Publication

Genomic Landscape of Non-Small Cell Lung Cancer in Smokers and Never-Smokers

Lung cancer patients with a history of smoking have 10 times more genetic mutations in their tumors than those with the disease who have never smoked.

Cell. 2012 Sep 14;150(6):1121-34. doi: 10.1016/j.cell.2012.08.024.

Abstract

We report the results of whole-genome and transcriptome sequencing of tumor and adjacent normal tissue samples from 17 patients with non-small cell lung carcinoma (NSCLC). We identified 3,726 point mutations and more than 90 indels in the coding sequence, with an average mutation frequency more than 10-fold higher in smokers than in never-smokers. Novel alterations in genes involved in chromatin modification and DNA repair pathways were identified, along with DACH1, CFTR, RELN, ABCB5, and HGF. Deep digital sequencing revealed diverse clonality patterns in both never-smokers and smokers. All validated EFGR and KRAS mutations were present in the founder clones, suggesting possible roles in cancer initiation. Analysis revealed 14 fusions, including ROS1 and ALK, as well as novel metabolic enzymes. Cell-cycle and JAK-STAT pathways are significantly altered in lung cancer, along with perturbations in 54 genes that are potentially targetable with currently available drugs.

Data Access

Study Summary
Lung cancer is a leading cause of cancer-related death globally. Non-small cell lung cancer (NSCLC) is the most common type of lung cancer. Approximately 10-40% of patients diagnosed with lung cancer report no history of tobacco smoking. Researchers at The Genome Institute and collaborators are using whole genome sequencing of tumor and adjacent normal tissue and transcriptome sequencing of tumor samples from 17 patients with NSCLC to investigate the mutational burden, spectrum of mutation, and affected genes in lung cancer tumors and how they differ between smokers and non-smokers. Analyses of these genomes have identified mutations in genes not previously reported in lung cancer, as well as recurrent lung cancer mutations. They have observed marked differences between the tumor genomes of smokers and non-smokers, including an increase in mutation frequency in smokers, varying types of mutations, and specific genes affected. Studies such as these that use comprehensive genomic analysis contribute to the understanding of the molecular genetics of cancer and the development and application of therapy.

Study Inclusion Criteria
Tumor and adjacent normal tissue samples for whole genome sequencing and tumor and one normal transcriptome samples were obtained from patients diagnosed with non-small cell lung carcinoma (NSCLC) who underwent definitive surgical resection prior to receiving chemotherapy or radiation at the Alvin J Siteman Cancer Center at Washington University School of Medicine. All samples were subjected to pathology review to establish the histologic diagnosis and tumor cellularity. Only samples with tumor nuclei greater than or equal to 50% of total cellular nuclei in the section were utilized for this study.

Restricted Access
Washington University will distribute to approved users the final research data (including whole-genome and transcriptome) of the study examining the relationship between genomic data and phenotypes of patients with non-small cell lung cancer (Govindan R, Ding L, Griffith M, et al. Genomic landscape of non-small cell lung cancer in smokers and never-smokers. Cell, Sept. 13, 2012).

Data access is intended only for scientific investigators pursuing cancer research.

If you wish to access the data, please send your initial inquiry to
wu-nsclc@genome.wustl.edu and The Genome Institute will provide you with the documents required to apply for approval.

Related Links
Lung Cancer Genomics Project Page

Authors

Govindan R, Ding L, Griffith M, Subramanian J, Dees N, Kanchi K, Maher C, Fulton R, Fulton L, Wallis J, Chen K, Walker J, McDonald S, Bose R, Ornitz D, Xiong D, You M, Dooling D, Watson M, Mardis E, Wilson RK.