Staff

Synopsis

The Conjoint Gastroenterology Laboratory conducts a program of research based around colorectal cancer, a common internal malignancy which occurs primarily in adults.  Colorectal cancer exists as a spectrum of genetic and environmental causation ranging from autosomal dominant early onset syndromes to the development of a sporadic malignancy in old age.  Our work explores the underlying molecular genetic changes in colorectal cancers and how these relate to clinicopathological variables in both sporadic and familial patient groups.  To date we have found colorectal cancer to be a condition associated with diverse beginnings and developmental pathways which if left untreated will lead to a common endpoint.  Our work in recent years has largely resulted in a molecular pathology classification of colorectal cancers based on the microsatellite status of the tumour.  This has in turn lead us to examine the initiating stages of various sub-types of colorectal cancer.

We have carefully defined the characteristics of a type of sporadic cancers called high-MSI tumours (high level MSI) using a combination of pathology and molecular biology and shown that they are a distinctive subset with different biological behaviour and a better prognosis. MSI-high cancers develop as a result of methylation of the mismatch repair gene MLH1.  In addition, we have described a third pathway of MSI-low cancers with patterns of molecular aberrations somewhat different to common colorectal cancer and to MSI-high tumours. MSI-low cancers constitute 10% of sporadic colorectal cancers and are largely formed when the DNA adduct repair gene O-6-MGMT is disabled by hypermethylation.  

Colorectal cancer has a well defined natural history of morphologically recognisable developmental stages.   In most cases, colorectal cancer develops in a stepwise manner from a neoplastic precursor lesion called an adenoma.  Strategies for the prevention and early detection of CRC depend on the existence of a precursor lesion (adenoma) that evolves into cancer over a period of years and may be detected endoscopically or through the detection of occult bleeding.  Our work has shown that in a significant portion of cases, cancer develops in another lesion, the hyperplastic polyp.  We have found the MSI-high group of cancers in particular to be lacking mutations found in colorectal adenomas, but to have features generally associated with hyperplastic polyps.

We have investigated this alternative pathway of colorectal cancer development through the condition of hyperplastic polyposis.  We have now shown that hyperplastic polyposis is associated with cancer in over half the cases examined. However, we also found the polyps in hyperplastic polyposis to be generally lacking in the traditional genetic changes found in adenomas and common colorectal cancer. So our attention turned towards methylation as a mechanism of progression.  Using a global method which scanned the tumour genome for methylation changes, we isolated a sequence which is differentially methylated in hyperplastic polyps and spans 370 bp of the 5'UTR and part of the first exon of a novel gene which we have called HPP1 (hyperplastic polyposis 1 ).  Importantly, HPP1 is highly expressed in normal colonic mucosa, and not expressed in 80% of colorectal cancers.  Its expression encompasses both the epithelium and the stroma of normal mucosa and is lost in both these components in 70% of hyperplastic polyps.  

Projects for Students

The Conjoint Gastroenterology Laboratory has a number of projects available for students.  These projects are outlined on the Student projects available at QIMR in 2000 page.

Key Publications

1. Young, J, Searle, J, Buttenshaw, R, Thomas, L, Ward, M, Leggett, B, Chenevix-Trench, G. (1995) An AluVpA marker on chromosome 1 offers sensitive detection of replication errors and suggests that they manifest  at malignant transformation in sporadic colorectal tumours. Genes Chromosomes Cancer 12, 251-254.

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

3. 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 52,455-460.

4. Wright, C.M., Dent, O.F., Newland, R.C., Chapuis, P.M., Young, J., Leggett, B.A., Jass, J.R., Macdonald, G.A. The prognostic significance of extensive microsatellite instability in sporadic ACPS (stage III) colorectal cancer. Br J Surg 2000; 87,1197-1202.

5. Jass JR, Young J, Leggett BA  Hyperplastic polyps and DNA microsatellite unstable cancers of the colorectum. Histopathology 2000 Oct;37(4):295-301

6. 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. HPP1 : a Novel Transmembrane Protein-Encoding Gene Commonly Methylated in Colorectal Polyps and Cancers.Proc Natl Acad Sci U S A. 2001 98:265-70