Oncogenomics

Nick Hayward Staff
Funding
Collaborators
Key Publications
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Lab Head: Dr Nick Hayward

Cancer develops through the accumulation of mutations in genes that control critical cellular processes such as cell growth, cell death and cell-cell contact. The majority of these aberrations occur purely by chance in a single cell in the body. The tissue/organ type from which that cell is derived determines the type of cancer into which it develops. A small proportion of individuals are at much higher risk of developing particular types of cancer than the general population because they carry an inherited mutation in one of the many key "cancer" genes. The major focus of our group is to identify novel cancer genes and to study the way in which defects in such genes are associated with cancer predisposition or development. The key approaches we are using include genome-wide linkage analysis, single nucleotide polymorphism association studies, candidate gene mutation screening, gene expression profiling, cellular phenotyping and transgenics.

Melanoma
We are members of the GenoMEL, the International Melanoma Genetics Consortium which has the primary objective of carrying out genome-wide linkage and association scans to map novel melanoma susceptibility genes and to clone and characterise these genes once they have been localised. Transgenic and knockout mouse models are also being established to investigate the contribution of the oncogenes CDK4 and HRAS, and the tumour suppressor genes TP53 and RB1, to melanoma development. Additionally, candidate tumour suppressor genes and oncogenes for melanoma development, which have been identified by array comparative genomic hybridization and microarray gene expression profiling, are being screened for mutations in melanoma cell lines and fresh tumours.

We are also carrying out expression profiling of a panel of melanoma cell lines and tumours to determine expression patterns that are correlated with phenotypic (e.g. cellular invasion or tumorigenicity) or genotypic (e.g. mutation status of the PTEN, BRAF, CDKN2A, ARF, TP53 or NRAS genes) features of the samples. Ultimately this information will be used to identify novel diagnostic and prognostic markers for melanoma, as well as key components of various cellular pathways involved in melanoma tumorigenesis which may prove to be useful targets for the design of novel therapeutics to treat this disease.

Multiple endocrine neoplasia type 1
Similar to the work on melanoma, we are studying the molecular genetics of the cancer syndrome multiple endocrine neoplasia type 1 (MEN 1) in collaboration with Dr Graham Kay from the Queensland Cancer Fund Transgenics Laboratory. We have found mutations of the MEN 1 susceptibility gene in a cohort of MEN 1 families, as well as in a panel of endocrine tumours. To characterise the role of the MEN 1 gene in development we have generated total and tissue-specific knockout mouse models of this disorder. The product of the MEN 1 locus (termed menin) has been identified as a transcriptional coregulator through its interaction with the transcription factors junD and SMAD3. We aim to identify that genes are transcriptionally regulated by menin using cDNA expression microarray analysis of murine embryonic stem cells, primary islet cell cultures or endocrine tumours in which the MEN1 gene has been is inactivated.

Oesophageal cancer and Barrett's oesophagus
In collaboration with Dr David Whiteman from the Cancer & Population Studies Group, we are involved in national population-based case-control studies of oesophageal cancer and Barrett's oesophagus. These investigations aim to identify environmental and genetic risk factors for these diseases. Additionally, we are using array comparative genomic hybridization, gene expression profiling and immunohistochemistry to study the cellular and molecular changes that occur in the progression of normal oesophageal epithelium, through Barrett's oesophagus, to oesophageal cancer.

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Staff

Labhead:	Dr Nick Hayward
Postdocs:	Graeme Walker Sandra Bloethner Derek Nancarrow Herlina Handoko Vanessa Bonazzi Magdalena Auret Arne Mould Elke Hacker Leisl Packer
Research Assistants:	Jane Palmer Mitchell Stark Judy Symmons

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Funding

We are grateful for funding support from the following agencies:

Collaborators

Dr Hayward has ongoing collaborations in melanoma with Professor Jeffrey Trent (Translational Genomics Institute, Phoenix, Arizona, USA) and Dr Boris Bastian (University of California, San Francisco, California, USA) and members of GenoMEL.

