Familial Cancer Laboratory

Joanne Young Staff
Funding
Collaborators
Key Recent Publications
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Lab Head: Associate Professor Joanne Young

Summary of Research Projects in the Laboratory
The Familial Cancer Laboratory studies genetic predisposition to cancer of the colon and endometrium largely by taking a tumour-centred approach. We study the features of tumours at the level of the individual patient, families and the population. Collaborative studies on endometrial cancer in families, and DNA sequence variation in colon cancer families are conducted with Dr Amanda Spurdle of the Molecular Cancer Epidemiology Laboratory.

STUDIES OF COLORECTAL CANCER IN FAMILIES

a) Collaborative Family Registry for Colorectal Cancer Studies (Colon CFR)
In 1997, an international consortium was established to study colorectal cancer occurring in families. Funded by the National Institutes of Health (USA), the program comprised centres located at the University of Melbourne, The Mayo Clinic, University of Hawaii, Cancer Care Ontario, University of Southern California, and the Fred Hutchinson Cancer Centre in Seattle. The CFR is dedicated to the establishment of a comprehensive collaborative infrastructure for interdisciplinary studies in the genetics and genetic epidemiology of colorectal cancer (CRC). The cooperating registries are collecting epidemiological information and biospecimens from families who represent the continuum of risk for CRC as well as from population-based controls. Families are invited to join through the participating Registry centers. The six Registry centers (and collaborating institutions) use standardized instruments and protocols to collect family history information, epidemiological and clinical data, screening behavior, and related biological specimens (blood samples and tumor blocks), with a strong emphasis on quality control (QC) measures throughout the collection, processing, and storing of data and samples. A unique feature of the CFR is the collection of a large number of families, ascertained through both clinic-based and population-based sampling using affected and unaffected probands, which are facilitating studies of penetrance and molecular pathology within established familial syndromes as well as studies characterizing new syndromes of familial colorectal cancer. Also, by design the CFR is establishing a cohort of probands and their families for future follow-up studies such as a cohort study of cancer-related outcomes in high-risk subjects, investigation of novel behavioral interventions and cancer prevention trials among at-risk family members. Consequently, the Registry is an invaluable resource for translational research in the genetic epidemiology of cancer. The Colon CFR site.

b) The Genetics of Serrated Neoplasia
Two major developmental pathways to colorectal cancer have been identified: the traditional adenoma-carcinoma sequence and the more recently described hyperplastic polyp-carcinoma sequence which has become known as the serrated pathway. The most well-characterised familial syndromes of colorectal cancer predisposition include FAP and Lynch syndrome which both evolve through the traditional pathway. We have recently described a novel syndrome of familial colorectal cancer which develops through the serrated pathway (SPS). In addition, we have recently shown that BRAF mutations are characteristic of both a subset of sporadic colorectal cancers and a condition called hyperplastic polyposis syndrome (HPS). Both of these conditions are associated with Anglo-Celtic ethnicity, and cigarette smoking. In HPS, patients usually develop multiple polyps and in half of the cases, patients present with at least one colorectal cancer. We propose that HPS, SPS and a subset of individuals with sporadic BRAF mutated cancers are part of a genetic continuum. We are currently searching for its underlying genetic cause using genome-wide linkage and association studies. The Genetics of Serrated Neoplasia site.

c) Breast and Colon Families Reports of families in which breast and colon cancer are frequent suggest that a proportion of these families have a dominantly inherited mutation that predisposes to both malignancies. In this project we are studying breast and colon families in the setting of Lynch syndrome, in serrated neoplasia families and in families where adenomas are the predominant precursor lesion.

d) Functional Significance of Unclassified Sequence Variants in Lynch Syndrome Families (collaboration headed by Dr Amanda Spurdle)
Lynch syndrome is an autosomal dominant cancer syndrome, mostly caused by mutations in mismatch repair (MMR) genes MLH1 and MSH2. MMR gene truncation mutations generally considered to be pathogenic can be identified in about half the families with suspected Lynch syndrome. However, >15% of Lynch syndrome families present with MMR gene sequence variants of uncertain clinical significance (UVs). Such UVs are well recognized to present a challenge in the clinical setting for genetic counselling, and thorough evaluation of their clinical significance would have direct clinical outcome for families concerned. Also, Loss of MMR tumour protein expression occurs in >90% of cases with clearly pathogenic mutations. Clinically, the MMR gene screened for mutations is often pre-selected on the basis of tumour expression results. MMR UVs will thus most often be detected in individuals with no tumour protein expression. It is thus more likely that MMR UVs, if they are the causative mutation, will cause transcript instability (inherent instability, or due to nonsense-mediated decay), or protein instability. We aim to test the functional consequences of a panel of UVs in vitro, and to compare the efficiency of a variety of bioinformatic approaches in predicting the observed aberrations associated with each UV.

