Southey laboratory - Cancer Genomics
| Contact: | Melissa Southey |
|---|---|
| Phone: | +61 3 8344 4895 |
| Fax: | +61 3 8344 4004 |
| Email: | msouthey@unimelb.edu.au |
The Southey laboratory conducts population-based studies of the genetic epidemiology of breast, pediatric, prostate and colorectal cancer. Only a small proportion of these cancers can be explained by what is currently known about their causes. The factors responsible for the majority of early-onset cancers arising in individuals with a strong family history are yet to be identified. Our program is utilising our international and local cancer research resources to:
1) further characterise identified cancer susceptibility genes, that may impact on clinical genetics services,
2) identify additional cancer susceptibility genes via:
- the conduct of new-generation linkage studies; and
- studies of the molecular determinants of mammographic density, and
3) develop methods that will identify young people who are most likely to carry a germline mutation in a known cancer predisposition gene at the time of their diadnosis of cancer.
This research will provide definitive information about cancer susceptibility genes and may identify further susceptibility genes that impact on clinical genetics services worldwide. This will have immediate and significant impact on the clinical management of all individuals and families with early-onset and miltiple-cases of cancer and may provide additional target information for future treatment strategies and drup development.
Key research areas are
Studies of the molecular determinants of mammographic density
Percent mammographic density (PMD) describes the relative proportion of white shadowing against the black appearance of predominantly fatty areas on a mammogram. The type of breast tissue represented by the white shadows is not understood, and remains controversial. Increasing PMD is associated with a substantial increase in breast cancer risk. Variation in MD is the most significant breast cancer risk factor outside the presence of a mutation in a known breast cancer predisposition gene, with an increased breast cancer risk of ~5 fold when comparing the highest versus lowest quintile categories of density. Despite this substantial increase in risk, the underlying biological explanations are poorly understood and somewhat controversial. It is clear that mammographic density is not simply a summation of the effect of other known breast cancer risk factors as there is a significant hereditary component to mammographic density (unrelated to known breast cancer predisposition genes). The histopathologic basis of mammographic density and its cellular and molecular basis remains unclear.
Our hypotheses are that genetic and epigenetic variation play a role in determining mammographic density and we are conducting several different studies to investigate these hypotheses including a large international linkage study, a GWAS of mammographic density extremes and a gene expression and methylation profiling study of highly characterized fresh breast tissues which together will start to unfold the molecular determinants of mammographic density and its associated breast cancer risk.
Research Resources
The Australian Twins and Sisters Study of Mammographic density.
The Breast Cancer Family Registry (NIH, USA).
Collaborative study prospectively collecting and mammographically characterizing fresh breast tissue for molecular analysis.
Breast Cancer
Some of the remaining familial aggregation of breast cancer, and a substantial proportion of families with multiple cases of early-onset disease, may be explained by rare genetic mutations that are associated with a high risk of breast cancer. Recent work by us and by others has confirmed that cancer predisposition genes (some not traditionally associated with multiple-case breast cancer families), such as TP53, explain some of the remaining genetic breast cancer susceptibility.
We are conducting linkage studies that improve upon prior international linkage studies focusing on early-onset multiple-case breast cancer families (carrying specific histological types of breast cancer) and only using families where it has been possible to exclude the involvement of other breast cancer susceptibility genes including BRCA1, BRCA2, TP53, CHEK2, ATM, BRIP1 and PALB2.
PALB2 is a gene for which deleterious mutations are associated with, on average, a “moderate” increase in risk (2- to 3-fold). However, the data are consistent with this increased risk depending on other familial/ genetic factors. If true, there are major implications for clinical practice. Some women who carry germline mutations in PALB2, in particular those with a strong family history of the disease, may be at high risk of breast cancer. We are conducting a large population-based and clinic-based case-control-family study to estimate breast cancer risk for carriers under different models. To complement this work we have established an international interest group to further advance our understanding of the genetic variation of PALB2, the associated histopathology and its underlying biology. We are also pursuing similar studies of BRIP1-associated breast cancer.
