PanCancer insights from The Cancer Genome Atlas: the pathologist's perspective

The Cancer Genome Atlas (TCGA) represents one of several international consortia dedicated to performing comprehensive genomic and epigenomic analyses of selected tumour types to advance our understanding of disease and provide an open‐access resource for worldwide cancer research. Thirty‐three tumour types (selected by histology or tissue of origin, to include both common and rare diseases), comprising >11 000 specimens, were subjected to DNA sequencing, copy number and methylation analysis, and transcriptomic, proteomic and histological evaluation. Each cancer type was analysed individually to identify tissue‐specific alterations, and make correlations across different molecular platforms. The final dataset was then normalized and combined for the PanCancer Initiative, which seeks to identify commonalities across different cancer types or cells of origin/lineage, or within anatomically or morphologically related groups. An important resource generated along with the rich molecular studies is an extensive digital pathology slide archive, composed of frozen section tissue directly related to the tissues analysed as part of TCGA, and representative formalin‐fixed paraffin‐embedded, haematoxylin and eosin (H&E)‐stained diagnostic slides. These H&E image resources have primarily been used to verify diagnoses and histological subtypes with some limited extraction of standard pathological variables such as mitotic activity, grade, and lymphocytic infiltrates. Largely overlooked is the richness of these scanned images for more sophisticated feature extraction approaches coupled with machine learning, and ultimately correlation with molecular features and clinical endpoints. Here, we document initial attempts to exploit TCGA imaging archives, and describe some of the tools, and the rapidly evolving image analysis/feature extraction landscape. Our hope is to inform, and ultimately inspire and challenge, the pathology and cancer research communities to exploit these imaging resources so that the full potential of this integral platform of TCGA can be used to complement and enhance the insightful integrated analyses from the genomic and epigenomic platforms. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

[1]  J. Desai,et al.  PLX4032 in metastatic colorectal cancer patients with mutant BRAF tumors. , 2010 .

[2]  Mithat Gönen,et al.  Morphological characterization of colorectal cancers in The Cancer Genome Atlas reveals distinct morphology–molecular associations: clinical and biological implications , 2017, Modern Pathology.

[3]  D. Stuart,et al.  The evolution of melanoma resistance reveals therapeutic opportunities. , 2013, Cancer research.

[4]  Mitko Veta,et al.  Going fully digital: Perspective of a Dutch academic pathology lab , 2013, Journal of pathology informatics.

[5]  Steven J. M. Jones,et al.  Comprehensive molecular characterization of human colon and rectal cancer , 2012, Nature.

[6]  S. Gabriel,et al.  Pan-cancer patterns of somatic copy-number alteration , 2013, Nature Genetics.

[7]  E. S. Kopetz,et al.  BRAF mutant colorectal cancer as a distinct subset of colorectal cancer: clinical characteristics, clinical behavior, and response to targeted therapies. , 2015, Journal of gastrointestinal oncology.

[8]  Tahsin Kurc,et al.  The tumor microenvironment strongly impacts master transcriptional regulators and gene expression class of glioblastoma. , 2012, The American journal of pathology.

[9]  Berkman Sahiner,et al.  Classification of follicular lymphoma: the effect of computer aid on pathologists grading , 2015, BMC Medical Informatics and Decision Making.

[10]  Nikhil Wagle,et al.  Clinical Acquired Resistance to RAF Inhibitor Combinations in BRAF-Mutant Colorectal Cancer through MAPK Pathway Alterations. , 2015, Cancer discovery.

[11]  Andrew H. Beck,et al.  Systematic Analysis of Breast Cancer Morphology Uncovers Stromal Features Associated with Survival , 2011, Science Translational Medicine.

[12]  Yuri E Nikiforov,et al.  High prevalence of BRAF mutations in thyroid cancer: genetic evidence for constitutive activation of the RET/PTC-RAS-BRAF signaling pathway in papillary thyroid carcinoma. , 2003, Cancer research.

[13]  Mari Mino-Kenudson,et al.  EGFR-mediated re-activation of MAPK signaling contributes to insensitivity of BRAF mutant colorectal cancers to RAF inhibition with vemurafenib. , 2012, Cancer discovery.

[14]  Cigall Kadoch,et al.  Mammalian SWI/SNF complexes in cancer: emerging therapeutic opportunities. , 2017, Current opinion in genetics & development.

[15]  Yi Gao,et al.  A Containerized Software System for Generation, Management, and Exploration of Features from Whole Slide Tissue Images. , 2017, Cancer research.

[16]  M. Stratton,et al.  Similarity of the phenotypic patterns associated with BRAF and KRAS mutations in colorectal neoplasia. , 2002, Cancer research.

[17]  Ganesh Rao,et al.  Identification of Histological Correlates of Overall Survival in Lower Grade Gliomas Using a Bag-of-words Paradigm: A Preliminary Analysis Based on Hematoxylin & Eosin Stained Slides from the Lower Grade Glioma Cohort of The Cancer Genome Atlas , 2017, Journal of pathology informatics.

[18]  Jesper Molin,et al.  Implementation of large-scale routine diagnostics using whole slide imaging in Sweden: Digital pathology experiences 2006-2013 , 2014, Journal of pathology informatics.

[19]  S. Sahlin,et al.  DNA ploidy and S-phase fraction in carcinoma of the gallbladder related to histopathology, number of gallstones and survival , 2014 .

[20]  A. Nicholson,et al.  Mutations of the BRAF gene in human cancer , 2002, Nature.