STUDIES OF ENDOMETRIAL NEOPLASIA

a) Endometrial Cancer and HNPCC in under 50s
Endometrial cancer is the most common malignancy which occurs in females with hereditary non-polyposis colon cancer (HNPCC), and therefore shares some common genetic features with colorectal cancer. In HNPCC, endometrial cancer occurs in younger women than in the general population. In this project we are examining a cohort of endometrial cancer cases aged 50 and under to determine how commonly cases of HNPCC occur within this age group. In addition, we are analysing the pathology features of HNPCC endometrial cancer and comparing these with cases without HNPCC as it is likely that HNPCC cases will exhibit a particular set of characteristics which will allow us to distinguish them using pathology examination. Identification of a HNPCC endometrial cancer has important implications for both the woman and her relatives as their risk of HNPCC spectrum tumours is significantly increased.

b) Molecular Pathways in Later Onset Endometrial Cancer
A proportion of endometrial cancers show methylation of CpG islands within gene promoters. Analogous tumours have been shown in colorectal cancer to be associated with lifestyle factors and genetic predispositions, and to have a particular set of genetic markers and pathology characteristics which separates them from the bulk of colorectal cancers. This project will determine whether there are subsets of endometrial cancers underpinned by distinct genetic pathways such as the methylator phenotype seen in colorectal cancer and the disturbance of polycomb gene function seen in other hormone-related cancers. We will assess associations with lifestyle factors and family history, and examine whether precursor lesions to endometrial cancer can be identified by the presence of early genetic and epigenetic changes.

Staff

Labhead:	Dr Joanne Young
PostDoc:	Dr Mark Clendenning
Research Assistant:	Mr Aedan Roberts
Scientific Technical Officers:	Mr Michael Walsh Mr Dan Buchanan Mr Sven Arnold Ms Erika Pavluk Mrs Diane McKeone Ms Rhiannon Walters Mr Michael McKeone Ms Lucy Young Ms Sally-Ann Pearson

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Collaborators

Serrated Pathway Studies in Colorectal Cancer
Professor Jeremy Jass (St Marks Hospital)
Professor Annika Lindbloom (Karolinska Institute)
Professor Jane Green (Memorial University of Newfoundland)
Dr Dave Duggan (TGen)
Dr Derek Nancarrow (QIMR)
Dr Susan Parry (Middlemore Hospital)
Professor Finlay Macrae (Royal Melbourne Hospital)
Professor Albert de la Chapelle (Ohio State University Medical Centre)

CpG Island Methylation in Cancer
Professor Peter Laird (University of Southern California)

Australian Colorectal Cancer Family Study
Professor John Hopper and Dr Mark Jenkins (University of Melbourne)

Health 2020
Professor Graham Giles (Cancer Council Victoria)
Professor Dallas English (University of Melbourne)

Endometrial Cancer
ANECS
Dr Mandy Spurdle(QIMR)
Dr Andreas Obermair (Royal Brisbane and Womens Hospital)

Student Projects

Research projects are available within the Familial Cancer Laboratory for Bsc Honours and PhD students.

Key Publications

Young J, Simms LA, Biden KG, Wynter CVA, Whitehall VLJ, Karamatic R, George J, Goldblatt J, Walpole I, Robin S, Borten M, Stitz R, Searle J, McKeone D, Fraser L, Purdie DR, Podger K, Buttenshaw R, Walsh MD, Barker M, Leggett BA, Jass JR (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. [pubmed abstract]

McGivern A, Wynter CVA, Whitehall VLJ, Kambara T, Spring KJ, Walsh MD, Barker MA, Arnold S, Simms LA, Leggett BA, Young J, Jass JR. (2004) Promoter hypermethylation frequency and BRAF mutations distinguish hereditary non-polyposis colon cancer from sporadic MSI-H colon cancer. Familial Cancer 3: 101-7. [pubmed abstract]

Young J, Barker M, Simms LA, Walsh MD, Biden KG, Buchanan D, Buttenshaw R, Whitehall VLJ, Arnold S, Jackson L, Kambara T, Spring KJ, Jenkins M, Walker GJ, Hopper JL, Leggett BA, Jass JR. (2005) Evidence for BRAF Mutation and Variable Levels of Microsatellite Instability in a Syndrome of Familial Colorectal Cancer. Clin Gastroenterology and Hepatology 3: 254-63. [pubmed abstract]

J R Jass, K Baker, I Zlobec, T Higuchi, M Barker, D Buchanan & J Young (2006) Advanced colorectal polyps with the molecular and morphological features of serrated polyps and adenomas: Concept of a 'fusion' pathway to colorectal cancer J Pathol 49, 121-31. [pubmed abstract]

