Conjoint Gastroenterology Laboratory

Staff
Funding
Collaborators
Student Projects
Key Recent Publications
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Lab Head: Professor Barbara Leggett

RBWH Department of Medicine and Queensland Health Pathology Services, RBWH Research Foundation Clinical Research Centre

Colorectal cancer continues to be one of the most common internal malignancies occurring in the Australian population. One in twenty-three of our population will develop it during their lifetimes and half of these cases will not survive beyond five years. However, colorectal cancer has a great potential for prevention as most of these malignancies develop within pre-cancerous growths called polyps which can be removed at colonoscopy.

Colorectal cancer is a somewhat heterogeneous disorder. Across the spectrum of colorectal cancer types, there is a gradient of genetic causation tempered by the effects of environment such as smoking, diet and the use of anti-inflammatory drugs. Over the last decade our laboratory has contributed to the growing understanding that these different influences result in a number of distinct subtypes of colorectal cancer. These develop along different molecular genetic pathways and have characteristic somatic changes. This work has important implications for improving prevention and therapy of the disease.

For example, the subtype of sporadic cancers characterised by a defect in DNA mismatch repair resulting in a high level of microsatellite instability (MSI-H) occurs predominantly in elderly women, has a better prognosis than other colorectal cancers and responds differently to chemotherapy. Further work understanding the genetic alterations in this subtype may lead to novel therapies and diagnostic tests. In addition, the research we are conducting with Professor Jeremy Jass has made a major contribution to the understanding of colorectal cancer development by highlighting the role of the serrated polyp in this disorder. Previously ignored as innocuous, these polyps are now increasingly recognised worldwide as the precursors of a significant proportion of colorectal cancers, especially MSI-H cancers. This is already changing colonoscopy practice to better prevent these cancers. Very recently we have further confirmed the existence of the serrated pathway of cancer development by showing it is strongly associated with activating mutations of the oncogene BRAF.

Ongoing work in our laboratory focuses on discovering further genetic changes underlying different subtypes of colorectal cancer, especially MSI-H and other cancers where silencing of genes by methylation is frequent. We are currently developing microarray-based methylation profiling to identify subgroups of tumours with similar methylation defects, and as a way to identfy molecualr markers for subgroups of tumours which have differing clinical outcomes. To further explore the functional role of oncogenic mutations of BRAF in the serrated pathway, we are generating a conditional mouse model.

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Staff

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Funding

Collaborators

• Professor Stephen Meltzer of the University of Maryland at Baltimore has spent several years working with us on the molecular pathways involved in colorectal cancer
• Dr Shuiji Ogino, Harvard Medical School, Dana-Farber Cancer Institute, Boston, is collaborating with us on aspects of the CpG Island Methylator Phenotype

Student Projects

Projects are available for prospective Honours and PhD candidates with an interest in the genetic events underlying colorectal cancer development. Please contact Barbara Leggett for further information.

Key Publications

Jass, JR, Do K-A, Simms, LA, Iino, H, Wynter, C, Pillay, SP, Searle, JW, Radford-Smith, G, Young, J, Leggett, B. (1998) Morphology of sporadic colorectal cancer with DNA replication errors. Gut 42, 673-679.

Jeremy R Jass, Kelli G Biden, Margaret Cummings, Lisa A Simms, Michael Walsh, Estelle Schoch, Stephen J Meltzer, Caroline Wright, Jeffrey Searle, Joanne Young, Barbara A Leggett (1999) Characterisation of a subtype of colorectal cancer combining features of the suppressor and mild mutator pathways. J Clin Path 52, 455-60.

Jass JR, Iino H, Ruszkiewiez A, Painter D, Solomon MJ, Koorey DJ, Cohn D, Furlong KL, Walsh MD, Palazzo J, Bocker Edmonston T, Fishel R, Young J, Leggett BA (2000). Neoplastic progression and DNA microsatellite instability in hyperplastic polyposis of the colorectum. Gut 47, 43-9.

Wright CM, Dent OF, Barker M, Newland RC, Chapuis PM, Bokey EL, Young J, Leggett BA, Jass JR, Macdonald GA. The prognostic significance of extensive microsatellite instability in sporadic ACPS (stage III) colorectal cancer. Br J Surg 2000; 87:1197-1202

Joanne Young, Kelli G Biden, Lisa A Simms, Phillip Huggard, Rozemary Karamatic, Helen J Eyre, Grant R Sutherland, Nirmitha Herath, Melissa Barker, Gregory J Anderson, David R Fitzpatrick, Grant A Ramm, Jeremy R Jass, Barbara A Leggett. (2001) HPP1: a Transmembrane Protein-Encoding Gene Commonly Methylated in Colorectal Polyps and Cancers. PNAS 98, 265-270.

