Cancer

Cancer

Cancer has been identified by the Global Alliance for Genomics and Health as one of two key areas where a collaborative data-sharing approach has the most immediate potential to directly benefit patients.

The Australian Genomics Flagship model is designed to drive our research into nationwide implementation of genomic testing, integrating with our four research programs as frameworks for translation.

Each Flagship project is underpinned by strong existing national and international clinical, diagnostic and research partnerships. The partnerships are supporting a ‘virtuous cycle’ of rapid translation and implementation through the exchange of information between clinicians and researchers to evaluate pathogenicity, gene discovery and the development of innovative diagnostic and treatment tools.

Super WGS

The Australian Genomics ‘SUPER WGS’ Flagship is investigating the use of whole genome sequencing to better profile complex cases of Cancers of Unknown Primary (CUP). The researchers hope to be the first to investigate the use of whole genome sequencing for CUP.

Cancer of Unknown Primary (CUP) describes when a cancer has spread (‘metastasised’) but the starting point of the cancer (the ‘primary tumour’) cannot be located despite many diagnostic investigations.

CUP is challenging to treat and clinical care varies widely in Australia because there are no guidelines to direct the management of patients with CUP.

The integration of modern molecular assays into standard care is needed to improve outcomes for those with CUP and to guide future clinical trial research.

This Flagship builds on an existing cohort study called SUPER (‘Solving Unknown Primary CancER’) funded by Cancer Australia and the Victorian Cancer Agency. The study was established to investigate ways to improve outcomes in CUP patients through the use of molecular profiling, including DNA panel sequencing and gene-expression based site-of-origin predictive tests, called ‘SUPERDx’.

The SUPER study is also exploring the unmet needs of patients with CUP and assessing the economic impact of molecular profiling methods for CUP. Clinicians providing care to CUP patients are also being surveyed to report the impact of molecular profiling on individual patient care.

Leads

A/Prof Linda Mileshkin
Peter MacCallum Cancer Centre

Dr Richard Tothill
The University of Melbourne

Dr Dariash Etemadamoghadam
Peter MacCallum Cancer Centre

A/Prof Oliver Hofmann
The University of Melbourne

Prof Stephen Fox
Peter MacCallum Cancer Centre

Prof Penelope Schofield
Swinburne Institute of Technology

Prof Sean Grimmond
The University of Melbourne

Prof David Bowtell
Peter MacCallum Cancer Centre

Clinical site / state leads

Dr Madhu Singh
Barwon Health

A/Prof Ian Collins
South West Health Care

Dr Mark Warren
Bendigo Health

Dr Bo Gao
Blacktown and Westmead Hospitals

Prof Anna DeFazio
Blacktown and Westmead Hospitals

Dr Christopher Steer
Border Medical Oncology

Dr Nicholas Wilcken
Nepean Hospital

Dr Desmond Yip
Canberra Hospital

Prof Chrisotos Karapetis
Flinders Medical Centre

Dr Narayan Karanth
Darwin Health

Working Group

Dr John Pearson
QIMR Berghofer Medical Research Institute

Dr Stephen Kazakoff
QIMR Berghofer Medical Research Institute

Dr Daniel James
Pathology Queensland

Dr Mahendra Singh
Pathology Queensland

Dr Lakshmi Nandakumar
Pathology Queensland

The SUPER WGS is a national study, with metropolitan and regional clinical centres enrolling adult participants across Australia.

The clinical centres include:

  • Peter MacCallum Cancer Centre
  • Barwon Health
  • South West Health Care, Warrnambool
  • Bendigo Hospital
  • Westmead Hospital
  • Blacktown Hospital
  • Nepean Hospital
  • Border Medical Oncology
  • Canberra Hospital
  • Flinders Medical Centre
  • Darwin Health

The SUPER study is a national collaborative study and receives funding from:

  • Cancer Australia
  • Victorian Cancer Agency
  • Australian Genomics

Australian Genomics funding has enabled the expansion of the SUPER study to investigate if whole genome sequencing can improve the outcomes of patients whose tumours have been difficult to classify using these current molecular profiling methods (Australian Genomics ‘SUPER WGS’).