Key Publications

Walker, G.J., Hussussian, C.J., Flores, J.F., Glendening, J.M., Haluska, F.G., Dracopoli, N.C., HAYWARD N.K., and Fountain, J.W. Mutations of the CDKN2/p16INK4 gene in Australian melanoma kindreds. Hum. Mol. Genet. 1995 Oct;4(10):1845-1852. [pubmed abstract]

Zuo, L., Weger, J., Yang, Q., Goldstein A.M., Tucker, M.A., Walker, G.J., HAYWARD, N.K. and Dracopoli, N.C. Germline mutations in the p16INK4a binding domain of CDK4 in familial melanoma. Nature Genet. 1996 Jan;12(1): 97-99. [pubmed abstract]

Grimmond, S., Lagercrantz, J., Drinkwater, C., Silins, G., Townson, S., Pollock, P., Gotley, D., Carson, E., Rakar, S., Nordenskjöld, M., Ward, L., HAYWARD, N., and Weber, G. Cloning and characterization of a novel human gene related to vascular endothelial growth factor. Genome Res. 1996 Feb;6(2)6: 124-131. [pubmed abstract]

Lemmens, I., Van de Ven, W. J. M., Kas, K., Zhang, C. X., Giraud, S., Wautot, V., Buisson, N., De Witte, K., Salandre, J., Lenoir, G., Pugeat, M., Calender, A., Parente, F., Quincey, D., Gaudray, P., De Wit, M. J., Lips, C. J. M., Hoppener, J. W. M., Khodeai, S., Grant, A., Weber, G., Kytola, S., Teh, B. T., Farnebo, F., Phelan, C., HAYWARD, N., Larsson, C., Pannett, A. A. J., Forbes, S. A., Bassett, J. H. D., and Thakker, R. V. Identification of the multiple endocrine neoplasia type 1 (MEN1) gene. The European Consortium on MEN1. Hum Mol Genet. 1997 Jul;6(7):1177-83. [pubmed abstract]

Stewart, C., Parente, F., Piehl, F., Farnebo, F., Quincey, D., Silins, G., Bergman, L., Carle, G.F., Lemmens, I., Grimmond, S., Xian, C.Z., Khodei, S., The, B.T., Lagercrantz, J., Siggers, P., Calender., A., Van de Vem, V., Kas, K., Weber, G., Hayward, N., Gaudray, P., Larsson, C. Characterization of the mouse Men1 gene and its expression during development. Oncogene 1998 Nov 12;17(19): 2485-2493. [pubmed abstract]

Aitken, J., Welch, J., Duffy, D., Milligan, M., Martin, N., Green, A., and Hayward, N. CDKN2A Mutations and Polymorphisms and Melanoma Risk in a Population-Based Sample of Queensland Families with Cutaneous Melanoma. J. Natl. Cancer Inst. 1999 Mar 3;91(5): 446-452. [pubmed abstract]

Zhu, G., Duffy, D.L., Eldridge, A., Grace, M., Mayne, C., O'Gorman, L., Aitken, J.F., Neale, M.C., Hayward, N.K.., Green, A.C., Martin, N.G. A major quantitative-trait locus for mole density is linked to the familial melanoma gene CDKN2A: a maximum-likelihood combined linkage and association analysis in twins and their sibs. Am. J. Hum. Genet. 1999 65(2): 483-492.[pubmed abstract]

Bellomo D, Headrick JP, Silins GU, Paterson CA, Thomas PS, Gartside M, Mould A, Cahill MM, Tonks ID, Grimmond SM, Townson S, Wells C, Little M, Cummings MC, Hayward NK, Kay GF. Mice lacking the vascular endothelial growth factor-B gene (Vegfb) have smaller hearts, dysfunctional coronary vasculature, and impaired recovery from cardiac ischemia. Circ Res. 2000 Feb 4;86(2):E29-35. [pubmed abstract]

