Integrated Genomic Study Uncovers Mutations Linked to Lung Cancer

Cancer researchers have integrated DNA sequencing, gene expression, and DNA copy number data in a large-scale genomic study of lung adenocarcinoma that calls attention to several important signaling pathways and suggests new molecular targets for treatment.

Investigators at Harvard University (Cambridge, MA, USA) were members of a large team that participated in a pilot project (the Tumor Sequencing Project or TSP) that investigated how various genomic technologies could be effectively applied and integrated to reveal the molecular underpinnings of lung adenocarcinoma. The report, which appeared in the October 23, 2008, online edition of the journal Nature, presented data obtained from studying 188 primary lung adenocarcinoma samples.

DNA sequencing of 623 genes with known or potential relationships to cancer revealed more than 1,000 somatic mutations across the samples. Analysis identified 26 genes that were mutated at significantly high frequencies and thus were probably involved in carcinogenesis. While some of these mutations were in genes already linked to lung adenocarcinoma, a substantial number were previously unrecognized. For example, the NF1, ATM, RB1, and APC genes, which had not before been associated with lung cancer, were mutated in a significant portion of the lung tumors analyzed. Mutations were also found that clustered in several groups of related tyrosine kinase genes, including the EGF, EPH, FGF, NTRK, and VEGF receptor gene families. Several of the mutated genes were tumor suppressors that already had been found to be involved in other cancers.

"DNA copy number analysis and gene expression analysis respectively, together with advanced computational methods, helped provide a detailed view of the genomic landscape of lung cancer,” explained contributing author Dr. Matthew Myerson, professor of oncology at Harvard University. "Integrative approaches like these allow us to more clearly pinpoint important genes than a single method alone would. One of the key findings from our study is that some of the newly discovered genes and pathways that are mutated in lung cancer are also known to be defective in other cancers. That gives us hope that targeted therapies could be used across multiple cancer types.”

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