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Genomics-based precision medicine has been successfully applied to heal cancer patients by ensuring that each patient receives the optimal treatment, but response rates are still often unexpectedly low. For some cancers, up to 50 % of patients may not respond to the predicted targeted drug treatment.2

being actively translated into proteins, which are the real drivers of biology.

Indeed, genomics will fail to distinguish the tadpole from the frog. Although these two are very distinct stages (phenotypes) in the life cycle of the very same organism, they share an identical genome but can be clearly differentiated by their proteomes. In a similar way, in many cases, the molecular basis of an individual cancer cannot be completely understood by using only genomic approaches. Therefore, the combination of genomic data with quantitative proteomic data on both protein expression and post-translational protein modifications – a novel approach termed proteogenomics3 – is now thought to be a very promising approach for improving precision medicine so that it better predicts individualized treatment for cancer patients. This unique combination will enable researchers and clinicians to address several fundamental questions: • Which genes and mutations are actually active and are being translated into proteins in a tumour? Although a tumour cell contains more than 10,000 different proteins4 and tumours are an

agglomerate of multiple cell types (cancerous and healthy), not every predicted mutation is actually present or relevant. • How many copies of each protein are really present in the tumour?

Depending on the protein, the copy number can vary from a few to a several million molecules per cell and copy number is often changed in tumours compared to healthy cells or tissues. Such changes can indicate increased or reduced activity of central pathways, and these changes are not readily predictable from the genome. • Are protein activities or signalling pathways altered? Dysregulated signalling (protein phosphorylation) is one of the main causes of cancer, and many drugs target tyrosine kinases.5 Protein phosphorylation levels and alterations, however, cannot be predicted from the genome.

Proteogenomic analysis of tumour biopsies holds the unique potential to allow researchers and clinicians to fully understand the molecular basis of an individual tumour by combining precise information on its genotype and its phenotype. Ideally, this will allow clinicians to select the best available treatment strategy, or to develop new treatments that not only effectively kill all of the cancer cells, but also prevent relapse.

At the Segal Cancer Proteomics Centre, we have already begun to translate our proteogenomics strategy into the clinic. We have extensively analyzed colorectal cancer tumour specimens using state-of-the-art proteomics technologies based on nano-LC-MS/MS using a non-targeted “shotgun” approach which provides an unbiased identification and quantification of proteins. This has enabled the high confidence identification of more than 8,000 proteins from individual tumours. Aligning this data with the corresponding genomic data from the same tumour samples (the genotype), has allowed us to clearly verify the presence of predicted mutations within the tumour on the protein level (the phenotype). Using this approach, we have been able to verify the presence of known driver mutations, such as KRAS G12V, in the tumour samples. After the specific mutation has been verified, we were then able to develop very sensitive targeted mass spectrometry assays which allow us to determine the actual level of that mutation in individual tumours using absolute quantification methods with high sensitivity and precision. Our goal is to provide unique molecular signatures for individual tumours. This will allow us to better define why specific patients do not respond to treatments predicted based on their genomic profiles, and thus improve the selection of appropriate treatment strategies.

References

1. Letai A. Functional precision cancer medicine-moving beyond pure genomics. Nat Med. 2017;23(9):1028-35. 2. Heist RS, Christiani D. EGFRtargeted therapies in lung cancer: predictors of response and toxicity. Pharmacogenomics. 2009;10(1):59-68. 3. Boja ES, Rodriguez H. Proteogenomic convergence for understanding cancer pathways and networks. Clin Prot. 2014;11(1):22. 4. Bekker-Jensen DB, Kelstrup CD,

Batth TS, Larsen SC, Haldrup C,

Bramsen JB, et al. An Optimized

Shotgun Strategy for the Rapid

Generation of Comprehensive

Human Proteomes. Cell Systems. 2017;4(6):587-99.e4. 5. Cohen P. Protein kinases--the major drug targets of the twenty-first century? Nature Reviews

Drug Discovery. 2002;1(4):30915.

Dr. Christoph H. Borchers is a professor at both the University of Victoria and McGill University, and director of the proteomics centres at both universities. Dr. Borchers’ expertise includes the improvement, development, and application of proteomics and metabolomics technologies, with a major focus on techniques for quantitative proteomics and metabolomics for clinical diagnostics.

Dr. René P. Zahedi is the Associate Director of the Segal Cancer Proteomics Center at McGill University. His research has focused on the mass spectrometrybased detection and quantitation of post-translationally modified proteins, with an emphasis on cancer-related signalling pathways and diagnostics.

