Molecular Pathology Approach to Cancer
5th EACR-OECI Joint Training Course Molecular Pathology Approach to Cancer part of the EACR Conference Series 2015 11 - 13 May 2015 De Rode Hoed, Amsterdam, the Netherlands Scientific Organising Committee Richard Marais (UK) • Jorge Reis-Filho (USA) Giorgio Stanta (Italy) • Marc van de Vijver (the Netherlands) Course Booklet Join EACR as a member today The European Association for Cancer Research is Europe’s largest membership association for cancer researchers Join EACR and support both your own professional development and the advancement of European cancer research, politically, economically and scientifically Membership fees Regular members: €40 for one year / €120 for four years Young Investigators*: €60 for four years * less than four years postdoctoral experience 98% of EACR members would recommend membership to colleagues * Students: €25 for duration of your studies (up to four years) We offer our members: • Representation and advocacy at the highest levels of European cancer policy discussion as a founding member of ECCO, the European Cancer Organisation • Communication via our excellent website with dedicated membership area, open forum and links to partner international cancer organisations • Reduced registration rates at the EACR Biennial Congress and meetings in the EACR Conference Series • Advance information: regular email bulletins on the latest deadlines, scientific meetings, awards and other significant events and initiatives • Travel Fellowships of up to €2,500 to gain knowledge, skills and experience in centres of excellence • Meeting Bursaries to support participation in the EACR Congress and other EACR meetings • Prestigious awards such as the Mike Price Gold Medal and the Pezcoller FoundationEACR Cancer Researcher Award * EACR Members’ Survey, December 2013 • Networking: make contact with members through the EACR Member Directory or discussion forums, at meetings, or through job and study opportunities on our website • Reduced subscription rates to European Journal of Cancer and other offers from publishers www.eacr.org 5th EACR-OECI Joint Training Course Molecular Pathology Approach to Cancer 11 - 13 May 2015 De Rode Hoed, Amsterdam, the Netherlands Monday 11 May 2015 11.30 Registration Registration and collection of badges takes place from 11.30 at the registration desk in the Reception Hall 12.30 - 13.30 Lunch 13.30 - 13.45 Welcome 13.45 - 14.15 “Molecular pathology: why bother?” Jorge Reis-Filho (USA) 14.15 - 14.30 Questions 14.30 - 15.00 “Principles of cell signal and signal transduction” Richard Marais (UK) 15.00 - 15.15 Questions 15.15 - 15.45 “Molecular pathology methods in research and practice” Giorgio Stanta (Italy) 15.45 - 16.00 Questions 16.00 - 16.30 Coffee Break 16.30 - 17.00 “The molecular pathology of breast cancer” Marc van de Vijver (Netherlands) 17.00 - 17.15 Questions 19.30 Course Dinner: Restaurant-Café In de Waag (pre-booked optional extra) Tuesday 12 May 2015 9.00 - 9.30 “Molecular testing in clinical practice: USA perspective” Anthony John Iafrate (USA) 9.30- 9.45 Questions 9.45 - 10.15 “The molecular pathology of ovarian cancer” David Huntsman (Canada) 10.15 - 10.30 Questions 10.30 - 11.00 “The molecular pathology of endometrial cancer” Anne Schultheis (USA) 11.00 - 11.15 Questions 11.15 - 11.45 Coffee Break 11.45 - 12.15 “The molecular pathology of lung cancer” Erik Thunnissen (Netherlands) 12.15 - 12.30 Questions 12.30 - 13.00 “The molecular pathology of prostate cancer” Arno van Leenders (Netherlands) 13.00 - 13.15 Questions 13.15 - 14.15 Lunch 14.15 - 14.45 “Tumour classification based on DNA methylation fingerprints” Stefan Pfister (Germany) - Keynote Speaker 14.45 - 15.00 Questions 15.00 - 15.30 “The molecular pathology of soft tissue sarcomas” Matt van de Rijn (USA) 