Assistant Professor of Oncology
Department of Cancer Genetics

Roswell Park Cancer Institute
Elm and Carlton Streets
Buffalo, NY 14263
Telephone: (716) 845-1347
Fax:            (716)845-1698
E-mail:        Dominic.Smiraglia@RoswellPark.org

Dominic J. Smiraglia, PhD, joined the Roswell Park Cancer Institute faculty in 2003 as an Assistant Member in the Department of Cancer Genetics.

Dr. Smiraglia comes to RPCI from the Division of Human Cancer Genetics at the Ohio State University (OSU), where he served as a Research Scientist. He earned his doctoral degree in the Department of Cell and Molecular Biology in 1997 from RPCI's Graduate Division and completed postdoctoral training in the Department of Molecular Virology, Immunology and Medical Genetics at OSU.

Dr. Smiraglia's research interests include the study of DNA methylation, its contribution to carcinogenesis and identification of potential DNA methylation targets for early detection and diagnosis of cancer.

Dr. Smiraglia is a Board Member of The DNA Methylation Society. He has authored or co-authored more than 30 journal publications, book chapters and abstracts.  He is an ad hoc reviewer for the Journal of Medical Genetics, Cancer Research, Blood, Oncogene, and Oncology and serves on the Editorial Board for Critical Reviews in Oncogenesis.

General Research Interests

DNA methylation in cancer and normal cells

Current Program

• The use of Restriction Landmark Genomic Scanning to identify frequent targets of CpG island methylation in head and neck squamous cell carcinoma.
• Study of DNA methylation in primary and androgen-independent human prostate cancer.
• Study of the TRAMP mouse model of prostate cancer to identify methylation events relating to the primary, metastatic and androgen-independent phenotypes.

Laboratory Personnel

Erika VanDette, BS - Research Technologist
Gaia Bistulfi, PhD

Description of Research

The attachment of a methyl (CH3) group to the 5? carbon of the cytosine residue in a CpG dinucleotide is a universal, required, and tightly regulated DNA modification found in mammals. This is referred to as an epigenetic modification, as it does not change the coding sequence of the DNA. Methylation of CpG dinucleotides is prevalent in bulk chromatin, particularly in repetitive elements found throughout mammalian genomes. This accounts for approximately 90% of the CpG dinucleotides in the genome. The other 10% are found in dense clusters called CpG islands.

CpG islands are found primarily in the promoters of genes and are almost exclusively unmethylated with the notable exceptions of most genes on the inactive X chromosome and some imprinted genes. In cancer, the tight regulation of DNA methylation breaks down, and the distribution of methyl-cytosine changes. The heavy methylation found in the bulk chromatin is reduced, while the normally unmethylated CpG islands become hypermethylated. The effect of such promoter hypermethylation can be analogous to genetic loss of function mutations such as point mutations and deletions. DNA hypermethylation of a promoter is thought to suppress transcription of the associated gene through the recruitment of chromatin remodeling complexes. Thus, promoter hypermethylation of a tumor suppressor gene is one way in which a cell may acquire one or more of the ?hits? that must accumulate in order to progress towards malignancy and/or metastasis.

Restriction landmark genomic scanning (RLGS) is a highly reproducible two-dimensional gel electrophoresis of genomic DNA that allows the assessment of over 2000 loci simultaneously. An example of an RLGS profile is shown in the figure. The technique has been used for various purposes including genetic mapping, identification of novel imprinted genes, genomic amplifications, regions of hypomethylation, regions of hypermethylation, candidate tumor suppressor genes, and measuring the degree of CpG island hypermethylation in cancer. Two primary observations have been made concerning DNA methylation in cancer: 1) genome wide hypomethylation with an over all decrease in the level of 5-methylcytosine, and 2) hypermethylation of CpG islands. In other words, regions of the genome that are normally heavily methylated become hypomethylated, while at the same time, regions of the genome normally unmethylated, become hypermethylated. A variety of molecular techniques have been developed to detect methylation changes in cancer through both global and gene-by-gene approaches. RLGS can be used to study both aberrant phenomena, although the real power of RLGS lies with study hypermethylation.

We are using the RLGS technique to study CpG island methylation in various cancers. Some questions being asked are: How frequently do CpG islands become hypermethylated in specific types of cancer? Which CpG islands become frequently methylated within a specific type of cancer, and also across multiple types of cancer? Can we use this knowledge of CpG island hypermethylation to develop sensitive biomarkers that might serve as early diagnostic markers or as prognostic markers? Can we identify genes which are frequent targets of hypermethylation and whose loss of expression is associated with the carcinogenic phenotype of the cells?

