Head and neck squamous cell carcinomas (HNSCC) constitute an anatomically heterogenous group of neoplasms that share in common a causal association with tobacco and alcohol exposure.  The clinical course of these neoplasms is difficult to predict based on established prognostic clinicopathological criteria.  Unfortunately, the 5-year survival rate has improved only marginally over the past decade; as a result, it is estimated that over 45,000 cases and over 11,000 deaths will occur each year in the United States from HNSCC.  To date, there are few molecular markers that can be reliably used in either early detection or as indicators of prognosis.

Evidence has now established that aberrant DNA methylation and chromatin remodeling associated with promoters, or first exons of genes, is one mechanism frequently associated with the transcriptional silencing of critical genes in HNSCC and other cancers.  One goal of our lab is the genome-wide analysis of aberrant DNA methylation events in head and neck tumor genomes.  These “epigenetic signatures” can be used to identify CpG island sequences frequently hypermethylated in HNSCC, and to characterize previously indistinguishable subtypes of this disease.  The long-term goal of our research is to identify genetic and epigenetic signatures associated with successful treatment and patient outcome in this disease, as well as those signatures that indicate that drug treatment will not work. This should lead to more unique gene discoveries and, in the future, new targets for anti-tumor drugs.

Belbin, T.J., Singh, B., Barber, I., Socci, N.D., Wenig, B., Smith, R., Prystowsky, M.B. and Childs, G.  Molecular classification of head and neck squamous cell carcinoma using cDNA microarrays.  Cancer Research 62:  1184-1190 (2002).

Sanchez-Carbayo, M., Belbin, T.J., Scotto, K., Scotlandi, K., Prystowsky, M., Baldini, N., Childs, G. and Cordon-Cardo, C.  Expression profiling of osteosarcoma transfected cells with MDR1 and NEO genes:  inhibition of cell adhesion, blockage of apoptosis and down-regulation of MRP.  Laboratory Investigation 83:  507-517 (2003).

Sanchez-Carbayo, M., Socci, N.D., Lozano, J.J., Li, W., Charytonowicz, E., Belbin, T.J., Prystowsky, M.B., Ortiz, A.R., Childs, G. and Cordon-Cardo, C.  Gene discovery in bladder cancer progression using cDNA microarrays.  American Journal of Pathology 163:  505-516 (2003).

Belbin, T.J., Gaspar, J., Haigentz, M., Perez-Soler, R., Keller, S.M., Prystowsky, M.B., Childs, G. and Socci, N.D.  Indirect measurements of differential gene expression with cDNA microarrays.  BioTechniques 36: 310-314 (2004).

Wreesman, V.B., Sieczka, E., Socci, N.D., Hezel, M., Belbin, T.J., Childs, G., Patel, S.G., Patel, K.N., Tallini, G., Prystowsky, M.B., Shaha, A.R., Kraus, D., Shah, J.P., Rao, P.H., Ghossein, R. and Singh, B.  Genome-wide profiling of papillary thyroid cancer identifies MUC1 as an independent prognostic marker.  Cancer Research 64: 3780-3789 (2004).

Cao, Q.J., Belbin, T.J., Socci, N., Balan, R., Prystowsky, M.B., Childs, G. and Jones, J.G.  Distinctive gene expression profiles by cDNA microarrays in endometrioid and serous carcinomas of the uterus.  International Journal of Gynecological Pathology 23: 321-329 (2004).

Belbin, T.J., Singh, B., Wreesmann, V., Socci, N.D., Sanchez-Carbayo, M., Masterson, J., Smith, R., Patel, S., Cordon-Cardo, C., Childs, G. and Prystowsky, M.B.  Molecular profiling of tumor progression in head and neck cancer.  Archives of Otolaryngology – Head and Neck Surgery 131: 10-18 (2005).

Adrien, L.R., Schlecht, N.F., Kawachi, N., Smith, R.V., Brandwein-Gensler, M., Massimi, A., Chen, S., Prystowsky, M.B., Childs, G. and Belbin, T.J.  Classification of DNA methylation patterns in tumor cell genomes using a CpG island microarray.  Cytogenetic and Genome Research 114: 16-23 (2006).

Smith, R.V., Schlecht, N.F., Childs, G., Prystowsky, M.B. and Belbin, T.J.  Pilot study of mucosal genetic differences in early smokers and nonsmokers.  Laryngoscope 116: 1375-1379 (2006).

Madan, R., Brandwein-Gensler, M., Schlecht, N.F., Elias, K., Gorboritsky, E., Belbin, T.J., Mahmood, R., Breining, D. Qian, H., Childs, G., Locker, J., Smith, R.V., Haigentz M., Gunn-Moore, F. and Prystowsky, M.B.  Differential tissue and subcellular expression of ERM proteins in normal and malignant tissues:  cytoplasmic ezrin expression has prognostic significance for head and neck squamous cell carcinoma.  Head and Neck 16: 1018-1027 (2006).