15.30 - 15.45 Questions 15.45 - 16.15 “The molecular pathology of GISTs” Brian Rubin (USA) 16.15 - 16.30 Questions 16.30 - 17.00 Coffee Break 17.00 - 17.30 “The molecular pathology of leukaemias” Tim Somervaille (UK) 17.30 - 17.45 Questions 17.45 - 18.15 “The molecular pathology of bone tumours” Judith Bovée (Netherlands) 18.15 - 18.30 Questions 18.30 - 18.40 Presentation of Awards 18.40 - 20.00 Drinks & Canapés Wednesday 13 May 2015 8.45 - 9.15 “The molecular pathology of central nervous system tumours” Pieter Wesseling (Netherlands) 09.15 - 9.30 Questions 9.30 - 10.00 “The molecular pathology of non-Hodgkin lymphomas” Andrew Wotherspoon (UK) 10.00 - 10.15 Questions 10.15 - 10.45 “Molecular testing in clinical practice: European perspective” Andreas Jung (Germany) 10.45 - 11.00 Questions 11.00 - 11.30 Coffee Break 11.30 - 12.00 “Massively-parallel sequencing” Serena Nik-Zainal (UK) 12.00 - 12.15 Questions 12.15 - 13.15 Round table discussion & conclusion 13.15 Lunch & Depart EACR, OECI and ESP Meeting Bursary Award Winners Congratulations to the winners of EACR, OECI and ESP Meeting Bursaries. Each winner received a full registration free of charge and funds of up to 500 Euros to assist with the cost of travel. EACR winners OECI winners ESP winners Hager Bouchareb Memni, Tunisia Alexander Kabakov, Russian Federation Omar Alishlash, United Kingdom Mariia Inomistova, Ukraine Joao Carvalho, Portugal Mohamed Arafa, Egypt Simonetta Buglioni, Italy Mohamed Ahmed, Egypt Tatjana Ivković-Kapicl, Serbia Course Evaluation, CME Credits and Certificate of Attendance Following the close of the course an online survey will be sent requesting participants’ evaluation and feedback on the course. A Certificate of Attendance conveying CME Credits will be available to download and print on completion of the online Evaluation Survey. The Accreditation Council of Oncology in Europe (ACOE) has appraised and approved this course. ACOE accreditation acknowledges the quality of the scientific programme and its educational value. ACOE credits have been endorsed by the European Accreditation Council for Continuing Medical Education (EACCME) – a body of the European Union of Medical Specialists (UEMS). These credits are also recognised as Physician’s Recognition Award (AMA PRA Category 1 credits) by the American Medical Association. 5th EACR - OECI Joint Training Course Molecular Pathology Approach to Cancer Course Speaker Profiles Listed in programme order Jorge Reis-Filho (USA) Richard Marais (UK) Giorgio Stanta (Italy) Marc van de Vijver (Netherlands) Anthony John Iafrate (USA) David Huntsman (Canada) Anne Schultheis (USA) Erik Thunissen (Netherlands) Arno van Leenders (Netherlands) Stefan Pfister (Germany) Matt van de Rijn (USA) Brian Rubin (USA) Tim Somervaille (UK) Judith Bovée (Netherlands) Pieter Wesseling (Netherlands) Andrew Wotherspoon (UK) Andreas Jung (Germany) Serena Nik-Zainal (UK) Molecular pathology: why bother? Jorge Reis Filho (USA) Jorge Reis-Filho is a surgical pathologist with experience in breast cancer gene expression profiling and genomics, and in combining traditional pathology information with data generated with high-throughput molecular techniques. The main focus of his research is on rare types of breast cancer, which together account for up to 25 percent of all invasive breast cancers. Unlike the common type of breast cancer, which comprises multiple entities with distinct biological features and clinical behaviours, tumours from each of the rare types have been shown to be relatively homogeneous at the molecular level. With the recent development of techniques that allow us to survey the entire repertoire of mutations tumour cells harbour, we now have the opportunity to ascertain which alterations drive the growth and ability of these rare types of breast cancer