If you look very closely, possibly with the aid of a magnifying glass, you’ll see my name among the authorship lists for two articles in the October 23 issue of Nature. The first of these is the Cancer Genome Atlas (TCGA) study of glioblastoma that came online a couple of weeks ago. The second is a study of lung adenocarcinoma, through the Tumor Sequencing Project (TSP). Both articles are the fruits of large-scale candidate gene resequencing efforts by genome centers at Washington University, Baylor, and the Broad Institute (MIT/Harvard).

One of the most interesting, if unsurprising, findings of the lung adenocarcinoma study was that the numbers of mutations per tumor were substantially higher in smokers than non-smokers. If you ever doubted the evidence that connects smoking to lung cancer, listen up. Tumors from smokers had as many as 49 mutations, whereas those from non-smokers never had more than 10. One basic way to interpret this: if you smoke, you have five times as many mutations as someone who doesn’t. Five times as many chances to have a mutation that leads to cancer.

Highly-Mutated Genes in the mTOR Pathway

A high-level view at the molecular pathways we studied for TSP reveals that some genes are mutated far more often than others. In the mTOR pathway, for example, highly-mutated genes included both oncogenes (RAS, EGFR, MDM2) and tumor-suppressor genes (TP53, STK11, CDKN2A). More than a third of the patients studied has mutations in this pathway, suggesting that rapamycin (whose target is mTOR) offers a promising therapy.

Sequence-based LOH Analysis

One of the genes we studied (STK11) did not have SNP-chip data. To examine potential LOH in STK11, we sequenced both tumors and normals at positions of known high-frequency variants. Then, we compared the tumor genotype to the normal genotype for each sample at each position. Several samples had extensive LOH in the tumor across STK11, suggesting a large-scale structural event (probably a deletion) across the gene region. There were even a couple of samples with both LOH and mutations in STK11; these patients are probably 0 for 2 on functioning proteins encoded by this tumor suppressor.

The Future of Cancer Genomics

It seems to me that TSP, TCGA, and other large-scale initiatives are yielding a wealth of information about cancer genomics. And these were all 3730-based sequencing efforts. I can hardly imagine the things we’ll learn from studies that apply next-generation sequencing platforms. You can bet they’re on the way.