[21]  Anant Madabhushi,et al.  Statistical shape model for manifold regularization: Gleason grading of prostate histology , 2013, Comput. Vis. Image Underst..

[22]  Steven J. M. Jones,et al.  Genomic Classification of Cutaneous Melanoma , 2015, Cell.

[23]  Sanghoon Lee,et al.  Interactive phenotyping of large-scale histology imaging data with HistomicsML , 2017, bioRxiv.

[24]  R. Bernards,et al.  Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR , 2012, Nature.

[25]  Benjamin J. Raphael,et al.  Multiplatform Analysis of 12 Cancer Types Reveals Molecular Classification within and across Tissues of Origin , 2014, Cell.

[26]  Chris Sander,et al.  Emerging landscape of oncogenic signatures across human cancers , 2013, Nature Genetics.

[27]  K. Flaherty,et al.  Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. , 2012, The New England journal of medicine.

[28]  Cynthia Cohen,et al.  Whole Slide Imaging for Analytical Anatomic Pathology and Telepathology: Practical Applications Today, Promises, and Perils. , 2017, Archives of pathology & laboratory medicine.

[29]  Joel H. Saltz,et al.  Research and applications: Cancer Digital Slide Archive: an informatics resource to support integrated in silico analysis of TCGA pathology data , 2013, J. Am. Medical Informatics Assoc..

[30]  Steven J. M. Jones,et al.  Comprehensive and Integrated Genomic Characterization of Adult Soft Tissue Sarcomas , 2017, Cell.

[31]  T. Helliwell,et al.  Morphometric analysis, ploidy and response to chemotherapy in squamous carcinomas of the head and neck. , 1989, Pathology, research and practice.

[32]  Joshua M. Stuart,et al.  The Cancer Genome Atlas Pan-Cancer analysis project , 2013, Nature Genetics.

[33]  Aleix Prat Aparicio Comprehensive molecular portraits of human breast tumours , 2012 .

[34]  Steven J. M. Jones,et al.  Comprehensive Molecular Portraits of Invasive Lobular Breast Cancer , 2015, Cell.

[35]  A. Rashid,et al.  Histopathological identification of colon cancer with microsatellite instability. , 2001, The American journal of pathology.

[36]  Steven J. M. Jones,et al.  Comprehensive molecular portraits of human breast tumors , 2012, Nature.

[37]  M. Brose,et al.  Vemurafenib in patients with BRAF(V600E)-positive metastatic or unresectable papillary thyroid cancer refractory to radioactive iodine: a non-randomised, multicentre, open-label, phase 2 trial. , 2016, The Lancet. Oncology.

[38]  Steven J. M. Jones,et al.  Comprehensive molecular characterization of urothelial bladder carcinoma , 2014, Nature.

[39]  Karsten Schlüns,et al.  Core classification of lung cancer: correlating nuclear size and mitoses with ploidy and clinicopathological parameters. , 2009, Lung cancer.

[40]  Anant Madabhushi,et al.  Adaptive Energy Selective Active Contour with Shape Priors for Nuclear Segmentation and Gleason Grading of Prostate Cancer , 2011, MICCAI.

[41]  Ewert Bengtsson,et al.  Screening for Cervical Cancer Using Automated Analysis of PAP-Smears , 2014, Comput. Math. Methods Medicine.

[42]  Ellery Wulczyn,et al.  Deep learning-based survival prediction for multiple cancer types using histopathology images , 2019, PloS one.

[43]  Alexander V Penson,et al.  Integrative Analysis Identifies Four Molecular and Clinical Subsets in Uveal Melanoma. , 2018, Cancer cell.

[44]  Chao Wang,et al.  Identifying survival associated morphological features of triple negative breast cancer using multiple datasets , 2013, Journal of the American Medical Informatics Association : JAMIA.

[45]  Yi Gao,et al.  Towards Generation, Management, and Exploration of Combined Radiomics and Pathomics Datasets for Cancer Research , 2017, AMIA Joint Summits on Translational Science proceedings. AMIA Joint Summits on Translational Science.

[46]  Steven J. M. Jones,et al.  Integrated Genomic Characterization of Pancreatic Ductal Adenocarcinoma. , 2017, Cancer cell.

[47]  Steven J. M. Jones,et al.  Comprehensive molecular portraits of human breast tumours , 2013 .

[48]  Jeffrey Weber,et al.  Long-Term Outcomes in Patients With BRAF V600-Mutant Metastatic Melanoma Who Received Dabrafenib Combined With Trametinib. , 2017, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[49]  Rehan Akbani,et al.  Integrated Molecular Characterization of Uterine Carcinosarcoma. , 2017, Cancer cell.

[50]  A. Hauschild,et al.  Improved survival with vemurafenib in melanoma with BRAF V600E mutation. , 2011, The New England journal of medicine.

[51]  M. Sperandio,et al.  Heterogeneity, histological features and DNA ploidy in oral carcinoma by image-based analysis. , 2005, Oral oncology.

[52]  A. Hauschild,et al.  Vemurafenib in patients with BRAFV600 mutation-positive metastatic melanoma: final overall survival results of the randomized BRIM-3 study , 2017, Annals of oncology : official journal of the European Society for Medical Oncology.

[53]  D. Grignon,et al.  Primary sarcomas of the kidney. A clinicopathologic and dna flow cytometric study of 17 cases , 1990, Cancer.

[54]  Jun Kong,et al.  Computerized Pathological Image Analysis For Neuroblastoma Prognosis , 2007, AMIA.