to metastasize, and to define potential therapeutic targets that can be used to manage not only these rare cancers but also subsets of the common types of the disease. Understanding the anatomical and biological characteristics of tumours that govern their outcome and response to specific therapies is germane for the realization of the potentials of personalized medicine. Principles of cell signal and signal transduction Richard Marais (UK) Recent publications: Girotti MR, Lopes F, Preece N, Niculescu-Duvaz D, Zambon A, Davies L, Whittaker S, Saturno G, Viros A, Pedersen M, Suijkerbuijk BM, Menard D, McLeary R, Johnson L, Fish L, Ejiama S, Sanchez-Laorden B, Hohloch J, Carragher N, Macleod K, Ashton G, Marusiak AA, Fusi A, Brognard J, Frame M, Lorigan P, Marais R, Springer C. Paradox-Breaking RAF Inhibitors that Also Target SRC Are Effective in DrugResistant BRAF Mutant Melanoma. Cancer Cell. 2015 Jan 12;27(1):85-96. Smith MP, Sanchez-Laorden B, O'Brien K, Brunton H, Ferguson J, Young H, Dhomen N, Flaherty KT, Frederick DT, Cooper ZA, Wargo JA, Marais R, Wellbrock C. The Immune Microenvironment Confers Resistance to MAPK Pathway Inhibitors through Macrophage-Derived TNFα. Cancer Discov. 2014 Oct;4(10):1214-29. Girotti MR, Saturno G, Lorigan P, Marais R.No longer an untreatable disease: How targeted and immunotherapies have changed the management of melanoma patients. Mol Oncol. 2014 Sep 12;8(6):1140-1158. Review. Viros A, Marais R. Hooked on UVR. Pigment Cell Melanoma Res. 2014 Nov;27(6):1009-10. Pedersen M, Viros A, Cook M, Marais R. G12 D NRAS and kinase-dead BRAF cooperate to drive naevogenesis and melanomagenesis. Pigment Cell Melanoma Res., 2014 Nov;27(6):1162-6. Viros A, Sanchez-Laorden B, Pedersen M, Furney SJ, Rae J, Hogan K, Ejiama S, Girotti MR, Cook M, Dhomen N, Marais R. Ultraviolet radiation accelerates BRAF-driven melanomagenesis by targeting TP53. Nature. 2014 Jul 24;511(7510):478-82. Orgaz JL, Pandya P, Dalmeida R, Karagiannis P, Sanchez-Laorden B, Viros A, Albrengues J, Nestle FO, Ridley AJ, Gaggioli C, Marais R, Karagiannis SN, Sanz-Moreno V. Diverse matrix metalloproteinase functions regulate cancer amoeboid migration. Nat Commun. 2014 Jun 25;5:4255 Furney SJ, Turajlic S, Stamp G, Meirion Thomas J, Hayes A, Strauss D, Gavrielides M, Xing W, Gore M, Larkin J, Marais R. The mutational burden of acral melanoma revealed by whole genome sequencing and comparative analysis. Pigment Cell Melanoma Res. 2014 Sep;27(5):835-8. Marusiak AA, Edwards ZC, Hugo W, Trotter EW, Girotti MR, Stephenson NL, Kong X, Gartside MG, Fawdar S, Hudson A, Breitwieser W, Hayward NK, Marais R, Lo RS, Brognard J. Mixed lineage kinases activate MEK independently of RAF to mediate resistance to RAF inhibitors. Nat Commun. 2014 May 22;5:3901. Sanchez-Laorden B, Viros A, Girotti MR, Pedersen M, Saturno, G, Zambon A, Niculescu-Duvaz D, Turajlic S, Hayes A, Gore M, Larkin J, Lorigan P, Cook M, Springer C and Marais R. BRAF inhibitors induce metastasis in RAS-mutant and inhibitor-resistant melanoma cells through MEK/ERK pathway reactivation. Science Signaling 2014 7(318), ra30. Turajlic S, Furney SJ, Stamp G, Rana S, Ricken G, Oduko Y, Saturno G, Springer C, Hayes A, Gore M, Larkin J, Marais R. Whole genome sequencing reveals complex mechanisms of intrinsic resistance to BRAF inhibition. Annals of Oncology, 2014 May;25(5):959-67. Gentien D, Kosmider O, Nguyen-Khac F, Albaud B, Rapinat A, Dumont AG, Damm F, Popova T, Marais R, Fontenay M, Roman-Roman S, Bernard OA, Stern MH. A common alternative splicing signature is associated with SF3B1 mutations in malignancies from different cell lineages. Leukemia, 2014 Jun;28(6):1355-7. Escuin-Ordinas H, Atefi M, Fu Y, Cass A, Ng C, Huang RR, Yashar S, Comin-Anduix B, Avramis E, Cochran AJ, Marais R, Lo RS, Graeber TG, Herschman HR, Ribas