BRCA1 mutation-associated breast cancers have distinctive morphological features that can assist the identification of young women at high risk of being carriers at the time of breast cancer diagnosis. We have devised criteria for identifying these women and are advancing research to validate these criteria and integrate them into clinical genetic practice. However, a proportion of women diagnosed with this type of breast cancer (BRCA1-like breast cancer) are not carriers of germline BRCA1 mutations. We are investigating the underlying genetic explanation of these cancers by conducting studies of BRCA1 promoter methylation, linkage studies involving families with early-onset multiple cases of BRCA1-like breast cancer and the possibility of other BRCA1 mutations that are not yet described and are not identifiable by our current mutation screening methods. We are also pursuing similar research with breast cancers carrying BRCA2 mutations to further unravel their heterogeneous molecular pathology.
Recently there has been substantial investigation into the role of common genetic variation in breast cancer risk. After much investment and almost predominantly null findings, especially from attempted replications, it appears that common genetic variants associated with an increased (or decreased) risk of breast cancer have such a low frequency and small associated risk that they cannot be detected by anything but extremely large studies, such as the pooled studies of 30,000 cases and controls of the Breast Cancer Association Consortium (BCAC), to which we are contributing.
Research Resources
Breast Cancer Linkage Consortium
Breast Cancer Family Registries (NIC, USA)
Breast Cancer Association Consortium
KConFab
Melbourne Collaborative Cohort Study
Colorectal Cancer
We have defined criteria that identify young people affected with colorectal cancer who carry germline mutations in mismatch repair genes. These criteria have been labelled by an editor in the Journal of Clinical Oncology as the “Melbourne Criteria” (superseding the Amsterdam and Bethesda criteria) and we are now pursing research that will validate these criteria and integrate them into clinical genetic practice. We are also conducting research to identify additional colorectal cancer susceptibly genes and to further characterise the molecular pathology of this disease.
Research Resources
Victorian Colorectal Cancer Family Study.
Colorectal Cancer Family Registry (NIH, USA)
Prostate Cancer
Prostate cancer is proving to be a genetically complex disease, with possibly many loci involved in development and progression. Over the last decade, we have been building resources in Australia, along with local and international scientific collaborations, to increase our ability to find and characterise prostate cancer susceptibility genes.
Via studies of breast cancer families, BRCA2 mutations are now thought to account for up to 5% of prostate cancer diagnosed under the age of 56 years and convey a 23-fold increased risk of prostate cancer to age 56. We are investigating the role of BRCA2 and other known cancer susceptibility genes (eg PALB2) in prostate cancer predisposition and progression.
Our group has been collaborating with international consortia for prostate cancer genetics research for more than a decade. Together we planned and performed a genome wide scan which identified many common genetic variants that are strong candidates to be prostate cancer risk genes/variants. Many of these variants have now been validated in our worldwide consortium of 13 groups (PRACTICAL). This study is providing strong confirmation of these susceptibility loci in multiple populations and shows that they make an important contribution to prostate cancer risk prediction.
Research Resources
KConFab
Australian Risk Factors for Prostate Cancer Study
Australian Prostate Cancer Family Study
Early Onset Prostate Cancer Study
Melbourne Collaborative Cohort Study
PRACTICAL
ACTANE
Objectives
- To conduct large well designed population-based studies of common cancers.
- To identify and characterise the molecular and genetic components of cancer predisposition, development and progression.
- To develop tools to identify individuals at high risk of carrying mutations in a cancer predisposition genes.
Recent Achievements
- Continue to build a significant biological repository for genetic epidemiological studies.
- Demonstrated the heterogeneity of common cancers.
- Demonstrated that for many cancer predisposition genes family history is neither sensitive or specific to an individual's mutation status.
- Population-based estimation of the prevalence and penetrance of key cancer predisposition genes.
Techniques
- Molecular Biology
- Genetic variation profiling
- Mutation scanning
- Expression profiling
- Linkage studies
- GWAS
- Biospecimen Handling
- Immunohistochemistry
- Histopathology/Molecular Pathology
- Tissue Culture
Collaborations
University:
Professor John Hopper, Centre for Molecular, Environmental, Genetic and Analytic Epidemiology.