Vicki Whitehall, Jeremy R. Jass, Michael D. Walsh, Joanne Young, Barbara A. Leggett.(2001) Methylation of 0-6-Methylguanine DNA Methyltransferase Characterises a Subset of Colorectal Cancer with Low Level DNA Microsatellite Instability. Cancer Res 61, 827-830.

Leggett BA, Devereaux B, Biden K, Searle J, Young J, Jass JR. (2001) Hyperplastic polyposis: association with colorectal cancer. Am J Surg Path 25, 177-84.

Joanne Young, Lisa A Simms, Kelli G Biden, Coral Wynter, Vicki Whitehall, Rozemary Karamatic, rge, Jack Goldblatt, Ian Walpole, Sally-Anne Robin, Michael M Borten, Russell Stitz, Jeffrey Searle, Diane McKeone, Leigh Fraser, David R Purdie, Kay Podger, Ron Buttenshaw, Michael D Walsh, Melissa Barker, Barbara A Leggett, Jeremy R Jass (2001) Features of colorectal cancers with high-level microsatellite instability (MSI-H) occurring in familial and sporadic settings: parallel pathways of tumorigenesis. Am J Path 159, 2107-16.

Jass JR, Young, J, Leggett, BA (2002) Evolution of Colorectal Cancer: Change of pace and change of direction. J Gastroenterol and Hepatol 17, 17-26.

Jass JR, Whitehall, VLJ, Young, J, Leggett, BA (2002) Emerging Concepts in Colorectal Neoplasia. Gastroenterology 123, 862-76.

Whitehall VLJ, Wynter CVA, Walsh MD, Simms LA, Purdie D, Pandeya N, Young J, Meltzer SJ, Leggett BA, Jass JR. Morphological and molecular heterogeneity within non-microsatellite instability-high colorectal cancer. Cancer Res 2002; 62:6011-6014

Mori Y, Selaru FM, Sato F, Yin J, Simms LA, Xu Y, Olaru A, Deacu E, Wang S, Taylor JM, Young J, Leggett B, Jass JR, Abraham JM, Shibata D, Meltzer SJ. The impact of microsatellite instability on the molecular phenotype of colorectal cancer. Cancer Res 2003; 63:4577-4582

Kambara T, Simms LA, Whitehall VLJ, Spring KJ, Wynter CVA,, Walsh MD, Barker MA, Arnold S, McGivern A, Matsubara N, Tanaka N, Higuchi T, Young J, Jass JR, Leggett BA. BRAF mutation is associated with DNA methylation in serrated polyps and cancers of the colorectum. Gut 2004; 53:1137-1144

Mori Y, Yin J, Sato F, Sterian A, Simms LA, Selaru FM, Schulmann K, Xu Y, Olaru A, Wang S, Deacu E, Abraham JM, Young J, Leggett BA, Meltzer SJ. Identification of genes uniquely involved in frequent microsatellite instability colon carcinogenesis by expression profiling combined with epigenetic scanning. Cancer Research 2004; 64:2434-2438

Wright CM, Dent OF, Newland RC, Barker M, Chapuis PH, Bokey EL, Young JP, Leggett BA, Jass JR, Macdonald GA. Low-level microsatellite instability may be associated with reduced cancer-specific survival in sporadic stage C colorectal carcinoma. Gut 2005; 54:103-108

Weisenberger DJ, Siegmund KD, Campan M, Young J, Long TI, Faasse MA, Kang GH, Widschwedter M, Weener D, Buchanan D, Koh H, Simms L, Barker M, Leggett B, Levine J, Kim M, French AJ, Thibodeau SN, Jass J, Haile R, Laird PW. A distinct CpG island methylator phenotype in human colorectal cancer is the underlying cause of sporadic mismatch repair deficiency and is tightly associated with BRAF mutation. Nature Genetics 2006; 38:787-793

Spring KJ, Zhao ZZ, Karamatic R, Walsh MD, Whitehall VLJ, Pike T, Simms LA, Young J, James M, Montgomery GW, Appleyard M, Hewett D, Togashi K, Jass JR, Leggett BA. High prevalence of sessile serrated adenomas with BRAF mutations: a prospective study of patients undergoing colonoscopy. Gastroenterology 2006; 131:1400-1407

Chia J, Simms L, Cozzi S-J, Young J, Jass J, Walsh M, Spring K, Leggett B and Whitehall V. SnoN expression is differently regulated in microsatellite unstable compared with microsatellite stable colorectal cancers, BMC Cancer 2006; 6:252

Loh K, Chia JA, Greco S, Cozzi S-J, Buttenshaw RL, Bond CE, Simms LA, Pike T, Young JP, Jass JR, Spring KJ, Leggett BA, Whitehall VLJ. Bone Morphogenic Protein 3 inactivation is an early and frequent event in colorectal cancer development. Genes, Chromosomes and Cancer 2008; 47:229-460

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