A. COX-2 inhibition prevents the appearance of cutaneous squamous cell carcinomas accelerated by BRAF inhibitors. Molecular Oncology 2014 8(2):250-60. Molecular pathology methods in research and practice Giorgio Stanta (Italy) The high level of complexity of molecular pathology applied to clinics requires further work for an effective improvement of clinical research. This is especially important because we need to apply in a shorter time the outstanding results obtained by basic research to patients. At the moment there are very problematic approaches showed by many meta-analysis studies in which no final decision on specific biomarkers can be taken. This is mostly related to several factors: inappropriate study designs, low level of standardization of the methods and microdissection of tissues, together with extremely variable pre-analytic conditions. Verification and validation processes of new prognostic and predictive biomarkers are not defined either. Specific discussions were carried out in Europe among the major institutions interested in clinical oncology. New proposals for study designs and validation paths were suggested (1). Standardization of methods is absolutely crucial to define standard operating procedures (SOPs) and specific internal quality controls (IQCs) not only in diagnostics, but also in clinical research. This is because the commercial offer of molecular kits is huge, also with clear differences in the results obtained (2). Pre-analytical conditions were extensively studied. A CEN committee (3) studied the problem of pre-analytical conditions in human tissues for DNA, RNA and protein extraction from fresh and paraffin embedded tissues, as well as blood for liquid biopsies. These have to be the specifications for pre-examination processes for fresh tissues, FFPE tissues, blood for DNA, RNA and proteins (technical specifications to ISO 15189). Heterogeneity is also widely discussed today because of the consequences that can be related to acquired resistance especially in the new targeted therapies. Some of the major organizations interested in oncology and in human tissue research, like OECI (4), ESP (5) and BBMRI-ERIC (6), are organizing a congress in Porto to discuss the issue from a practical point of view for clinical research and diagnostics (7). References: 1. 2. 3. 4. 5. 6. 7. Stanta G, Zatloukal K, Riegman P. White Paper on Retrospective Studies in Archive Tissues - Workshop “Tissue-based Biomarkers for Advancement of Personalized Cancer Treatment”. Graz, 28th – 29th March 2014: http://www.impactsnetwork.eu/Sections.aspx?section=170 Bonin S, Stanta G. Nucleic acid extraction methods from fixed and paraffin-embedded tissues in cancer diagnostics. Expert review of molecular diagnostics. 2013;13(3):271-82. European Committee for Standardization (www.cen.eu) Organisation of European Cancer Institutes (www.oeci.eu) European Society of Pathology (www.esp-pathology.org) Biobanking and Biomolecular Resources Research Infrastructure (http://bbmri-eric.eu/) http://www.oeci.eu/Attachments%5COECI_PORTO_2015.pdf The molecular pathology of breast cancer Marc J van de Vijver (the Netherlands) Breast cancer is presently classified based on tumor diameter, histologic type and grade, lymph node status and estrogen receptor, progesterone receptor and HER2 status. This classification has important impications for the surgical, radiotherapy and systemic treatment of breast cancer patients. A more refined classification should be possible based on genetic alterations and gene expression profiles. Based on histological features, breast cancer is categorized as invasive ductal carcinoma, comprising approximately 70% of all cases; invasive lobular carcinoma, comprising approximately 10% of all cases; and several special and rare types, together comprising 