Assessing the clinical value of targeted massively parallel sequencing in a longitudinal, prospective population-based study of cancer patients.
BACKGROUND
Recent discoveries in cancer research have revealed a plethora of clinically actionable mutations that provide therapeutic, prognostic and predictive benefit to patients. The feasibility of screening mutations as part of the routine clinical care of patients remains relatively unexplored as the demonstration of massively parallel sequencing (MPS) of tumours in the general population is required to assess its value towards the health-care system.


METHODS
Cancer 2015 study is a large-scale, prospective, multisite cohort of newly diagnosed cancer patients from Victoria, Australia with 1094 patients recruited. MPS was performed using the Illumina TruSeq Amplicon Cancer Panel.


RESULTS
Overall, 854 patients were successfully sequenced for 48 common cancer genes. Accurate determination of clinically relevant mutations was possible including in less characterised cancer types; however, technical limitations including formalin-induced sequencing artefacts were uncovered. Applying strict filtering criteria, clinically relevant mutations were identified in 63% of patients, with 26% of patients displaying a mutation with therapeutic implications. A subset of patients was validated for canonical mutations using the Agena Bioscience MassARRAY system with 100% concordance. Whereas the prevalence of mutations was consistent with other institutionally based series for some tumour streams (breast carcinoma and colorectal adenocarcinoma), others were different (lung adenocarcinoma and head and neck squamous cell carcinoma), which has significant implications for health economic modelling of particular targeted agents. Actionable mutations in tumours not usually thought to harbour such genetic changes were also identified.


CONCLUSIONS
Reliable delivery of a diagnostic assay able to screen for a range of actionable mutations in this cohort was achieved, opening unexpected avenues for investigation and treatment of cancer patients.
1] Department of Pathology, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia [2] Division of Cancer Research, Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, Victoria 3002, Australia.
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Wong
Department of Pathology, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia.
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Fellowes
1] Division of Cancer Research, Department of Bioinformatics, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia [2] Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria 3010, Australia.
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Doig
Division of Cancer Research, Department of Bioinformatics, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia.
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Ellul
Department of Pathology, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia.
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Bosma
Agena Bioscience, Herston, Brisbane 4006, Australia.
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Irwin
Department of Pathology, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia.
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Vedururu
Department of Pathology, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia.
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Tan
Translational Genomics and Epigenomics Laboratory, Olivia Newton-John Cancer Research Institute, The Olivia Newton-John Cancer and Wellness Centre, Heidelberg, Victoria 3084, Australia.
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Weiss
Department of Pathology, Singapore General Hospital, Singapore 169608, Singapore.
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Chan
Clinical Informatics and Data Management Unit, Alfred Centre, Monash University, Melbourne, Victoria 3004, Australia.
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Lucas
1] Division of Cancer Research, Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, Victoria 3002, Australia [2] Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria 3010, Australia [3] The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Victoria Street, Darlinghurst, New South Wales 2010, Australia.
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Thomas
1] Department of Pathology, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia [2] Division of Cancer Research, Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, Victoria 3002, Australia [3] Translational Genomics and Epigenomics Laboratory, Olivia Newton-John Cancer Research Institute, The Olivia Newton-John Cancer and Wellness Centre, Heidelberg, Victoria 3084, Australia [4] Department of Pathology, The University of Melbourne, Parkville, Victoria 3010, Australia.
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Dobrovic
1] Division of Cancer Research, Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, Victoria 3002, Australia [2] Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria 3010, Australia.
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Parisot
1] Department of Pathology, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia [2] Division of Cancer Research, Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, Victoria 3002, Australia [3] Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria 3010, Australia [4] Department of Pathology, The University of Melbourne, Parkville, Victoria 3010, Australia.
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Fox
D004252:DNA Mutational Analysis / Q000379:methods*; D004273:DNA, Neoplasm / Q000032:analysis; D005260:Female; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics*; D009369:Neoplasms / Q000235:genetics*; D011446:Prospective Studies
D004273:DNA, Neoplasm; D009363:Neoplasm Proteins