Genome-Wide Scan Show Extra Copies of Sox2 in Deadly Lung Cancers

Researchers from several cancer research laboratories, including laboratories from Johns Hopkins, Genentech, the University of Texas Southwestern Medical Center and the University of Colorado Cancer Center have collaborated in a remarkable series of whole genome scans of lung cancers that reveal some potentially troubling results for the use of induced pluripotent stem cells.

Genome-wide scans use next generation sequencing to sequence the entire genome of cells. Such sequencing has dropped the price of DNA sequencing dramatically and also greatly accelerated the speed at which whole genome can be sequenced. Also, advances in computation all rapid comparison of the whole genome of cells allows rapid identification of mutations that might contribute to diseases.

These scientists used whole genome scans to examine very aggressive types of lung cancers, known as small cell lung cancer. Small cell lung cancer exhibits aggressive behavior, with rapid growth, and early spread to distant sites.

Among the mutations found in small cell lung cancers, these scientists, including those at the Johns Hopkins Kimmel Cancer Center, found an alteration in a gene called SOX2; a gene that is very active during early embryonic development.

Charles Rudin said: “Small cell lung cancers are very aggressive. Most are found late, when the cancer has spread and typical survival is less than a year after diagnosis. Our genomic studies may help identify genetic pathways responsible for the disease and give us new ideas on developing drugs to treat it.”

In this study, the research groups scanned the coding regions in the entire genomes of 63 small cell lung cancers. They also included 42 cancer samples whose sequenced genomes were matched with from the patients’ normal cells.

The scientists found an increase in the copy number of the SOX2 gene in about 27 percent of all screened small cell lung cancer samples. These copy number increases caused overproduction of proteins made by the SOX2 gene, and this plays a role in driving the abnormal cell growth observed in small cell lung cancer. Therefore, SOX2 offers a potential new target for those scientists working to develop new drugs to combat this intractable cancer. “SOX2 is an important clue in finding new ways to treat small cell lung cancer,” says Rudin. “We may be able to link a patient’s outcome to this gene and develop a drug to target it or other genes it regulates.” Rudin says his team will further explore the function of SOX2 and how to target it.

The SOX2 protein forms a complex with other proteins that bind to DNA and controls when and how genes are expressed. Sox2 is one of the four genes used by scientists to convert adult cells into an embryonic state. This study also seems to sound a caution to the use of induced pluripotent stem cells (iPSCs) in a clinical setting. iPSCs are made by overexpressing Sox2 and three other genes in adult cells. Overexpression of these genes de-differentiates adult cells to an embryonic state, but the activated growth also causes increased chances of acquiring mutations.

This study shows that acquisition of extra copies of Sox2 can increase the aggressive behavior of small cell lung cancers. However, iPSCs are made by endowing them with extra copies of the Sox2 gene. Also, the iPSC-derivation procedure tends to cause them to possess extra copies of particular regions of the genome too. Therefore, iPSCs would seem to be at risk for more aggressive, tumor-like behavior in the first place, and this would also seem to make iPSCs much more risky as treatment options than other options.

Having said all that, I must point out that induced pluripotent stem cell lines differ tremendously from one line to another, and clearly some iPSC lines have a greater tendency to cause tumors than others. Therefore, this finding is almost certainly not fatal to iPSCs. It just means that if iPSCs are going to be used for clinical purposes, they must be rigorously tested and evaluated for safety before they are used.

This study was published online Sept. 2 in Nature Genetics.