20% of all cases. This histologic classification can be supplemented with categories based on genetic alterations; and categories based on gene expression profiles. Whole genome sequence data will provide the next supplement to a better subclassification of breast cancer, and recently the first such sequence has been presented for an invasive lobular cancer. The genetic alterations identified in breast cancer are amplification of between 10 and 20 oncogenes (or genomic regions with as yet not an identified “driving” oncogenes) and mutations in oncogenes and tumor suppressor genes. Over 1,000 breast carcinomas have been subjected to whole genome sequence analysis of exome sequence analysis. From this work it has become clear that there are only three mutations that occur in >10% of breast carcinomas (those in P53, GATA3 and PIK3CA) and also few genes that are amplified in >10% of cases (including HER2, cyclinD1 and CMYC). There are hundreds of mutations that each occur at low frequency in breast cancer. Gene expression profiling has led to the identification of subsets of breast cancer revealed by unsupervised classification termed basal type, ERBB2 like, luminal A, luminal B and normal epithelial like cancers; and supervised classification has revealed good- and poor prognosis subtypes. A growing number of prognostic tests based on gene expression profiling is used clinically. While identification of prognostic gene expression profiles has been successful, it has not been possible yet to identify robust clinically useful predictors of response to systemic treatment. Integration of histologic, genomic and gene expression data of breast carcinomas is leading to an increasingly refined classification that elucidates the initiation and progression of breast cancer at the molecular level; and the identification of novel prognostic and predictive markers that can guide treatment of individual patients. For a review see: Molecular tests as prognostic factors in breast cancer. M.J. van de Vijver Virchows Arch. 2014 Mar;464(3):283-91 Molecular testing in clinical practice: USA perspective Anthony John Iafrate (USA) A new era of targeted molecular therapeutics has emerged for treating cancer during the past few years. Consequently, the prospects for more effective and less toxic treatments have greatly improved. Paralleling the discovery of targeted inhibitory drugs has been the realization that the molecular genetic features of an individual’s tumor play a critical role in determining the clinical response to a particular targeted drug. For example, the HER2 receptor-directed therapeutic antibody trastuzumab exhibits clinical efficacy specifically in a subset of breast cancers with an amplified HER2 gene. The selective EGFR kinase inhibitors gefitinib and erlotinib are particularly effective in lung cancers that harbor mutationally activated EGFR alleles, and crizotinib in patients harboring ALK or ROS1 fusions. Such findings have led to the concept of “personalized medicine” for cancer treatment, the goal of which is to match patients to specific therapies based on individualized tumor molecular analysis and thereby optimize the likelihood of successful treatment. Effective clinical application of tumor genetic analysis has been limited by the fact that only a small fraction of tumors of any particular histologic type will harbor a drug-sensitizing mutation or amplification within a given gene. Furthermore, subsets of tumors arising in distinct organ sites may harbor the same genetic abnormality and therefore exhibit a common pattern of sensitivity to targeted therapy. For example, like breast cancers, approximately 20% of gastric cancers exhibit HER2 amplification, and patients with HER2-amplified gastric cancer experience improved overall survival when treated with