Relevant Publications

Carcinoma of unknown primary – rare but ripe for help from genomics?
Guccione L, Mileshkin L, Schofield P, Bowtell D. Carcinoma of unknown primary – rare but ripe for help from genomics?. Cancer Forum. 2015. 39 (1) : 44—46.

Massively-parallel sequencing assists the diagnosis and guided treatment of cancers of unknown primary
Tothill RW, Li J, Mileshkin L, Doig K, Siganakis T, Cowin P, et al. Massively-parallel sequencing assists the diagnosis and guided treatment of cancers of unknown primary. Journal of Pathology. 2013. 231 (4) : 413-23.

Epigenetic profiling to classify cancer of unknown primary: a multicentre, retrospective analysis
Moran S, Martinez-Cardus A, Sayols S, Musulen E, Balana C, Estival-Gonzalez A, et al. Epigenetic profiling to classify cancer of unknown primary: a multicentre, retrospective analysis. Lancet Oncology. 2016. 17 (10) : 1386-1395.

Lung Cancer Diagnosis

Lung cancer is the most common cause of cancer death in Australia. More than 11,500 people are diagnosed each year, with about 30 per cent surviving just one year.

Recent discoveries have demonstrated some patients benefit from therapy that targets certain genetic changes in their cancer cells. While current genetic testing approaches lead to about 15 per cent of lung cancer patients gaining benefit from these targeted therapies, this Flagship study aims to better these outcomes by using improved methods for cancer tissue collection, and more comprehensive approaches to genetic testing.

The Australian Genomics Lung Cancer Flagship builds on an existing research project funded by the QIMR Berghofer Medical Research Institute, Cancer Council Queensland and Cancer Australia that aims to improve the collection of cancer tissue for primary diagnoses and genetic testing using a reliable and highly-sensitive technique called Endobronchial Ultrasound Transbronchial Needle Aspiration (EBUS-TBNA).

The Flagship is expanding on this study to investigate the use of genomic testing (using whole exome sequencing and whole genome sequencing) following EBUS-TBNA in an effort to identify not only the small number of genetic changes currently tested for, but to potentially reveal all the different genetic changes that are present in the cancer.

The researchers hope that EBUS-TBNA and genomic testing will lead to better diagnostic approaches and identify a wider spectrum of genetic changes in lung cancer tissue that could be treated with new targeted therapies in the future.

Leads

Dr David Fielding
Royal Brisbane & Women’s Hospital
The University of Queensland

Dr Katia Nones
QIMR Berghofer Medical Research Institute

Dr Nicola Waddell
QIMR Berghofer Medical Research Institute

Dr Peter Simpson
The University of Queensland

Dr Valentine J Hyland
Pathology Queensland

Dr Andrew Dalley
The University of Queensland

Flagship Coordinator

Jun Hwa Son
Royal Brisbane & Women’s’ Hospital

Clinical site / state leads

Dr Jonathan Williamson
Liverpool Hospital

Dr Daniel Steinfort
Royal Melbourne Hospital

Dr Phan Tien Nguyen
Royal Adelaide Hospital

Working Group

Dr John Pearson
QIMR Berghofer Medical Research Institute

Dr Stephen Kazakoff
QIMR Berghofer Medical Research Institute

Dr Daniel James
Pathology Queensland

Dr Mahendra Singh
Pathology Queensland

Dr Lakshmy Nandakumar
Pathology Queensland

The following clinical centres are participating in the Lung Cancer Diagnosis Flagship:

  • Royal Brisbane and Women’s Hospital
  • Liverpool Hospital
  • Royal Melbourne Hospital
  • Royal Adelaide Hospital

The Lung Cancer Diagnosis Flagship receives funding from:

  • QIMR Berghofer Medical Research Institute
  • Cancer Council Queensland
  • Cancer Australia
  • Australian Genomics

Several of the Flagship researchers are also involved in the International Cancer Genome Consortium.

Relevant Publications

Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration for Diagnosis and Staging of Lung Cancer
Fielding D, Kurimoto N. Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration for Diagnosis and Staging of Lung Cancer. Clinical in chest medicine. 2018. 39 (1): 111-123.

