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Molecular Pathology Research Laboratory
Molecular pathology

Molecular Pathology Research Laboratory

All disease processes in humans have a genetic component, either inherited or acquired by somatic mutation during cell division. It is important to identify genes and mutations that cause disease, predispose families to diseases, or are acquired during disease progression as these are important diagnostic and prognostic markers. They also provide direct targets and biological pathways for therapeutic intervention.

We are interested in how and why genetic mutations occur, how these changes cause diseases or disease predisposition such as cancer and autoimmunity, and ways of better treating and monitoring these diseases. Our model diseases are typically, blood cell diseases, such as leukaemias, lymphomas and autoimmunity (such as arthritis). We also work on rare or orphan diseases with unmet clinical needs, such as genetic diagnoses for family planning.

Our department is co-located with the ACRF Cancer Genomics Facility, which provides access to powerful cutting edge genetic/genomic technologies including bioinformatics, next-generation sequencing and sample preparation robotics. The Department performs both basic and translational research, which includes implementing these new technologies into its diagnostic tests for personalized medicine.

Current research projects

1. Genetics and pathologic mechanisms of haematological malignancy (HM = leukaemia and lymphoma) predisposition and progression
Our laboratory focuses on disease gene discovery and confirmation utilizing latest genomic technologies. We have accrued samples from over 90 families with predisposition to HM, which are invaluable resource for the identification of genetic and epigenetic changes leading to these and other cancers. Using a combination of strategies including state-of-the-art whole exome and genome next generation sequencing, we have found additional genes that segregate with diseased individuals in some of these families and/or are mutated in sporadic samples. We continue to hunt for additional genes/mutations in families and sporadic samples. Functional studies on potential and identified genes in vitro, ex vivo and in vivo in mice continue to expose mechanisms for predisposition and progression to HM.

2. Diagnostic implementation of NGS for personalised medicine
Next generation sequencing has the power to dramatically increase diagnostic test efficiencies, including pricing, and help in personalised medicine for genetic diseases and cancer. We are implementing NGS sequencing tests including panel sequencing for cancers such as lung, melanoma and colorectal, and whole exome sequencing for genetic diseases such as inherited familial cancers.

3. Genetic autopsy of perinatal death: diagnosis and discovery by Whole Genome Sequencing 
The causes of perinatal death and genetic termination of pregnancy (GTOP) often cannot be established despite autopsy and extensive investigation, often with long term psychological consequences for families. Establishing a cause of perinatal death or congenital abnormalities relies on post-mortem examination, which includes analysis of tissue samples, x-rays, chromosome studies and DNA-based testing. Despite this, the cause is often not identified. The advent of whole genome sequencing (WGS) has provided a powerful new tool for genetic testing. We are implementing WGS analysis to diagnose "unsolved" perinatal death and GTOP cases, which, together with functional assays, will also provide insights into the genetic mechanisms that underlie them.

Recent publications

Lewinsohn, M., A. L. Brown, L. M. Weinel, C. Phung, G. Rafidi, M. K. Lee, A. W. Schreiber, J. Feng, M. Babic, C. E. Chong, Y. Lee, A. Yong, G. K. Suthers, N. Poplawski, M. Altree, K. Phillips, L. Jaensch, M. Fine, R. J. D'Andrea, I. D. Lewis, B. C. Medeiros, D. A. Pollyea, M. C. King, T. Walsh, S. Keel, A. Shimamura, L. A. Godley, C. N. Hahn, J. E. Churpek and H. S. Scott. "Novel germ line DDX41 mutations define families with a lower age of MDS/AML onset and lymphoid malignancies." Blood 127: 1017-1023. (2016) 

Gagliardi L, Schreiber AW, Hahn CN, Feng J, Cranston T, Boon H, Hotu C, Oftedal BE, Cutfield R, Adelson DL, Braund WJ, Gordon RD, Rees DA, Grossman AB, Torpy DJ, Scott HS. (2014). ARMC5 mutations are common in familial bilateral macronodular adrenal hyperplasia. J Clin Endocrinol Metabol. 99, E1784-1792.