Sudha, R., Kawachi, N., Du, P., Nieves, E., Belbin, T.J., Negassa, A., Angeletti, R.H. and Prystowsky, M.B.  Global proteomic analysis distinguishes biologic differences in head and neck squamous carcinoma.  Laboratory Investigation 87: 755-766 (2007).

Basu, I., Cordovano, G., Das, I., Belbin, T.J., Guha, C. and Schramm, V.L.  A transition state analogue of 5'-methylthioadenosine phosphorylase induces apoptosis in head and neck cancers.  Journal of Biological Chemistry 282: 21477-21486 (2007).

Loudig, O., Milova, E., Brandwein-Gensler, M., Massimi, A., Belbin, T.J., Childs, G., Singer, R.H., Rohan, T. and Prystowsky, M.B.  Molecular restoration of archived transcriptional profiles by complementary-template reverse transcription (CT-RT).  Nucleic Acids Research 35(15): e94. (2007).

Schlecht, N.F., Burk, R.D., Adrien, L., Dunne, A., Kawachi, N., Sarta, C., Chen, Q., Brandwein-Gensler, M., Prystowsky, M.B., Childs, G., Smith, R.V. and Belbin, T.J.  Gene expression profiles in HPV infected head and neck cancer.  Journal of Pathology 213: 283-293 (2007).

Aleman, A., Adrien, L., Lopez-Serra, L., Cordon-Cardo, C., Esteller, M., Belbin, T.J. and Sanchez-Carbayo, M.  Identification of DNA hypermethylation of SOX9 in association with bladder cancer progression using CpG microarrays.  British Journal of Cancer 98(2): 466-473 (2008).

Belbin, T.J., Schlecht, N.F., Smith, R.V., Adrien, L.R., Kawachi, N., Brandwein-Gensler, M., Bergman, A., Chen Q, Childs G, Prystowsky MB.  Site-specific molecular signatures predict aggressive disease in HNSCC. (2008). Head and Neck Pathology 2(4): 243-256.

Schramm, V.L., Gutierrez, J.A., Cordovano, G., Basu, I., Guha, C., Belbin, T.J., Evans, G.B., Tyler, P.C. and Furneaux, R.H.  Transition state analogues in quorum sensing and SAM recycling.  Nucleic Acids Symposium Series (Oxford) 52: 75-76 (2008).

Sikora, M.J., Bauer, J.A., Verhaegen, M., Belbin, T.J., Prystowsky, M.B., Taylor, J.C., Brenner, J.C., Wang, S., Soengas, M.S., Bradford, C.R. and Carey, T.E. Anti-oxidant treatment enhances anti-tumor cytotoxicity of (-)-gossypol.  Cancer Biology and Therapy 7(5): 767-776 (2008).

Childs, G., Fazarri, M., Kung, G., Kawachi, N., Brandwein-Gensler, M., McLemore, M., Chen, Q., Burk, R.D., Smith, R.V., Prystowsky, M.B., Belbin, T.J. and Schlecht, N.F.  Low level expression of microRNA’s let7-d and miR-205 are prognostic markers of head and neck squamous cell carcinoma.  American Journal of Pathology 174(3):736-745 (2009).

Prystowsky, M.B., Adomako, A., Smith, R.V., Kawachi, N., McKimpson, W., Atadja, P., Chen, Q., Schlecht, N.F., Parish, J.L., Childs, G. and Belbin, T.J.  The histone deacetylase inhibitor LBH589 inhibits expression of mitotic genes causing G2/M arrest and cell death in head and neck squamous cell carcinoma cell lines.  Journal of Pathology 218(4): 467-477 (2009).

Ostrower, S.T., Fischer, T.C., Smith, R.V., Belbin, T.J., Bent, J.P., and Parikh, S.R.  Gene expression in the oropharynx of children exposed to secondhand smoke.  Laryngoscope 120(12): 2467-2472 (2010).

Basu, I., Locker, J., Cassera, M.B., Belbin, T.J., Merino, E.F., Dong, X., Hemeon, I., Evans, G.B., Guha, C., and Schramm, V.L.  Growth and metastases of human lung cancer are inhibited in mouse xenografts by a transition state analogue of 5'-methylthioadenosine phosphorylase.  Journal of Biological Chemistry 286(6): 4902-4911 (2011).

Lleras, R.A., Adrien, L.R., Smith, R.V., Brown, B., Jivraj, N., Keller, C., Sarta, C., Schlecht, N.F., Harris, T.M., Childs, G., Prystowsky, M.B., and Belbin, T.J.  Hypermethylation of a cluster of Krüppel-type zinc finger protein genes on chromosome 19q13 in oropharyngeal squamous cell carcinoma. American Journal of Pathology 178(5):1965-1974 (2011).