Actionable Targets in High Risk Acute Lymphoblastic Leukaemia

There are 300 new cases of Acute Lymphoblastic Leukaemia (ALL) each year, affecting both children (~60% of all diagnoses) and adults. ALL is the largest cause of non-traumatic death in children, and many adults with ALL will die of their disease.

A number of recent genomic discoveries, that have the potential to improve outcomes for ALL patients, have been made using next generation genomic sequencing.  Many of these genomic alterations are potentially targetable with drugs that we currently have. Importantly patients with these genomic changes are not readily identified, using current diagnostic approaches.

Australian Genomics is working with a number of leukaemia researchers and clinicians around Australia to improve the outcomes of ALL patients. We work with the leading clinical trialist networks in the country, interacting with adult haematologists through the Australasian Leukaemia and Lymphoma Group (ALLG), and paediatric haemato-oncologists through the Australian and New Zealand Children’s Haematology/Oncology Group (ANZCHOG). Through these networks, we provide access to genomic testing for patients with ALL, and foster collaborations between clinicians and researchers.

Our goal is to develop a diagnostic pipeline in a clinical setting, to allow timely intervention using precision medicine approaches with the ultimate aim of improving outcomes for our patients. The project will also enable evaluation of the cost benefit of these approaches, particularly with respect to clinical outcomes (disease free and overall survival), and also compare quality of life outcomes between current and these future approaches.

Lead

Prof Deborah White
South Australian Health and Medical Research Institute (SAHMRI)

Project Manager

Bron Cambareri
South Australian Health and Medical Research Institute

Working Group

Dr Luciano Dalla-Pozza
The Children’s Hospital at Westmead.

A/Prof Paul Ekert
Murdoch Childrens Research Institute

Dr Chris Fraser
Children’s Health Queensland Hospital and Health Service

Dr Matthew Greenwood
Royal North Shore Hospital

Dr Rishi Kotecha
Perth Children’s Hospital

Prof Richard Lock
Children’s Cancer Institute

Prof Glenn Marshall
Sydney Children’s Hospital

Dr Andrew Moore
Children’s Health Queensland Hospital and Health Service

Dr Michael Osborn
Women’s and Children’s Hospital

A/Prof Tom Revesz
Women’s and Children’s Hospital

Dr Rosemary Sutton
Children’s Cancer Institute

Dr Toby Trahair
Sydney Children’s Hospital Randwick

Dr David Yeung
Royal Adelaide Hospital/SAHMRI

  • Austin Health
  • John Hunter Children’s Hospital
  • Liverpool Hospital
  • Perth Children’s Hospital
  • Prince of Wales Hospital
  • Princess Alexandra Hospital
  • Queensland Children’s Hospital
  • Royal Adelaide Hospital
  • Royal Melbourne Hospital
  • St Vincent’s Hospital
  • Sydney Children’s Hospital, Randwick
  • The Royal Children’s Hospital
  • Westmead Children’s Hospital
  • Westmead Hospital
  • Women’s and Children’s Hospital
  • Australian Genomics
  • Australasian Leukaemia and Lymphoma Group
  • Australian and New Zealand Children’s Haematology/Oncology Group
  • The REGALLIA study
  • National Health and Medical Research Council
  • Zero Childhood Cancer
  • Beat Cancer
  • Childhood Cancer Association

Relevant Publication

Pre-B acute lymphoblastic leukaemia recurrent fusion, EP300-ZNF384, is associated with a distinct gene expression.
McClure, B.J., Heatley, S.L., Kok, C.H., Sadras, T., An, J., Hughes, T.P., et al. (2018). Pre-B acute lymphoblastic leukaemia recurrent fusion, EP300-ZNF384, is associated with a distinct gene expression. Br J Cancer, 118(7), 1000—1004.

Precision medicine approaches may be the future for CRLF2 rearranged Down Syndrome Acute Lymphoblastic Leukaemia patients.
Page, E.C., Heatley, S.L., Yeung, D.T., Thomas, P.Q., & White, D.L. (2018). Precision medicine approaches may be the future for CRLF2 rearranged Down Syndrome Acute Lymphoblastic Leukaemia patients. Cancer Letters, 432, 69—74.

