Toland, Amanda PhD
Department of Molecular Virology, Immunology and Medical Genetics Human Cancer Genetics Program
For More Information:
Please visit Human Cancer Genetics
998 Biomedical Research Tower
460 W 12th Avenue
Columbus, OH 43210
Ph. (614) 247-8185
950 Biomedical Research Tower
460 W. 12th Ave, Columbus, OH 43210
Identification of cancer susceptibility genes
Dr. Toland's laboratory is interested in the identification of human cancer susceptibility genes with a particular focus on identifying combinations of susceptibility genes that work together to influence an individual's risk of developing cancer. Because traditional genetic methods for the identification of low risk genes are less then ideal, the laboratory employs an integrated approach using mouse models, tumor imbalance data, tumor expression data, and human population studies to address this problem.
Using an integrated mouse-human approach, we identified a variant in Aurora-A (STK15) that modestly increases risk of developing breast, ovarian, prostate, non-melanoma skin, lung, esophageal, and colon cancers. From our mouse models, we know that a gene mapping to the Aurora-A locus interacts with two other genes. When a mouse carries susceptibility alleles at all three loci, the risk of developing cancer is 8-9 times higher then carrying susceptibility alleles at none of these loci. A major focus of the laboratory is to identify the gene at one of these loci, Skts5, using our combined mouse/human approach. Once a top candidate gene has been identified, we will study the gene using cell culture, mouse models and a variety of other techniques to determine the mechanism underlying the cancer risk and why the combination with Aurora-A is important.
Other projects in the lab are the identification of genetic risk determinants of squamous cell carcinoma of the skin in individuals who have had organ transplants and characterization of BRCA1 and BRCA2 variants of uncertain significance.
For current publications please visit The National Center for Biotechnology Information's PubMed website at Toland A PubMed.org or Ewart-Toland PubMed.org
Gerber MM, Hampel H, Schulz NP, Fernandez S, Wei L, Zhou XP, de la Chapelle A, Toland AE. Evaluation of allele-specific somatic changes of genome-wide association study susceptibility alleles in human colorectal cancers. PLoS One 7(5):e37672, 2012.
Bolton KL, Chenevix-Trench G, Goh C, Sadetzki S, Ramus SJ, Karlan BY, Lambrechts D, Despierre E, Barrowdale D, McGuffog L, Healey S, Easton DF, Sinilnikova O, Benítez J, García MJ, Neuhausen S, Gail MH, Hartge P, Peock S, Frost D, Evans DG, Eeles R, Godwin AK, Daly MB, Kwong A, Ma ES, Lázaro C, Blanco I, Montagna M, D'Andrea E, Nicoletto MO, Johnatty SE, Kjær SK, Jensen A, Høgdall E, Goode EL, Fridley BL, Loud JT, Greene MH, Mai PL, Chetrit A, Lubin F, Hirsh-Yechezkel G, Glendon G, Andrulis IL, Toland AE, Senter L, Gore ME, Gourley C, Michie CO, Song H, Tyrer J, Whittemore AS, McGuire V, Sieh W, Kristoffersson U, Olsson H, Borg Å, Levine DA, Steele L, Beattie MS, Chan S, Nussbaum RL, Moysich KB, Gross J, Cass I, Walsh C, Li AJ, Leuchter R, Gordon O, Garcia-Closas M, Gayther SA, Chanock SJ, Antoniou AC, Pharoah PD; EMBRACE; kConFab Investigators; Cancer Genome Atlas Research Network. Association between BRCA1 and BRCA2 mutations and survival in women with invasive epithelial ovarian cancer. JAMA 307(4):382-390, 2012.
Efird JT, Toland AE, Lea CS, Phillips CJ. The combined influence of oral contraceptives and human papillomavirus on cutaneous squamous cell carcinoma. Clin Med Insights Oncol. 27(5):55075, 2011.
