October 8, 2009
Researchers track down cancer-causing gene in some lung and esophageal cancers
Within a stretch of chromosome bristling with extra genetic material in a common form of lung and esophageal cancers, Dana-Farber investigators have found a cancer-causing gene called SOX2.
In a study published on the Nature Genetics website, Dana-Farber's Adam Bass, MD, Hideo Watanabe, MD, Matthew Meyerson, MD, PhD, and colleagues report that SOX2 is an oncogene – able to turn normal cells cancerous – and especially plentiful in squamous cell cancers of the lung and esophagus (food pipe). Such cancers account for about half of esophageal cancers in the United States (and 80-90 percent worldwide) and about 20 percent of non-small cell lung cancers worldwide.
In its normal state, SOX2 is active in stem cells at the earliest phase of life and also guides the development of the lungs and esophagus in the embryo. In adults, the gene seems to be most active in the less-developed, "primitive" cells of the esophagus and airway, where it helps these cells proliferate and patch up damaged or injured tissue. It had not, however, been previously implicated in causing cancer in these tissues. The discovery that SOX2 can be an oncogene will be of particular value in the field of stem cell research, where researchers are exploring ways of producing stem cells that can be used to regenerate damaged or diseased tissue, Bass explains.
"In recent years scientists have developed techniques for converting normal adult cells, such as skin cells, into stem cells that could, theoretically, give rise to a variety of different tissue types," he says. "This is accomplished by introducing a small number of genes to reset the cells' basic programming. One of the genes most often added in these techniques is SOX2. Researchers will need to bear in mind that SOX2 has the potential to be an oncogene as cell-reprogramming methods are refined."
Avidly seeking oncogenes
To find potential oncogenes in lung and esophageal squamous cell cancers, researchers scanned samples of the two malignancies looking for areas of "genomic amplification" – sections of chromosome with extra copies of genes. Such regions often turn out to be the lair of oncogenes. The area of greatest amplification was found on chromosome 3q26.33, and the gene most over-copied in that zone was SOX2.
SOX2 is a transcription factor gene – in effect, an on-off switch for other genes – that normally plays a role in forming the esophagus and trachea (the main air trunk of the lungs), and cooperates with other genes to produce mature, specialized cells in those tissues from stem cells. When researchers lowered SOX2's activity in cells with above-normal copies of the gene, the cells did not grow as well. When they added copies of SOX2 to normal cells, the cells became cancerous. These findings confirmed that SOX2 is indeed an oncogene.
Transcription factor genes tend to be very difficult to stifle with drugs, Bass says, but knowing that SOX2 is involved in squamous cell cancers of the lung and esophagus may allow scientists to develop drugs against genes activated by SOX2 that are essential to the tumors.
Dana-Farber co-authors of the study include Craig Mermel; Soyoung Yu; Roel Verhaak, PhD; So Young Kim, PhD; Leslie Wardwell; Alex Ramos; Michele Woo, PhD; Barbara Weir, PhD; Rameen Beroukhim, MD, PhD; Amit Dutt, PhD; Orit Rozenblatt-Rosen, PhD; Piotr Dziunycz; Justin Komisarof; Ramesh Shivdasani, MD, PhD; Kwok-Kin Wong, MD, PhD; and William Hahn, MD, PhD.
— Rob Levy
Robert_Levy@dfci.harvard.edu
Scans showed that lung and esophageal squamous cancer cells have extra genetic material on a region of chromosome called 3q26.33, which is the site of the cancer-causing gene SOX2.