trastuzumab. Finally, both the number of such tumor genetic abnormalities for which targeted therapies are available, and the number of compounds and potential combinations available for clinical trials is large and ever-expanding. Together, these points argue for a broad-based tumor genetic analysis across the spectrum of human cancers. The presentation will also focus on the importance of gene fusion event in solid tumors. While fusions have been long known to critical in subsets of cancers, such as leukemias and sarcomas, only recently have we realized the importance of fusions in epithelial malignancies. Lung cancer has been a major focus of this field, with the discovery of ALK, RET and ROS1 fusions over the past few years, and the development of highly effective therapies in these genetic subtypes. We will discuss the diagnostic approached to gene fusion detection including IHC, FISH, and sequencing. The development of broad fusion panels should soon allow for cost effective and comprehensive patient stratification. Relevant reading includes: Shaw, AT, Yeap, BY, Mino-Kenudson, M, Digumarthy, SR, Costa, DB, Heist, RS, Solomon, B, Stubbs, H, Admane, S, McDermott, U, Settleman, J, Kobayashi, S, Mark, EJ, Rodig, SJ, Chirieac, LR, Kwak, EL, Lynch, TJ, and Iafrate, AJ. Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK. J Clin Oncol. 2009 27(26):4247-4253. Dias-Santagata, D, Akhavanfard, S, David, SS, Vernovsky, K, Kuhlmann, G, Boisvert, SL, Stubbs, H, McDermott, U, Settleman, J, Kwak, EL, Clark, JW, Isakoff, SJ, Sequist, LV, Engelman, JA, Lynch, TJ, Haber, DA, Louis, DN, Ellisen, LW, Borger, DR, and Iafrate, AJ. Rapid targeted mutational analysis of human tumours: a clinical platform to guide personalized cancer medicine. EMBO Mol Med. 2010 2(5):146-158. Kwak, EL, Bang, YJ, Camidge, DR, Shaw, AT, Solomon, B, Maki, RG, Ou, SH, Dezube, BJ, Janne, PA, Costa, DB, Varella-Garcia, M, Kim, WH, Lynch, TJ, Fidias, P, Stubbs, H, Engelman, JA, Sequist, LV, Tan, W, Gandhi, L, Mino-Kenudson, M, Wei, GC, Shreeve, SM, Ratain, MJ, Settleman, J, Christensen, JG, Haber, DA, Wilner, K, Salgia, R, Shapiro, GI, Clark, JW, and Iafrate, AJ. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med. 2010 363(18):1693-1703. Bergethon, K, Shaw, AT, Ignatius Ou, SH, Katayama, R, Lovly, CM, McDonald, NT, Massion, PP, SiwakTapp, C, Gonzalez, A, Fang, R, Mark, EJ, Batten, JM, Chen, H, Wilner, KD, Kwak, EL, Clark, JW, Carbone, DP, Ji, H, Engelman, JA, Mino-Kenudson, M, Pao, W, and Iafrate, AJ. ROS1 Rearrangements Define a Unique Molecular Class of Lung Cancers. J Clin Oncol. 2012. Nishino, M, Klepeis, VE, Yeap, BY, Bergethon, K, Morales-Oyarvide, V, Dias-Santagata, D, Yagi, Y, Mark, EJ, Iafrate, AJ, and Mino-Kenudson, M. Histologic and cytomorphologic features of ALKrearranged lung adenocarcinomas. Mod Pathol. 2012 25(11):1462-1472. Ou, SH, Bartlett, CH, Mino-Kenudson, M, Cui, J, and Iafrate, AJ. Crizotinib for the treatment of ALKrearranged non-small cell lung cancer: a success story to usher in the second decade of molecular targeted therapy in oncology. Oncologist. 2012 17(11):1351-1375. Shaw AT, Ou SH, Bang YJ, Camidge DR, Solomon B, Salgia R, Riely GJ, Varella-Garcia M, Shapiro GI, Costa DB, Doebele RC, Le LP, Zheng Z, Tan W, Stephenson P, Shreeve SM, Tye LM, Christensen JG, Wilner K, Clark JW, Iafrate AJ: Crizotinib in ROS1-Rearranged Non-Small Cell Lung Cancer. N Engl J Med. Sept. 27, 2014. Zheng Z, Liebers M, Zhelyazkova B, Cao Y, Panditi D, Chen J, Robinson HE, Chmielecki J, Pao W, Engelman JA, Iafrate AJ, Le LP: Anchored multiplex PCR for targeted next-generation sequencing. Nat Medicine. Nov. 10 2014. The molecular pathology of ovarian cancer David Huntsman (Canada) David Huntsman’s lab studies genetic predisposition to ovarian cancer. This research focuses on understanding the