Antoniou AC, Wang X, Fredericksen ZS, McGuffog L, Tarrell R, Morrison J, Kartsonaki C, Lesnick T, Ghoussaini M, Barrowdale D, Peock S, Sinilnikova OM, Stoppa-Lyonnet D, Hogervorst FBL, Devilee P, Lubinski J, Jakubowska A, Spurdle A, Healey S, John EM, Hopper JL, Buys SS, Daly MB, Southey S, Terry M-B, Schmutzler RK, Domchek SM, Nathanson KL, Greene M, Friedman E, Andrulis I, Offit K, Borg A, Harbst K, Gerdes A-M, Thomassen M, Peterlongo P, Radice P, Caldes T, Singer CF, Greene MH, Guidugli L, Lindor NM, Hansen TVO, Lindblom A, Rantala J, Guillermo IB, Lazaro C, Garber J, Ramus S, Gayther S, Phelan C, Narod S, Szabo CI, Osorio A, Caligo MA, Beattie M, Hamann U, Godwin AK, Montagna M, Pasini B, Neuhausen SL, Karlan BY, Tung N, Nevanlinna H, Toland AE, Weitzel J, Olopade F, Rubinstein W, Martin NG, Montgomery GW, Chang-Claude J, Brauch H, Severi G , Cox A, Miron P, Eccles D, Eckel-Passow J, Vachon C, Dunning A, Pharoah PPD, Pankratz VS, Hakonarson H, Chenevix-Trench G, Easton DF, Couch FJ. A locus on 19p13 modifies risk of breast cancer in BRCA1 mutation carriers and is associated with hormone receptor-negative breast cancer in the general population. Nat Genet 42(10):885-92, 2010.
Ransburgh DJR, Chiba N, Ishioka C, Toland AE, Parvin JD. Identification of breast tumor mutations in BRCA1 that abolish its function in homologous DNA recombination. Cancer Res 70(3):998-995, 2010
Sweet K, Senter L, Pilarski R, Tseng SY, Toland AE. Classification of BRCA1 ring domain variants of uncertain significance. Br Cancer Res Treat 119(3):737-743, 2010
Dworkin AM, Ridd K, Bautista D, Allain DC, Iwenofu OH, Roy R, Bastian BC, Toland AE. Germline variation controls the architecture of somatic alterations in tumors. PLoS Genet 6(9):e1001136, 2010.
Dworkin AM, Spearman AD, Tseng, SY, Sweet K, Toland AE. BRCA promoter methylation is not a frequent “second hit” in tumors from BRCA carriers. Fam Cancer 8(4):339-346, 2009.
Dworkin AM, Tseng SY, Allain DC, Iwenofu OH, Peters SB, Toland AE. Merkel cell polyomavirus in cutaneous squamous cell carcinoma of immunocompetent individuals. J Invest Dermatol 129(12):2868-2874, 2009
Dworkin AM, Tober KL, Duncan FJ, Yu L, VanBuskirk AM, Oberyszyn TM, Toland AE. Chromosomal aberrations in UVB-induced tumors of immunosuppressed mice. Genes Chromosome Cancer 48(6):490-501, 2009. PMC2739622
Fleming JL, Huang THM, Toland, AE. The role of parental and grandparental epigenetic alterations in familial cancer risk. Cancer Res. 68(22):9116-9121, 2008.
Spearman AD, Sweet K, Zhou X-P, McLennan J, Couch FJ, Toland AE. Clinically applicable models to characterize BRCA1 and BRCA2 variants of uncertain significance. J Clin Oncol, 26: 5393-5400, 2008.
Toland AE, Rozek LS, Presswala S, Rennert G, Gruber SB. PTPRJ haplotypes and colorectal cancer risk. Cancer Epidemiol Biomarkers Prev, 17(10): 2782-2785, 2008.
Mahler KL, Fleming JL, Dworkin AM, Gladman N, Cho H-Y, Mao J-H, Balmain A, Toland AE. Sequence divergence of Mus Spretus and Mus Musculus across a skin cancer susceptibility locus. BMC Genomics, 9(1):626, 2008.
Ewart-Toland, A, Dai, Q, Gao, Y-T, Nagase, H, Dunlop, MG, Farrington, SM, Barnetson, RA, Anton-Culver, H, Peel, D, Ziogas, A, Lin, D, Miao, X, Sun, T, Ostrander, EA, Stanford, JL, Langlois, M, Chan, JM, Yuan, J, Harris, CC, Bowman, ED, Clayman, GL, Lippman, SM, Lee, JJ, and Balmain, A. Aurora-A/STK15 T+91A is a general low penetrance cancer susceptibility gene: a meta-analysis of multiple cancer types. Carcinogenesis, 26: 1368-1373, 2005.
Ewart-Toland, A, Briassouli, P, de Koning, JP, Mao, J-H, Yuan, J, Chan, F., MacCarthy-Morrogh, L, Ponder, BAJ, Nagase, H, Burn, J, Ball, S, Almeida, M, Linardopoulos, S, and Balmain A. Identification of Stk6/STK15 as a candidate modifier of cancer risk in mouse and man. Nat. Genet. 34:403-412, 2003
Ewart, AK, Morris, CM, Atkinson, DA, Jin, W. Sternes, K., Spallone, P, Stock, D.A., Leppert, M, and Keating, MT. Hemizygosity at the elastin locus in a developmental disorder, Williams syndrome. Nat. Genet. 5: 11-16, 1993.