email powers@cshl.edu, phone (516) 422-4085

The goals of our research are (1) to use whole-genome technologies to identify candidate cancer genes and to evaluate their functional role in cell transformation and tumor biology, and (2) to use whole-genome technologies to guide development of novel cancer diagnostics and therapeutics. Our central approach has been DNA copy number analysis to pinpoint novel amplified oncogenes. We couple this genetic approach with functional studies to address candidate gene validity and oncogenic mechanism.

In the past five years, often in close collaboration with other laboratories at CSHL, we’ve discovered and validated nine novel amplified oncogenes that affect major human cancers, including breast, lung, prostate, and liver cancers.
Our discovery of amplified oncogenes not only provides new therapeutic targets but also can provide insights into mechanisms of cancer progression. We recently discovered and characterized the 14q13 amplicon that is involved in 15 to 20% of lung cancers. The 14q13 lung amplicon, besides being frequent, is notable in two aspects: first, all three genes within the amplicon play essential oncogenic roles and show pronounced synergy in promoting lung cell proliferation; and second, the 14q13 amplicon is observed only in lung tumors and not in other tumor types. The lung-tissue specificity of this amplicon is underscored by the tissue-specificity of the normal developmental role of these genes: they encode transcription factors that promote the proliferation and differentiation of fetal lung cells. This leads to an interesting hypothesis that the oncogenic mechanism of this common genetic event in lung cancer involves re-establishment of an earlier fetal gene expression program.

Finally, discovery of amplified oncogenes can provide a strong foothold on developing new diagnostics. Towards this end, we performed trancriptome analysis to determine whether the global effects these amplified transcription factor genes exerted on the gene expression program of normal lung epithelial cells could be used to uncover clinically useful subtypes of human lung cancer. In collaboration with a group at Duke University, we’ve found that gene expression patterns corresponding to different combinations of these transcription factor oncogenes can predict both sensitivity and resistance to cisplatin – the standard treatment for advanced lung cancer - with much greater accuracy than any predictor, including clinical parameters, previous genomic predictors, and p53 and K-ras status. This exciting result underscores the value of cancer genomics and provides a strong rationale for continuing efforts to uncover and characterize all of the frequent genomic alterations that drive the progression of human cancer.

Selected Publications

Harrison, M., Li, J., Degenhardt, Y., Hoey, T., and Powers, S. 2004. Wip1-deficient mice are resistant to common cancer genes. Trends Mol. Med. 10: 359–361.

Pei, L., Wiser, O., Slavin, A., Mu, D., Powers, S., Jan, L.Y., and Hoey, T. 2003. Oncogenic potential of TASK3 (KCNK9) depends on K⁺ channel function. Proc. Natl. Acad. Sci. USA 100: 7803–7807.

Mu, D., Chen, L., Zhang, X., See, L.H., Koch, C.M., Yen, C., Tong, J.J., Spiegel, L., Nguyen, K.C.Q., Servoss, A., Peng, Y., Pei, L., Marks, J.R., Lowe, S.W., Hoey, T., Jan, L.Y., McCombie, W.R., Wigler, M.H., and Powers, S. 2003. Genomic amplification and oncogenic properties of the KCNK9 potassium channel gene. Cancer Cell 3: 297–302.

Pei, L., Peng, Y., Yang, Y., Ling, X.B., Van Eyndhoven, W.G., Nguyen, K.C., Rubin, M., Hoey, T., Powers, S., and Li, J. 2002. PRC17, a novel oncogene encoding a Rab GTPase-activating protein, is amplified in prostate cancer. Cancer Res. 62: 5420–5424.

Li, J., Yang, Y., Peng, Y., Austin, R.J., van Eyndhoven, W.G., Nguyen, K.C., Gabriele, T., McCurrach, M.E., Marks, J.R., Hoey, T., Lowe, S.W., and Powers, S. 2002. Oncogenic properties of PPM1D located within a breast cancer amplification epicenter at 17q23. Nat. Genet. 31: 133–134.