Professor Ingrid Winship, Chair in Adult Clinical Genetics.
A/Prof Mark Jenkins, Centre for Molecular, Environmental, Genetic and Analytic Epidemiology.
Professor Dallas English, Centre for Molecular, Environmental, Genetic and Analytic Epidemiology.
Dr Jennifer Stone, Centre for Molecular, Environmental, Genetic and Analytic Epidemiology.
External:
National Collaborators:
Prof Graham Giles, Cancer Council Victoria.
A/Prof Melissa Brown, University of Queensland.
A/Prof Ian Campbell, Peter MacCallum Cancer Institute.
A/Prof Rik Thompson, St Vincent’s Institute of Medical Research.
Dr Izi Haviv, Baker IDI Heart and Diabetes Institute.
Dr Vanessa Hayes, Children’s Cancer Institute Australia.
Dr Gianluca Severi, Cancer Council Victoria.
Professor Stephen Fox, Peter MacCallum Cancer Institute.
Dr Alex Dobrovic, Peter MacCallum Cancer Institute
kConFab
International Collaborators:
Professor Rosalind Eales, University of Cambridge, UK.
Professor William Foulkes, McGill University, Canada.
Professor Ian Tomlinson, Cancer Research UK London, UK.
Professor David Goldgar, University of Utah, USA.
Professor Robert Winquist, Oulu University Hospital and University of Oulu, Finland.
Professor Doug Easton, University of Cambridge, UK.
Dr Susan Ramus, University College London, UK.
Dr Magali Olivier, International Agency for Research on Cancer, France.
Dr Sean Tavtigian, International Agency for Research on Cancer, France.
Dr Johanna Rommens, Hospital for sick Children, Canada.
Dr Leda Carvalho, Guilherme Alvaro Hospital, San Paulo, Brazil.
Professor Boris Pasche, The University of Alabama at Birmingham, USA.
Professor Susan Neuhausen, University of California Irvine, USA.
Dr Graham Byrnes, International Agency for Research on Cancer, France.
Professor Peter Devilee, University of Leiden, The Netherlands.
The Breast Cancer Family Registry, NCI, USA.
Coriell Cell Repositories, USA.
Funding
- NHMRC
- Cancer Council Victoria
- Cancer Australia
- NCI/NIH (USA)
- The University of Melbourne
- Victorian Breast Cancer Research Consortuim
- Prostate Cancer Foundation of Australia
- National Breast Cancer Foundation
Recent Publications
- Southey, M.C., MA. Jenkins, L. Mead, J. Whitty, G. Grubb, DJB. St John, F. Macrae, J. Young, M. Barker, M. Walsh, SG. Royce, J Jass, GG. Giles, JL. Hopper. Mismatch repair gene mutation testing, immunohistochemistry and microsatellite instability testing in a population-based series of unselected early-onset colorectal cancers. J. Clin. Oncol. 2005 Sep 20;23(27):6524-32.
- Hopper JL, Hayes V, Spurdle AM, Chenevix-Trench G, Jenkins MA, Milne RL, Dite GS, McCredie MRE, Giles GG, Southey, M.C.. A protein truncating mutation in CYP171A in three sisters with early-onset breast cancer. Hum Mutat. 2005 Oct;26(4):298-302.
- A Tesoriero, E Wong, M Jenkins, JL Hopper, M Brown, G Chenevix-Trench, A Spurdle, Southey, M.C.. Characterization of BRCA1 and BRCA2 splice site variants identified in multiple case breast cancer families. Hum Mutat. 2005 Oct 6;26(5):495
- K. Alsop, S. Royce, M.Jenkins, L. Mead, L. Smith, A. Tesoriero, G. Giles, J. Hopper and Southey, M.C.. Distinct pathways of tumourigenesis in early onset colorectal cancer. Eur J Cancer. 2006 Jul;42(10):1357-61.