Bittner M, Meltzer P, Chen Y, Jiang Y, Seftor E, Hendrix M, Radmacher M, Simon R, Yakhini Z, Ben-Dor A, Dougherty E, Wang E, Marincola F, Gooden C, Lueders J, Glatfelter A, Pollock P, Gillanders E, Leja D, Dietrich K, Berens C, Alberts D, Sondak V, Hayward, N.K., and Trent J. (2000) Molecular Classification of Cutaneous Malignant Melanoma by Gene Expression Profiling. Nature 406: 536-540. [pubmed abstract]

Box NF, Duffy DL, Chen W, Stark M, Martin NG, Sturm RA, Hayward NK. MC1R genotype modifies risk of melanoma in families segregating CDKN2A mutations. Am J Hum Genet. 2001 Oct;69(4):765-73. [pubmed abstract]

Bishop DT, Demenais F, Goldstein AM, Bergman W, Bishop JN, Bressac-de Paillerets B, Chompret A, Ghiorzo P, Gruis N, Hansson J, Harland M, Hayward N, Holland EA, Mann GJ, Mantelli M, Nancarrow D, Platz A, Tucker MA. Geographical variation in the penetrance of CDKN2A mutations for melanoma. J Natl Cancer Inst. 2002 Jun 19;94(12):894-903. [pubmed abstract]

Walker GJ, Hayward NK. Pathways to melanoma development: lessons from the mouse. J Invest Dermatol. 2002 Oct;119(4):783-92. [pubmed abstract]

Pollock PM, Harper UL, Hansen KS, Yudt LM, Stark M, Robbins CM, Moses TY, Hostetter G, Wagner U, Kakareka J, Salem G, Pohida T, Heenan P, Duray P, Kallioniemi O, Hayward NK, Trent JM, Meltzer PS. High frequency of BRAF mutations in nevi. Nat Genet. 2003 Jan;33(1):19-20.[pubmed abstract]

Whiteman DC, Watt P, Purdie DM, Hughes MC, Hayward NK, Green AC. Melanocytic nevi, solar keratoses, and divergent pathways to cutaneous melanoma. J Natl Cancer Inst. 2003 Jun 4;95(11):806-12. [pubmed abstract]

Duffy DL, Box NF, Chen W, Palmer JS, Montgomery GW, James MR, Hayward NK, Martin NG, Sturm RA. Interactive effects of MC1R and OCA2 on melanoma risk phenotypes. Hum Mol Genet. 2004 Feb 15;13(4):447-61. [pubmed abstract]

Hughes CM, Rozenblatt-Rosen O, Milne TA, Copeland TD, Levine SS, Lee JC, Hayes DN, Shanmugam KS, Bhattacharjee A, Biondi CA, Kay GF, Hayward NK, Hess JL, Meyerson M. Menin associates with a trithorax family histone methyltransferase complex and with the hoxc8 locus. Mol Cell. 2004 Feb 27;13(4):587-97. [pubmed abstract]

Zhu G, Evans DM, Duffy DL, Montgomery GW, Medland SE, Gillespie NA, Ewen KR, Jewell M, Liew YW, Hayward NK, Sturm RA, Trent JM, Martin NG. A genome scan for eye color in 502 twin families: most variation is due to a QTL on chromosome 15q. Twin Res. 2004 Apr;7(2):197-210. [pubmed abstract]

Biondi CA, Gartside MG, Waring P, Loffler KA, Stark MS, Magnuson MA, Kay GF, Hayward NK. Conditional inactivation of the MEN1 gene leads to pancreatic and pituitary tumorigenesis but does not affect normal development of these tissues. Mol Cell Biol. 2004 Apr;24(8):3125-31. [pubmed abstract]

Pavey S, Johansson P, Packer L, Taylor J, Stark M, Pollock PM, Walker GJ, Boyle GM, Harper U, Cozzi SJ, Hansen K, Yudt L, Schmidt C, Hersey P, Ellem KA, O'Rourke MG, Parsons PG, Meltzer P, Ringner M, Hayward NK. Microarray expression profiling in melanoma reveals a BRAF mutation signature. Oncogene. 2004 May 20;23(23):4060-7. [pubmed abstract]