molecular differences between the different ovarian cancer subtypes, which will hopefully lead to more specific treatments. Recently, Dr. Huntsman headed the research group that discovered a new mutation in a gene called FOXL2, which appears to be responsible for the development of granulosa cell tumours of the ovary. Dr. Huntsman has active research programs in the development of predictive and prognostic tissue based cancer biomarkers of hereditary gastric cancer and a wide variety of other tumor types. His team created a blueprint for subtype specific ovarian cancer control and have been leaders in the application of novel genomics technologies to ovarian cancer. Dr. Huntsman happily leads and engages in a wide number of multidisciplinary research groups. Most recently he has been working with Professor Pieter Cullis on the creation of broad based personalized medicine initiative for British Columbia. Background reading: Ann Oncol. 2013 Nov;24 Suppl 8:viii28-viii35. doi: 10.1093/annonc/mdt308. Coming into focus: the nonovarian origins of ovarian cancer. Dubeau L, Drapkin R. Rare Diseases 2:1, e967148; October 1, 2014. Loss of the tumor suppressor SMARCA4 in small cell carcinoma of the ovary, hypercalcemic type (SCCOHT). Ramos et al. Multifocal endometriotic lesions associated with cancer are clonal and carry a high mutation burden. Anglesio MS, Bashashati A, Wang YK, Senz J, Ha G, Yang W, Aniba MR, Prentice LM, Farahani H, Li Chang H, Karnezis AN, Marra MA, Yong PJ, Hirst M, Gilks B, Shah SP, Huntsman DG. J Pathol. 2015 Feb 18. doi: 10.1002/path.4516. [Epub ahead of print] Nat Rev Cancer. 2011 Sep 23;11(10):719-25. doi: 10.1038/nrc3144. Rethinking ovarian cancer: recommendations for improving outcomes. Vaughan S1, Coward JI, Bast RC Jr, Berchuck A, Berek JS, Brenton JD, Coukos G, Crum CC, Drapkin R, Etemadmoghadam D, Friedlander M, Gabra H, Kaye SB, Lord CJ, Lengyel E, Levine DA, McNeish IA, Menon U, Mills GB, Nephew KP, Oza AM, Sood AK, Stronach EA, Walczak H, Bowtell DD, Balkwill FR. The molecular pathology of cancers of the uterus Anne M Schultheis (USA) The uterine corpus represents the most common site for gynecologic malignancies in the western world. Endometrial cancer comprises a heterogeneous group of tumors with distinct risk factors, histopathological features, and clinical outcome. Genomic studies are continuing to unveil the constellation of genetic alterations in uterine cancer, which have the potential to be used as molecular markers for classification, risk-stratification and therapy decision-making. This presentation will focus on the recently updated classification of endometrial cancer and the advances in the molecular characterisation of the disease, including novel therapeutic targets, targeted therapies, and strategies for their successful implementation for the treatment of women with endometrial cancer. The limitations of the current classification systems and the challenges for the development of a taxonomy for endometrial cancer that accurately reflects its biological behaviour and molecular characteristics will be discussed. Selected publications: The Cancer Genome Atlas Research Network, Kandoth C, Schultz N, Cherniack AD, Akbani R, Liu Y, Shen H, et al. Integrated genomic characterization of endometrial carcinoma. Nature 2013;497(7447):6773. Murali R, Soslow RA, Weigelt B. Classification of endometrial carcinoma: more than two types. Lancet Oncol 2014;15(7):e268-78. Jones S, Stransky N, McCord CL, Cerami E, Lagowski J, Kelly D et al. Genomic analyses of gynaecologic carcinosarcomas reveal frequent mutations in chromatin remodelling genes. Nat Commun 2014;5:5006. The molecular pathology of lung cancer Erik Thunnissen (the Netherlands) Background reading: Prognostic and predictive biomarkers in lung cancer. A review Virchows Arch (2014) 