- L. Smith, A. Tesoriero, L. Mead, S. Royce, G. Grubb, J. Young, G. G. Giles, M. Jenkins, F Macrae, J. L. Hopper and Southey MC. Genomic rearrangements in hMSH2 and hMLH1 in early-onset colorectal cancer: A population-based study. Clinical Genetics, 2006 Sep;70(3):250-2.
- Paula Smith, Lesley McGuffog, Douglas F Easton.Australia group: Graham J Mann, Gulietta M Pupo, Beth Newman, Georgia Chenevix-Trench, kConFab Investigators.IARC group: Csilla Szabo, Melissa Southey, Hélène Renard, Fabrice Odefrey, Henry Lynch, Dominique Stoppa-Lyonnet, Fergus Couch, John L Hopper, Sandra Buys, Irene Andrulis, Rubie Senie, BCFS, BRCAX Collaborators group, David E Goldgar. Netherlands group: Rogier Oldenburg, Karin Kroeze-Jansema, Jaennelle Kraan, Hanne Meijers-Heijboer, Jan GM Klijn, Christi van Asperen, Inge van Leeuwen, Hans F.A. Vasen, Cees J. Cornelisse, Peter Devilee, UK group: Linda Baskcomb, Sheila Seal, Rita Barfoot, Jon Mangion, Anita Hall, Sarah Edkins, Elizabeth Rapley, Richard Wooster, Jenny Chang-Claude, Diana Eccles, D. Gareth Evans, P Andrew Futreal, Katherine L Nathanson, Barbara L Weber, the Breast Cancer Susceptibility Collaboration (UK), Nazneen Rahman, Michael R Stratton. A genome wide linkage search for breast cancer susceptibility genes. Genes Chromosomes Cancer, 2006 Jul;45(7):646-55.
- Jenkins MA, Baglietto L, Dowty JG, Van Vliet CM, Smith L, Mead LJ, Macrae FA, St John DJ, Jass JR, Giles GG, Hopper JL, Southey, M.C.. Cancer risks for mismatch repair gene mutation carriers: a population-based early onset case-family study. Clin Gastroenterol Hepatol. 2006 Apr;4(4):489-98.
- Smith LD, Tesoriero AA, Ramus SJ, Dite G, Royce SG, Giles GG, McCredie MRE, Hopper JL, Southey, M.C.. BRCA1 promoter deletions in young women with breast cancer and a strong family history: a population based study. Eur J Cancer. 2007 Mar;43(5):823-7.
- Southey, M.C., Jenkins MA, Hopper JL, Macrae F, Giles GG. Is it time to abandon microsatellite instability as a pre-screen for selecting families for mutation testing for mismatch repair genes? Reply. Journal of Clinical Oncology 2006;24(12):1962-1963
- DF Easton et al., (Breast Cancer Association Consortium). A genome-wide association study identifies multiple novel breast cancer susceptibility loci, Nature, May 2007.
- Cox A, Dunning AM, et al (Breast Cancer Association Consortium). A common coding variant in CASP8 is associated with breast cancer risk. Nature Genetics 2007 Mar;39(3):352-8.
- Saunders IW, Hannan GN, Brohede J, Giles GG, Jenkins MA, Hopper JL, Southey MC. A range of simple summary genome-wide statistics for detecting genetic linkage using high density marker data. Genet Epidemiol. 2007 Apr 18
- LJ Mead, MA Jenkins, J Young, SG Royce, L Smith, DJB St John, F Macrae, GG. Giles, JL Hopper and MC Southey. Microsatellite instability markers for identifying early-onset colorectal cancers caused by germ-line mutations in DNA mismatch repair genes. Clin Cancer Res. 2007 May 15;13(10):2865-9.
- F Hammet, J George, AA Tesoriero, MA Jenkins, C Schroen, L Smith, A Grabosch-Meehan, G Dite, MRE McCredie, GG Giles, SV Tavtigian, JL Hopper, MC Southey Is BRCA2 c.9079 G>A a predisposing variant for early onset breast cancer? Breast Cancer Research and Treatment 2007 Jun 5;