In this laboratory, we elucidate the molecular genetic changes that drive the progression of various types of cancer. We concentrate on identifying new genetic changes in smoking-associated tumors including lung cancer, head and neck cancer, and bladder cancer. We also investigate the molecular epidemiology of smoking-induced cancers and the link between tobacco smoke and mutations of critical oncogenes. Two recent discoveries are now driving our basic research—p63, a p53 family member, is commonly amplified in SCC and drives cancer progression. We know that WT p53 binds to p63 and degrades p63. Moreover, p63 binds to B56/PP2A, resulting in upregulation of b-catenin and downstream signaling. We also recently discovered BRAF mutations in 70 percent of thyroid tumors. We are identifying downstream signaling mechanisms for BRAF and are working with new BRAF inhibitors for targeted molecular therapy.
Our laboratory is best known for our efforts in molecular-detection approaches based on the identification of clonal genetic changes in many bodily fluids, including urine, saliva, stool and blood. Several major recent innovations in this area have been pioneered by our laboratory. Many of these approaches, such as the hypermethylation of p16 in human cancers and the discovery of mitochondrial mutations at high frequency in many tumor types have shed new light in the field of cancer biology and detection. We also discovered that circulating free DNA was in fact derived from tumor cells by showing that this DNA shared the identical genetic changes present in the primary tumor. This approach may one day lead to a simple blood test to detect cancers at an early stage. Our team also has led new approaches in molecular staging based on the identification of micrometastatic disease in various tumors. This approach may one day be the standard for staging patients with cancer and will allow for more aggressive therapy in patients with minimal residual disease. No matter what area we research, we always try to bridge basic research into the clinical setting.
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- Roh, J.L.; Kang, S.K.; Minn, I.; Califano, J.A.; Sidransky, D.; Koch, W.M. p53-Reactivating small molecules induce apoptosis and enhance chemotherapeutic cytotoxicity in head and neck squamous cell carcinoma. Oral Oncol. 2010 Dec 15.
- Pattani, K.M.; Zhang, Z.; Demokan, S.; Glazer, C.; Loyo, M.; Goodman, S.; Sidransky, D.; Bermudez, F.; Jean-Charles, G.; McCaffrey, T.; Padhya, T.; Phelan, J.; Spivakovsky, S.; Bowne, H.Y.; Goldberg, J.D.; Rolnitzky, L.; Robbins, M.; Kerr, A.R.; Sirois, D.; Califano, J.A. Endothelin receptor type B gene promoter hypermethylation in salivary rinses is independently associated with risk of oral cavity cancer and premalignancy. Cancer Prev Res (Phila). 2010 Sep;3(9):1093-1103.
- Loyo, M.; Guerrero-Preston, R.; Brait, M.; Hoque, M.O.; Chuang, A.; Kim, M.S.; Sharma, R.; Liegeois, N.J.; Koch, W.M.; Califano, J.A.; Westra, W.H.; Sidransky, D. Quantitative detection of Merkel cell virus in human tissues and possible mode of transmission. Int J Cancer. 2010 Jun 15;126(12):2991-2996.
- Loyo, M.; Brait, M.; Kim, M.S.; Ostrow, K.L.; Jie, C.C.; Chuang, A.Y.; Califano, J.A.; Liegeois, N.J.; Begum, S.; Westra, W.H.; Hoque, M.O.; Tao, Q.; Sidransky, D. A survey of methylated candidate tumor suppressor genes in nasopharyngeal carcinoma. Int J Cancer. 2010 May 6.
- Lee, J.; Jang, S.J.; Benoit, N.; Hoque, M.O.; Califano, J.A.; Trink, B.; Sidransky, D.; Mao, L.; Moon, C. Presence of 5-methylcytosine in CpNpG trinucleotides in the human genome. Genomics. 2010 Aug;96(2):67-72.
- Huang, Y.; Chang, X.; Lee, J.; Cho, Y.G.; Zhong, X.; Park, I.S.; Liu, J.W.; Califano, J.A.; Ratovitski, E.A.; Sidransky, D.; Kim, M.S. Cigarette smoke induced promoter methylation of single-strand DNA-binding protein 2 in human esophageal squamous cell carcinoma. Int J Cancer. 2010 Jul 23.
- Hoque, M.O.; Brait, M.; Rosenbaum, E.; Poeta, M.L.; Pal, P.; Begum, S.; Dasgupta, S.; Carvalho, A.L.; Ahrendt, S.A.; Westra, W.H.; Sidransky, D. Genetic and epigenetic analysis of erbB signaling pathway genes in lung cancer. J Thorac Oncol. 2010 Dec;5(12):1887-1893.
- Durr, M.L.; Mydlarz, W.K.; Shao, C.; Zahurak, M.L.; Chuang, A.Y.; Hoque, M.O.; Westra, W.H.; Liegeois, N.J.; Califano, J.A.; Sidransky, D.; Ha, P.K. Quantitative methylation profiles for multiple tumor suppressor gene promoters in salivary gland tumors. PLoS One. 2010;5(5):e10828.
- Demokan, S.; Chang, X.; Chuang, A.; Mydlarz, W.K.; Kaur, J.; Huang, P.; Khan, Z.; Khan, T.; Ostrow, K.L.; Brait, M.; Hoque, M.O.; Liegeois, N.J.; Sidransky, D.; Koch, W.; Califano, J.A. KIF1A and EDNRB are differentially methylated in primary HNSCC and salivary rinses. Int J Cancer. 2010 Nov 15;127(10):2351-2359.
- Dasgupta, S.; Koch, R.; Westra, W.H.; Califano, J.A.; Ha, P.K.; Sidransky, D.; Koch, W.M. Mitochondrial DNA mutation in normal margins and tumors of recurrent head and neck squamous cell carcinoma patients. Cancer Prev Res (Phila). 2010 Sep;3(9):1205-1211.
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