Haigentz, M. Jr, Kim, M., Sarta, C., Lin, J., Keresztes, R.S., Culliney, B., Gaba, A.G., Smith, R.V., Shapiro, G.I., Chirieac, L.R., Mariadason, J.M., Belbin, T.J., Greally, J.M., Wright, J.J., Haddad, R.I. Phase II trial of the histone deacetylase inhibitor romidepsin in patients with recurrent/metastatic head and neck cancer. Oral Oncology 48(12):1281-1288 (2012).

Harris, T., Jimenez, L., Kawachi, N., Fan, J.B., Chen, J., Belbin, T.J., Ramnauth, A., Loudig, O., Keller, C.E., Smith, R., Prystowsky, M.B., Schlecht, N.F., Segall, J.E., Childs, G. Low-level expression of miR-375 correlates with poor outcome and metastasis while altering the invasive properties of head and neck squamous cell carcinomas. American Journal of Pathology 180(3):917-928 (2012).

Schlecht, N.F., Brandwein-Gensler, M., Smith, R.V., Kawachi, N., Broughel, D., Lin, J., Keller, C.E., Reynolds, P.A., Gunn-Moore, F.J., Harris, T., Childs, G., Belbin, T.J., Prystowsky, M.B. Cytoplasmic ezrin and moesin correlate with poor survival in head and neck squamous cell carcinoma. Head and Neck Pathology 6(2):232-243 (2012).

Qian, X., Hulit, J., Suyama, K., Eugenin, E.A., Belbin, T.J., Loudig, O., Smirnova, T., Zhou, Z.N., Segall, J., Locker, J., Phillips, G.R., Norton, L. and Hazan, R.B.  p21CIP1 mediates reciprocal switching between proliferation and invasion during metastasis.  Oncogene 32(18): 2292-2303 (2013).

Lleras, R.A., Smith, R.V., Adrien, L.R., Schlecht, N.F., Burk, R.D., Harris, T.M., Childs, G., Prystowsky, M.B., Belbin, T.J. Unique DNA Methylation Loci Distinguish Anatomic Site, HPV Status and Tumor Aggressiveness in Head and Neck Squamous Cell Carcinoma.  Clinical Cancer Research 19(19): 5444-5455 (2013).

Salazar, C.R., Smith, R.V., Garg, M.K., Haigentz, M. Jr., Schiff, B.A., Kawachi, N., Anayannis, N., Belbin, T.J., Prystowsky, M.B., Burk, R.D., Schlecht, N.F.  Human papillomavirus-associated head and neck squamous cell carcinoma survival: a comparison by tumor site and initial treatment. Head and Neck Pathology 8(1): 77-87 (2014).

Salazar, C.R., Anayannis, N., Smith, R.V., Wang, Y., Haigentz Jr., M., Garg, M., Schiff, B., Kawachi, N., Elman, J., Belbin, T.J., Prystowsky, M.B., Burk, R.D., Schlecht, N.F.  Combined P16 and HPV testing predicts head and neck cancer survival.  International Journal of Cancer 135(10): 2404-2412 (2014).

Harris, T.M., Du, P., Kawachi, N., Belbin, T.J., Wang, Y., Schlecht, N.F., Ow, T.J., Keller, C.E., Childs, G.J., Smith, R.V., Angeletti, R.H., Prystowsky, M.B., Lim, J.  Proteomic Analysis of Oral Cavity Squamous Cell Carcinoma Specimens Identifies Patient Outcome-Associated Proteins. Archives of Pathology and Laboratory Medicine 139(4):494-507 (2015).

Schlecht, N.F., Ben-Dayan, M., Anayannis, N., Lleras, R.A., Thomas, C., Wang, Y., Smith, R.V., Burk, R.D., Harris, T.M., Childs, G., Ow, T.J., Prystowsky, M.B., Belbin, T.J.  Epigenetic changes in the CDKN2A locus are associated with differential expression of P16INK4A and P14ARF in HPV-positive oropharyngeal squamous cell carcinoma. Cancer Medicine 4(3):342-53 (2015).

Muller, K., Kazimiroff, J., Fatahzadeh, M., Smith, R.V., Wiltz, M., Polanco, J., Grossberg, R.M., Belbin, T.J., Strickler, H.D., Burk, R.D., Schlecht, N.F.  Oral Human Papillomavirus Infection and Oral Lesions in HIV-Positive and HIV-Negative Dental Patients. Journal of Infectious Diseases 212(5):760-8 (2015).

Ben-Dayan, M., MacCarthy, T., Schlecht, N.F., Belbin, T.J., Childs, G., Smith, R.V., Prystowsky, M.B., Bergman, A.  Cancer as the disintegration of robustness: population-level variance in gene expression identifies key differences between tobacco- and HPV-associated oropharyngeal carcinogenesis. Archives of Pathology & Laboratory Medicine 139(11):1362-72 (2015).

Wijetunga, N.A., Belbin, T.J., Burk, R.D., Whitney, K., Abadi, M., Greally, J.M., Einstein, M.H., Schlecht, N.F. Novel epigenetic changes in CDKN2A are associated with progression of cervical intraepithelial neoplasia. Gynecologic Oncology [Epub ahead of print] (2016).