Walker GJ, Indsto JO, Sood R, Faruque MU, Hu P, Pollock PM, Duray P, Holland EA, Brown K, Kefford RF, Trent JM, Mann GJ, Hayward NK. Deletion mapping suggests that the 1p22 melanoma susceptibility gene is a tumor suppressor localized to a 9-Mb interval. Genes Chromosomes Cancer. 2004 Sep;41(1):56-64. [pubmed abstract]

Tonks ID, Hacker E, Irwin N, Muller HK, Keith P, Mould A, Zournazi A, Pavey S, Hayward NK, Walker G, Kay GF. Melanocytes in conditional Rb-/- mice are normal in vivo but exhibit proliferation and pigmentation defects in vitro. Pigment Cell Res. 2005 Aug;18(4):252-64. [pubmed abstract]

Mould AW, Greco SA, Cahill MM, Tonks ID, Bellomo D, Patterson C, Zournazi A, Nash A, Scotney P, Hayward NK, Kay GF. Transgenic overexpression of vascular endothelial growth factor-B isoforms by endothelial cells potentiates postnatal vessel growth in vivo and in vitro. Circ Res. 2005 Sep 16;97(6):e60-70. [pubmed abstract]

James MR, Roth RB, Shi MM, Kammerer S, Nelson MR, Stark MS, Dumenil T, Montgomery GW, Hayward NK, Martin NG, Braun A, Duffy DL. BRAF Polymorphisms and Risk of Melanocytic Neoplasia. J Invest Dermatol. 2005 Dec;125(6):1252-8. [pubmed abstract]

Goldstein, AM, Chan M, Harland M, Hayward NK, Demenais F, Bishop DT, Azizi E, Bergman W, Bianchi-Scarra G, Bruno W, Calista D, Cannon-Albright LA, Chaudru V, Chompret A, Cuellar F, Elder DE, Ghiorzo P, Gillanders EM, Gruis N, Hansson J, Hogg D, Holland EA, Kanetsky PA, Kefford RF, Landi MT, Lang JM, Leachman S, Mackie RM, Magnusson V, Mann G, Newton-Bishop J, Palmer JM, Puig S, Puig-Butille JA, Stark M, Tsao H, Tucker MA, Whitaker L, Yakobson E, The Lund Melanoma Study Group, and the Melanoma Genetics Consortium (GenoMEL). Features associated with germline CDKN2A mutations: A GenoMEL study of melanoma-prone families from three continents. J. Med. Genet. 2006 Aug 11; [Epub ahead of print]. [pubmed abstract]

Packer L, Pavey S, Parker A, Stark M, Johansson P, Clarke B, Pollock P, Ringner M, HAYWARD NK. Osteopontin is a downstream effector of the PI3-kinase pathway in melanoma. Carcinogenesis. 2006 Sep;27(9):1778-86. [pubmed abstract]

Goldstein AM, Chan M, Harland M, Gillanders EM, Hayward NK, Avril MF, Azizi E, Bianchi-Scarra G, Bishop DT, Bressac-de Paillerets B, Bruno W, Calista D, Cannon Albright LA, Demenais F, Elder DE, Ghiorzo P, Gruis NA, Hansson J, Hogg D, Holland EA, Kanetsky PA, Kefford RF, Landi MT, Lang J, Leachman SA, Mackie RM, Magnusson V, Mann GJ, Niendorf K, Newton Bishop J, Palmer JM, Puig S, Puig-Butille JA, de Snoo FA, Stark M, Tsao H, Tucker MA, Whitaker L, Yakobson E; Melanoma Genetics Consortium (GenoMEL). High-risk melanoma susceptibility genes and pancreatic cancer, neural system tumors, and uveal melanoma across GenoMEL. Cancer Res. 2006 Oct 15;66(20):9818-28. [pubmed abstract]

Loffler KA, Biondi CA, Gartside M, Waring P, Stark M, Serewko-Auret MM, Muller HK, Hayward NK, Kay GF. Broad tumour spectrum in a mouse model of multiple endocrine neoplasia type 1. Int J Cancer. 2006 Oct 16;120(2):259-267. [pubmed abstract]