High prevalence of relapse in children with Philadelphia-like acute lymphoblastic leukemia despite risk-adapted treatment.
Heatley, S.L., Sadras, T., Kok, C.H., Nievergall, E., Quek, K., Dang, P., et al. (2017). High prevalence of relapse in children with Philadelphia-like acute lymphoblastic leukemia despite risk-adapted treatment. Haematologica, 102(12), e490—e493.

Differential expression of MUC4, GPR110 and IL2RA defines two groups of CRLF2-rearranged acute lymphoblastic leukemia patients with distinct secondary lesions
Sadras, T., Heatley, S.L., Kok, C.H., Dang, P., Galbraith, K.M., McClure, B.J., et al. (2017). Differential expression of MUC4, GPR110 and IL2RA defines two groups of CRLF2-rearranged acute lymphoblastic leukemia patients with distinct secondary lesions. Cancer Letters, 408, 92-101.

A novel somatic JAK2 kinase-domain mutation in pediatric acute lymphoblastic leukemia with rapid on-treatment development of LOH
Sadras, T., Heatley, S.L., Kok, C.H., McClure, B.J., Yeung, D., Hughes, T.P., et al. (2017). A novel somatic JAK2 kinase-domain mutation in pediatric acute lymphoblastic leukemia with rapid on-treatment development of LOH. Cancer Genetics, 216-217, 86-90.

iPredict Somatic Cancer Flagship

Solid tumours are growths of cancerous cells that can occur in many parts of the body and genomic sequencing of these cells can identify specific genetic changes within an individual’s cancer that are driving this growth.

This project is examining the clinical impact of a complex genomic sequencing program in advanced solid cancers in Australia as well as investigating the genomic testing experience from both patient and clinician perspectives.

Our goals are to enhance clinical trial participation and expand treatment options for patients through molecular profiling of a wide range of cancer types including a paediatric cohort, and focussed groups of lung, melanoma and rare cancers.

In addition to modelling the impact of large panel sequencing versus current standard of care testing, the cost/benefit of the personalised medicine approach will be evaluated, as well as analysis of clinical and laboratory processes to inform practices for efficient and patient focussed genomic testing advanced cancer patients in the future.

Leads

Prof Stephen Fox
Peter MacCallum Cancer Centre

Dr Jayesh Desai
Peter MacCallum Cancer Centre

Flagship Coordinator

Sophie O’Haire
Peter MacCallum Cancer Centre

Working Group

Andrew Fellowes
Peter MacCallum Cancer Centre

Kortnye Smith
Peter MacCallum Cancer Centre

A/Prof Paul Ekert
Murdoch Children’s Research Institute

A/Prof Hui Gan
Austin Health

Dr Ben Markman
Monash Health

Prof Michael Millward
Sir Charles Gairdner Hospital

Prof Kenneth O’Byrne
Princess Alexandra Hospital

  • Princess Alexandra
  • Austin Health
  • Monash Medical Centre
  • Peter MacCallum Cancer Centre
  • The Royal Children’s Hospital
  • Sir Charles Gairdner Hospital
  • Australian Genomics
  • Melbourne Genomics Health Alliance
  • NOMINATOR trial

Managing Patient Risk - Paediatric / AYA

This project is studying individuals with early-onset cancer expanding upon existing research cohorts: a paediatric cancer cohort (<16 years) and an AYA cohort (16-40 years) at diagnosis, by Whole Genome Sequencing.

It aims to investigate the heritable genetic drivers of cancer and to identify the spectrum of clinically actionable variants across a broad range of cancers.

We are linking genomic, pathology, clinical and pedigree data generated from the patients to create a knowledge bank. Participants with clinically ‘actionable’ germline variants will be offered participation in a risk management program through genetic services.

