were the predominant nucleotide changes in counterpart normal controls (CNCs). 16 genes had a variant rate of more than 2%, and CNC variations in MUC5B, ZXDB, PLIN4, CCDC144NL, CNTNAP3B, and CCDC180 were associated with poor prognosis whereas alterations in CHD3 and KRTAP5-5 were associated with favorable clinical outcome of the patients
Variations in 6 representative genes in the normal lung tissues were validated by RT-polymerase chain reaction (PCR) assays and subsequent sequencing, and the results confirmed the existence of CNC alterations (Figure 1)

Summary

Introduction

Comprehensive sequencing efforts over the past decade have confirmed that cancer is a disease of the genome [1]. Abnormalities in oncogenes and tumor suppressors act as driver mutations to initiate the onset and progression of cancers. These alterations are identified by comparing the cancer genome sequence with a reference human genome and excluding those found in normal controls (counterpart normal tissues or peripheral blood) and single nucleotide polymorphisms (SNPs) [2]. This strategy is effective to uncover somatic genomic alterations in tumor tissues. Whether there is any genomic alteration in counterpart normal controls (CNCs) but not cancer tissues, remains unclear

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