To see this story online visit

https://laboratory focus.ca/proteogenomics-asan-approach-to-improvecancer-treatment/

neW Products

Vacuum ovens

The BEING line of Vacuum Ovens offers a variety of sizes to fit the unique needs of the users. Due to design, the BEING vacuum oven offers more usable space than similarly sized ovens. A large viewing window allows the user to quickly view their samples from a distance. The BEING controller offers superior temperature control and safety features. Features Include: • Easy to read color LCD display. • Real-time display of measured vacuum helps the user to monitor the progress of the drying sample • Inert Gas Inlet • Interior Chamber made from 304 stainless steel with a mirror polished finish making for easy cleaning • Adjustable shelves for added flexibility to accommodate various size containers • Exhaust valve switching and pump switch comes with an electromagnetic valve controller which is safe and reliable. • User-friendly and reliable operation while at the same time conserving vacuum pump power • The BEING Controller provides programmability for 7 periods and 9 steps for each period making for a total of 63 programmable steps

The BOV series consists of three models. The chamber sizes are 0.9 cu ft, 1.8 cu ft, and 3.2 cu ft. The temperature range is from 10° C above ambient to 200° C. www.beinglab-usa.com/vacuum-oven-200/.

liquid Biopsy Test

Roche announces the global availability of FoundationOne Liquid, a liquid biopsy test. Many cancer patients have an insufficient or inadequate tissue for genomic testing and may therefore benefit from FoundationOne Liquid. This new test joins FoundationOne CDx to deliver a complementary portfolio which provides insights to personalise a patient’s treatment plan. FoundationOne Liquid can identify circulating tumour DNA in the blood of people living with cancer and can identify 70 of the most commonly mutated genes in solid tumours, including microsatellite instability, a genomic signature which may help inform cancer immunotherapy-based treatment decisions. From a single blood sample, the liquid biopsy offers a quick and convenient option for some patients with solid tumours. FoundationOne Liquid meets a need for comprehensive genomic profiling for people who have an insufficient or inadequate tissue, including those with advanced non-small cell lung cancer, where an estimated 15 per cent of patients are not eligible for tissue biopsy and approximately 10 per cent have a biopsy size that is insufficient to evaluate. FoundationOne Liquid works well with FoundationOne CDx, a tissue-based genomic profiling test launched in the US earlier this year, to deliver a portfolio of comprehensive genomic profiling services for healthcare professionals. www.roche.com/products/product-details.htm?productid=9f2fe5f0baf4-434f-9bca-1e03c8c2b6e1

Mobile real-time PCR system

Ubiquitome Limited launches the Liberty16 at the American Society of Human Genetics conference, the latest product in its range of mobile real-time PCR systems. Designed to give users access to mobile, cutting-edge DNA testing, the Liberty16 offers DNA quantitation capability whenever and wherever it’s needed. The Liberty16 starts at $1,500, and Ubiquitome is taking pre-orders from researchers on a “first-come first-served” basis for the device at http://www.ubiquitomebio.com/Liberty16preorder. The Liberty16 comes with built-in lithium-ion batteries for two to three hours of mobile running time, as well as Bluetooth paired with an iPhone app that means you can run your samples anywhere. The device is sized to fit with whatever space a researcher must work with and is easily transported from site to site. It acts as a personal qPCR device that: • Offers great quality and value • Fits easily into your workspace • Comes with a sliding lid so samples are easy to load • s light, compact and easy to move around • Is designed for individual use, meaning you can test samples without waiting An open platform, the Liberty16 is compatible with industry standard consumables and chemistries such as Taqman®and SYBR® and comes in a sleek, robust, easy-to-clean package. http://www.ubiquitomebio.com/

DNA sequencing kit

The QuantideX NGS DNA Hotspot 21 Kit is an in vitro diagnostic, nextgeneration sequencing (NGS) panel for the detection of clinically relevant variants across a multitude of tumour types, including non-small cell lung cancer, colorectal cancer, and melanoma. The kit screens for over 1,500 known genomic variants, including single nucleotide variants (SNVs), insertions/deletions (indels), and structural rearrangements, many of which are treatable with novel therapies, inform on patient management, or are the subject of further clinical evaluation. The panel provides a robust and reliable NGS solution for the identification of clinically relevant targets. The QuantideX NGS DNA Hotspot 21 Kit combines Asuragen’s unique NGS-in-a-Box solution with a streamlined testing workflow to enable unprecedented NGS workflow efficiency and high sensitivity at low input amounts from precious FFPE samples. Reduced Complexity Assay incorporates sample-to-data solutions in a unique NGS-in-a-Box™ configuration • Detects >1,500 variants from commonly mutated genomic regions across multiple tumour types • End-to-end kitted solution • Fully integrated data analysis pipeline

Optimized Workflow Provides operational efficiencies to reduce testing costs, hands-on and total turnaround time • Reduced labour required for library preparation • Improved turnaround time enables higher throughput • Common workflow across portfolio streamlines training & implementation

Quality Performance Highly sensitive assay with integrated, Sample-Aware bioinformatics software and built-in quality checks to minimize erroneous results and sample failures • Highly sensitive detection of DNA-based variants • Low input (~20ng) of DNA from FFPE • Sample-Aware bioinformatics analysis and sample quality control https://asuragen.com/portfolio/oncology/quantidex-ngs-dna-hs21/