Lead

Prof David Thomas
Garvan Institute of Medical Research

Flagship Coordinator

Dr Kelly Prendergast
Garvan Institute of Medical Research

Paediatric Working Group

A/Prof Paul Ekert
Murdoch Children’s Research Institute

Prof Glenn Marshall
Sydney Children’s Hospital

Prof Roger Reddel
Children’s Medical Research Institute

Ms Vanessa Tyrrell
Children’s Cancer Institute

Young Adult Working Group

Dr Mandy Ballinger
Garvan Institute of Medical Research

A/Prof Paul James
Peter MacCallum Cancer Centre

Dr Mark Pinese
Garvan Institute of Medical Research

Dr Nicola Waddell
QIMR Berghofer Medical Research Institute

Companion Programs

Ms Mary-Anne Young
Genome.One

  • Garvan Institute of Medical Research
  • St Vincent’s Hospital
  • Prince of Wales Hospital
  • Chris O’Brien Lifehouse
  • Garvan Institute of Medical Research
  • Australian Genomics
  • NSW Office of Health and Medical Research
  • Lions Club International Foundation
  • Australian Genomic Cancer Medicine Program
  • Zero Childhood Cancer Initiative

The PiGeOn project: protocol for a longitudinal study examining psychosocial, behavioural and ethical issues and outcomes in cancer tumour genomic profiling
Best M, Newson AJ, Meiser B, Juraskova I, Goldstein D, Tucker K, et al. The PiGeOn project: protocol for a longitudinal study examining psychosocial, behavioural and ethical issues and outcomes in cancer tumour genomic profiling. BMC Cancer. 2018. 18 (1<) : 389.

Hereditary Cancer Syndromes - ICCon

The ICCon Partnership is a Cancer Council NSW-funded national collaboration of Familial Cancer Centres, research groups and consumer advocates focused on hereditary cancer syndromes.

Empirical observations at Familial Cancer Centres across Australia reveal many families with unusual clusters of cancers, or individuals with multiple primary cancers, often occurring at an early age. Such observations point toward the likelihood of a hereditary cancer syndrome. Hereditary (or ‘familial’) cancers are caused by the presence of one or more ‘gene variants’ that increase the risk of cancer. These gene variants are present from birth and are usually inherited from a parent. Individuals with such an inherited gene variant have a 50 per cent chance of passing it to each of their children.

The rapid evolution in genomic technology means that an adoption of a whole genome approach to germline genetic testing is fast approaching. However, this needs to be tested in the clinical environment to ensure its adoption is useful, safe and cost efficient. Furthermore, to integrate whole genome sequencing into routine clinical practice it needs to be ensured that the necessary infrastructure is in place.

In this Flagship we are working with families with a suspected familial cancer syndrome where previous routine genetic testing has not provided a diagnosis. For each affected cancer patient we are creating a report of possibly clinically actionable variants identified in a panel of 107 genes known to cause familial cancers, and discussing with the treating clinics the potential consequences of these variants for the affected families.

A further research component analyses the entire genome. We are developing sequence analysis methods to identify structural changes that would impact the function of known hereditary cancer genes, and we are also looking for variants impacting genes not yet known to play a role in hereditary cancers. If considered relevant, findings from this research component and the potential consequences for the affected families will be discussed with the clinics.

Lead

Prof Robyn Ward
The University of Sydney

A/Prof Paul James
Peter MacCallum Cancer Centre

A/Prof Gillian Mitchell
Peter MacCallum Cancer Centre

A/Prof Amanda Spurdle
QIMR Berghofer Medical Research Institute

Flagship Coordinator

Dr Uwe Dressel
The University of Queensland

Working Group

Aimee Davidson
QIMR Berghofer Medical Research Institute

Dr Helen Mar Fan
Genetic Health Queensland

Dr John Pearson
QIMR Berghofer Medical Research Institute

Dr Nicola Poplawski
Adult Genetics Unit at the Royal Adelaide Hospital

Emma Tudini
QIMR Berghofer Medical Research Institute

Dr Nic Waddell
QIMR Berghofer Medical Research Institute

  • Peter MacCallum Cancer Centre
  •  The Royal Melbourne Hospital
  • Monash Health Familial Cancer Centre
  • Austin Health Clinical Genetics Service
  • Prince of Wales Hospital
  • Royal Prince Alfred Hospital
  • Westmead Hospital
  •  The Royal Brisbane and Women’s Hospital
  • Royal Adelaide Hospital
  • King Edward Memorial Hospital
  • Royal Hobart Hospital
  • Australian Genomics
  • Cancer Council NSW
  • Bioplatforms Australia
  • QIMR Berghofer Medical Research Institute