Key Publications

• Smith JF, Mahmood S, Song F, Morrow A, Smiraglia D, Zhang X, Rajput A, Higgins MJ, Krumm A, Petrelli NJ, Costello JF, Nagase H, Plass C, Held WA.  Identification of DNA methylation in 3' genomic regions that are associated with upregulation of gene expression in colorectal cancer.  Epigenetics 2007; 3:161-172.
• Oakes CC, LaSalle S, Smirgalia D, Robaire B, Trasler JM.  Development acquisition of genome-wide DNA methylation occurs prior to meiosis in male germ sales.  Dev Biol 2007; 307(2)368-379.
• Oakes CC, LaSalle S, Smiraglia DJ, Robaire B, Trasler JM. A unique configuration of genome-wide DNA methylation patterns in the testis. Proc Natl Acad Sci USA 2007; 104:238-233.
• Morey SR, Smiraglia DJ, James SR, Yu J, Moser MT, Foster BA, Karpf AR.  DNA methylation pathway alterations in an autochthonous murine model of prostate cancer.  Cancer Res 2006; 66:11659-11667.
• Kazhiyur-Mannar R, Smiraglia DJ, Plass C, Wenger R.  Contour area filtering of two-dimensional electrophoresis images.  Med Image Analysis 2006; 10:353-365.
• Plass C, Smiraglia DJ. Genome-wide analysis of DNA methylation changes in human malignancies. Current Topics in Microbiology and Immunology 2006; 310:179-198.
• Smith LT, Lin M, Smiraglia DJ, Brena RM, Lang JC, Schuller DE, Otterson GA, Morrison CD, Plass C.  TCF21:  An epigentically altered tumor suppressor on 6q23-q24 in NSCLC and HNSCC. Proc Natl Acad Sci USA 2006; 103:982-987.
• Lin M, Smith LT, Smiraglia DJ, Kazhiyur-Mannar R, Lang JC, Schuller DE, Kornacker K, Wenger R, Plass C. DNA copy number gains in head and neck squamous cell carcinoma. Oncogene 2006; 25:1424-1433.
• Dai Z, Zhu WG, Morrison CD, Brena RM, Smiraglia DJ, Raval A, Wu YZ, Rush LJ, Ross P, Molina JR, Otterson GA, Plass C. A comprehensive search for DNA amplification in lung cancer identifies inhibitors of apoptosis cIAP1 and cIAP2 as candidate oncogenes. Hum Mol Genet 2003; 12:791-801.
• Li H, Myeroff L, Smiraglia D, Romero MF, Pretlow TP, Kasturi L, Lutterbaugh J, M Rerko RM, Casey G, Issa JP, Willis J, Willson JK, Plass C, Markowitz SD. SLC5A8, a sodium transporter, is a tumor suppressor gene silenced by methylation in human colon aberrant crypt foci and cancers. Proc Natl Acad Sci USA 2003; 100:8412-8417.
• Oakes CC, Smiraglia DJ, Plass C, Trasler JM, Robaire B. Aging results in hypermethylation of ribosomal DNA in sperm and liver of male rats. Proc Natl Acad Sci USA 2003; 100:1775-1780.
• Smiraglia DJ, Smith LT, Lang JC, Rush LJ, Dai Z, Schuller DE, Plass C. Variable CpG island hypermethylation phenotypes in primary and metastatic head and neck squamous cell carcinoma. J Med Genet 2003; 40(1):25-33.
• Smiraglia DJ, and Plass C. The development of CpG island methylation biomarkers using restriction landmark genomic scanning. Annal NY Acad Sci 2003; 983:110-119.
• Smiraglia DJ,and Plass C. The study of aberrant methylation in cancer via restriction landmark genomic scanning. Oncogene 2002; 21:5414-5426.
• Smiraglia DJ, Szymanska J Kraggerud S, Lothe RA, Peltom P, Plass, C. Distinct epigenetic phenotypes in seminomatous and nonseminomatous testicular germ cell tumors. Oncogene 2002; 21:3909-3916.
• Moinova HR, Chen WD, Shen L, Smiraglia D, Olechnowicz J, Ravi L, Kasturi L, Myeroff L, Plass C, Parsons R, Minna J, Willson JK, Green SB, Issa P, Markowitz SD.  HLTF gene silencing in human colon cancer.  Proc Natl Acad Sci USA 2002; 99:4562-4567.
• Smiraglia DJ, Rush LJ, Fr M, Dai Z, Held WA, Costello JF, Lang JC, Eng C, Li B, Wright FA, Caligiuri MA, Plass C. Excessive CpG island hypermethylation in cancer cell lines versus primary human malignancies. Human Molec Genet 2001; 10(13):1413-1419.
• Costello JF, Fruhwald MC, Smiraglia DJ, Rush LJ, Robertson GP, Gao X, Wright FA, Feramisco JD, Peltomaki P, Lang JC, Schuller DE, Yu L, Bloomfield CD, Caligiuri MA, Yates A, Nishikawa R, Su Huang H, Petrelli NJ, Zhang X, O'Dorisio MS, Held WA, Cavenee WK, Plass C. Aberrant CpG-island methylation has non-random and tumour-type-specific patterns. Nat Genet 2000; 24(2):132-138.
• Smiraglia DJ, Fruhwald MC, Costello JF, McCormick SP, Dai Z, Peltomaki P, O'Dorisio MS, Cavenee WK, Plass C. A new tool for the rapid cloning of amplified and hypermethylated human DNA sequences from restriction landmark genome scanning gels. Genomics 1999; 58:254-262.