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TSP Consortium Uncovers Lung Cancer Culprits Using Genomic Approaches

NEW YORK (GenomeWeb News) – An international team of researchers has integrated gene sequencing, SNP array, and gene expression data to begin characterizing lung adenocarcinoma, the most common form of lung cancer. The work, the largest such study on lung adenocarcinoma so far, appears online today in Nature.
The Tumor Sequencing Project consortium sequenced more than six hundred genes in lung cancer tumors from nearly 200 individuals, uncovering dozens of new lung cancer gene mutations. By combining this information with copy number and gene expression data, the researchers were able to pinpoint genes and pathways that are frequently altered during lung adenocarcinoma.
And, they said, by looking at subgroups of patients with different tumor features, smoking status, and other variables, the researchers gained insight into tumor biology as well as potential treatments.
“By harnessing the power of genomic research, this pioneering work has painted the clearest and most complete portrait yet of lung cancer’s molecular complexities,” National Human Genome Research Institute acting director Alan Guttmacher, said in a statement. “This big picture perspective will help to focus our research vision and speed our efforts to develop new strategies for disarming this common and devastating disease.”
Lung cancer causes more than a million deaths each year. And lung adenocarcinoma, a type of non-small cell lung cancer, is the most commonly diagnosed type of lung cancer. The disease is difficult to treat and has a five-year survival rate of roughly 15 percent.
Prior to this study, just a handful of genes had been linked to lung adenocarcinoma. In an effort to flesh out that list and start deciphering the biological changes associated with the lung cancer, the TSP team sequenced 623 genes that were known or suspected to contribute to cancer formation in 188 lung cancer patients and matched controls.
By combining mutation information with copy number and expression data for 41 lung adenocarcinomas, they were also able to determine whether specific mutations affected gene activity and/or copy number.
“Integrative approaches like these allow us to more clearly pinpoint important genes than a single method alone would,” co-senior author Matthew Meyerson, a researcher affiliated with the Broad Institute and the Dana-Farber Cancer Institute, said in a statement.
The researchers detected 1,013 non-synonymous somatic mutations in 163 of these lung tumors. Most of these — more than 900 — were point mutations, though the researchers also detected insertions, deletions, and dinucleotide mutations.
Overall, the researchers found 26 genes that were most often mutated in lung adenocarcinoma. Among them: some genes that had not previously been tied to lung cancer, but which have been linked to other types of cancer.
For instance, the team unearthed mutations in potential tumor suppressors, including NF1, a gene that is inactivated in those with a nervous system disease called neurofibromatosis; ATM, a cell-cycle checkpoint kinase gene that is mutated in an inherited neurological disorder and in some leukemia and lymphoma; RB1, a susceptibility gene for retinoblastoma; and APC, a gene that is frequently mutated in colon cancer.
Along with potential tumor suppressor genes, which tend to be less active in tumors, the team also found proto-oncogenes that tend to become more active in tumor cells, including the EGFR homolog ERBB4.
And once researchers began placing the individual mutations into pathways the complex picture started becoming a bit clearer.
“Generally we found that each mutation only occurs in a small percentage of the tumor samples,” co-senior author Richard Wilson, director of Washington University’s Genome Sequencing Center, said in a statement, “but when we looked at all the mutations that intersect a particular signaling pathway, we were surprised to find a lot of overlap in only a handful of pathways. This gives us a much better idea of what goes wrong in cells when they become cancerous.”
For instance, genes involved in the MAP kinase pathway were mutated in some 70 percent of tumors tested. About half of the tumors tested had one or more mutations in the p53 pathway, while components of the mTOR pathway, a signaling pathway associated with tuberous sclerosis, were mutated in about a third of the tumors.
The researchers also began classifying mutations by clinical subgroup, allowing them to draw distinctions between mutations in smokers and non-smokers and based on tumor grade and histology. For example, smokers’ tumors contained as many as 49 mutations, while tumors from those who had never smoked had less than five mutations. In addition, smokers were more likely to carry KRAS mutations whereas those who’d never smoked frequently had tended to have EGFR mutations.
In the future, researchers say, applying such approaches to larger patient groups and a broader range of cancers could provide even more information about lung cancer and other cancers — and eventually guide more personalized cancer treatment.
“Clearly much still remains to be discovered,” co-author Richard Gibbs, director of Baylor College of Medicine’s Human Genome Sequencing Center, said in a statement. “We have just begun to realize the tremendous potential of large-scale, genomic studies to unravel the many mysteries of cancer.”
The TSP, which began as an NHGRI-funded pilot project for characterizing cancer genomes, is intended to complement another NHGRI-funded project, the Cancer Genome Atlas. Last month, TCGA reported that it had characterized a type of brain cancer called glioblastoma. That group is also working on unraveling the genetics of squamous cell lung cancer and ovarian cancer.

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