Shah S, Schrader KA, Waanders E, Timms AE, Vijai J, Miething C, Wechsler J, Yang J, Hayes J, Klein RJ, Zhang J, Wei L, Wu G, Rusch M, Nagahawatte P, Ma J, Chen SC, Song G, Cheng J, Meyers P, Bhojwani D, Jhanwar S, Maslak P, Fleisher M, Littman J, Offit L, Rau-Murthy R, Fleischut MH, Corines M, Murali R, Gao X, Manschreck C, Kitzing T, Murty VV, Raimondi SC, Kuiper RP, Simons A, Schiffman JD, Onel K, Plon SE, Wheeler DA, Ritter D, Ziegler DS, Tucker K, Sutton R, Chenevix-Trench G, Li J, Huntsman DG, Hansford S, Senz J, Walsh T, Lee M, Hahn CN, Roberts KG, King MC, Lo SM, Levine RL, Viale A, Socci ND, Nathanson KL, Scott HS, Daly M, Lipkin SM, Lowe SW, Downing JR, Altshuler D, Sandlund JT, Horwitz MS, Mullighan CG, Offit K. (2013). A recurrent germline PAX5 mutation confers susceptibility to pre-B cell acute lymphoblastic leukemia. Nat Genet. 45, 1226-1231.

Leong, D. W., J. C. Komen, C. A. Hewitt, E. Arnaud, M. McKenzie, B. Phipson, M. Bahlo, A. Laskowski, S. A. Kinkel, G. M. Davey, W. R. Heath, A. K. Voss, R. P. Zahedi, J. J. Pitt, R. Chrast, A. Sickmann, M. T. Ryan, G. K. Smyth, D. R. Thorburn and H. S. Scott. (2012). Proteomic and metabolomic analyses of a mitochondrial complex I deficient mouse model generated by spontaneous B2 Short Interspersed Nuclear Element (SINE) insertion into the NADH dehydrogenase (ubiquinone) Fe-S protein 4 (Ndufs4) gene. J Biol Chem. 287, 20652-20663.

Kazenwadel, J., G. A. Secker, Y. J. Liu, J. A. Rosenfeld, R. S. Wildin, J. Cuellar-Rodriguez, A. P. Hsu, S. Dyack, C. V. Fernandez, C. E. Chong, M. Babic, P. G. Bardy, A. Shimamura, M. Zhang, T. Walsh, S. M. Holland, D. D. Hickstein, M. S. Horwitz, C. N. Hahn, H. S. Scott and N. L. Harvey. (2012). Loss-of-function germline GATA2 mutations in patients with MDS/AML or MonoMAC syndrome and primary lymphedema reveal a key role for GATA2 in the lymphatic vasculature. Blood 119, 1283-1291.

Parker, W.T., Lawrence, R.M., Ho, M., Irwin, D.L., Scott, H.S., Hughes, T.P., and Branford, S. (2011). Sensitive Detection of BCR-ABL1 Mutations in Patients With Chronic Myeloid Leukemia After Imatinib Resistance Is Predictive of Outcome During Subsequent Therapy. J Clin Oncol 29, 4250-4259.

Hubert, F.X., Kinkel, S.A., Davey, G.M., Phipson, B., Mueller, S.N., Liston, A., Proietto, A.I., Cannon, P.Z., Forehan, S., Smyth, G.K., Wu, L., Goodnow, C.C., Carbone, F.R., Scott, H.S., and Heath, W.R. (2011). Aire regulates the transfer of antigen from mTECs to dendritic cells for induction of thymic tolerance. Blood 118, 2462-2472.

Hahn, C.N., Chong, C.-E., Carmichael, C.L., Wilkins, E.J., Brautigan, P.J., Li, X.-C., Babic, M., Lin, M., Carmagnac, A., Lee, Y.K., Butcher, C.M., Friend, K.L., Ekert, P.G., Kok, C.H., Gagliardi, L., Brown, A.L., Lewis, I.D., To, L.B., Timms, A.E., Storek, J., Moore, S., Altree, M., Escher, R., Bardy, P.G., Suthers, G.K., D'Andrea, R.J., Horwitz, M.S., and Scott, H.S. (2011). Heritable GATA2 mutations associated with familial myelodysplastic syndrome and acute myeloid leukemia. Nature Genetics 43, 1012-1017.