Young, J and Jass JR (2006) The Case for a Genetic Predisposition to Serrated Neoplasia in the Colorectum: Hypothesis and Review of the Literature Cancer Epi Biomarkers Prev 15, 1778-1784. [pubmed abstract] [pubmed abstract]

Daniel J. Weisenberger, Kimberly Siegmund, Mihaela Campan, Joanne Young, Tiffany I. Long, Mark A. Faasse, Gyeong Hoon Kang, Martin Widschwendter, Deborah Frieswyk, Joan Levine, Jeremy Jass, Robert Haile, Peter W. Laird (2006) A Distinct CpG Island Methylator Phenotype in Human Colorectal Cancer Is Tightly Associated with BRAF Mutation and Underlies Sporadic Mismatch Repair Deficiency. Nature Genetics 38, 787-93. [pubmed abstract]

Parham Minoo, Kristi Baker, Rashmi Goswami, George Chong, William D. Foulkes, Andrew R. Ruszkiewicz, Melissa Barker, Daniel Buchanan, Joanne Young, Jeremy R. Jass (2006) Extensive DNA methylation in normal colorectal mucosa in hyperplastic polyposis. Gut 55, 1467-74. [pubmed abstract]

Martin Widschwendter, Heidi Fiegl, Daniel Egle, Elisabeth Mueller-Holzner, Gilbert Spizzo, Christian Marth, Daniel J. Weisenberger, Mihaela Campan, Joanne Young, Ian Jacobs, Peter W. Laird (2007) Epigenetic stem cell signature in cancer Nature Genetics 39, 157-8. [pubmed abstract]

Andrew Yeoman, Joanne Young, Julie Arnold, Jeremy Jass and Susuan Parry, (2007) Hyperplastic Polyposis in the New Zealand Population: A condition associated with increased colorectal cancer risk and European ancestory. NZMJ 120, 31-39. [pubmed abstract]

Joanne Young, Mark Jenkins, Susan Parry, Bruce Young, Derek Nancarrow, Dallas English, Graham Giles, Jeremy Jass (2007). Serrated Pathway Colorectal Cancer in the Population: genetic considerations. Gut 56, 1453-1459.[pubmed abstract]

Michael D. Walsh, Margaret C. Cummings, Daniel D. Buchanan, Wendy Dambacher, Sven Arnold, Diane McKeone, Rebecca Byrnes, Melissa A. Barker, Barbara A. Leggett, Jeremy R. Jass, Amanda B. Spurdle, Joanne Young and Andreas Obermair (2008) Molecular, Pathology and Clinical Features of Early-Onset Endometrial Cancer: identifying presumptive Lynch syndrome patients. Clin Cancer Res 14, 1692-700 [pubmed abstract]

Young J (2008) Serrated Neoplasia of the Colorectum and Cigarette Smoking Gastroenterology (In Press) English DR, Young, JP, Simpson, JA, Jenkins MA, Southey, MC, Walsh MD, Buchanan DD, Barker MA, Haydon AM, Royce, SG, Roberts, A, Parry, S, Hopper JL, Jass JR, Giles GG (2008) Ethnicity and risk for colorectal cancers showing somatic BRAF V600E mutation or CpG Island Methylator Phenotype Cancer Epidemiology Biomarkers Prevention (In Press)

Funding Support

ID 496616. NHMRC 2008-2010. (Spurdle, Brown, Young) Assessment of mismatch repair gene sequence variants for clinical relevance.

ID 496615. Cancer Council Queensland 2008-2009. (Spurdle, Young, Stewart) Characterization of population-based endometrial cancer families: Redefinition of familial cancer syndromes.

UO1-CA74778, National Cancer Institute, 1997-2008. Hopper, Jass, Jenkins, Young et al Co-operative Family Registry for Colorectal Cancer Studies.

ID 442916, NHMRC 2007-2009 (Young, Jass) Studies of Genetic Predisposition to Develop Serrated Neoplasia in the Colorectum.

1 R01 CA123010 National Cancer Institute, 2007-2010 (Young, Jass) Genetics of Serrated Neoplasia

1 R01 CA118699 National Cancer Institute, 2007-2012 (Laird PI) CpG Island Methylator Phenotype in Human Colorectal Cancer

ID 496646 Cancer Council Queensland, 2008-2009 (Young, Jass) The Relationship Between Hyperplastic Polyposis and Serrated Colorectal Cancers in the Population

ID 509438 NHMRC, 2008-2010 (English, Young, Jenkins) Risk Factors for Subsets of Colorectal Cancer

Cancer Council Queensland 2007-2011 (Young) Senior Research Fellowship