464:347–358 DOI 10.1007/s00428-014-1535-4 E. Thunnissen (*) : K. van der Oord, Departments of Pathology, VU University Medical Center, De Boelelaan 1117, 1081 HVAmsterdam, The Netherlands e-mail: [email protected] M. den Bakker, Departments of Pathology, Maasstad Ziekenhuis, Rotterdam, The Netherlands Abstract: In lung cancer, clinically relevant prognostic information is provided by staging. Staging forms the basis for the treatment options and this is briefly summarized in the introduction. Epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase are biomarkers used for prediction of chemotherapy and prediction of targeted treatment. Other driver biomarkers in lung cancer (point mutations and rearrangements in specific genes including Her2, BRAF, NUT, MET, ROS1, DDR2, FGFR1, KRAS, and PTEN) might potentially provide additional information for clinical decisionmaking. Owing to the low prevalence of mutations in predictive markers, patient numbers in studies are usually small, with the exception of EGFR. These mutations increase our understanding of the biology of lung cancer. Mutation analysis as a basis for treatment choice can have an impressive clinical impact with dramatic responses. However, as yet the impact of these approaches to overall survival is less striking. To be confirmed Arno van Leenders (the Netherlands) Dr. Van Leenders is an Associate Professor in pathology and director of the pathology residency program at Erasmus MC. Tumour classification based on DNA methylation fingerprints Stefan Pfister (Germany) Background: Recent revolutionary advances in genomics technologies have fostered a large variety of new discoveries in the field of neurooncology, but at the same time pose the option & challenge of applying these new methods in a clinical setting. Accurate classification of some entities at the time of diagnosis remains a major clinical challenge. To this end, we have developed a national program, namely Molecular Neuropathology 2.0 for the accurate molecular classification of CNS tumors, which uses DNA methylation fingerprints and gene panel sequencing. Methods: In MNP2.0, DNA methylation fingerprints, which are thought to closely reflect the cell of origin, are used to accurately classify brain tumors into biologically and clinically meaningful subgroups. Amongst a total of ~10.000 analyzed CNS tumor specimens, we have established a reference set of 2200 samples with very good histopathological and clinical annotation covering ~80 different entities and subgroups. This reference is now used for an individual sample as a comparison to identify the class with the best fit. A web interface to make this reference dataset available to the community is currently being built. Results: First evidence from ~800 diagnostic cases within the MNP2.0 study suggests that in about 10% of cases the histopathological diagnosis will be changed in a way that affects clinical management of the patient. In about an additional 20% of cases, the diagnosis is refined by revealing a meaningful subgroup that cannot be established by conventional neuropathology alone (e.g., molecular subgroup of medulloblastoma or ependymoma). Ongoing round robin experiments with other centers indicate that the methodology is very robust and it is very well feasible to establish this diagnostic pipeline at other centers. In 2015, a pilot study is starting, which will enable all pediatric brain tumor patients across Germany to benefit from this new diagnostic aid. Conclusion: Nationwide diagnostic programs in neurooncology based on rapid methylation profiling and nextgeneration sequencing are feasible. Through MNP2.0 we have already analyzed ore than 800 CNS tumor samples prospectively and find changes or refinement of the diagnosis in about one third of cases, which seems to be a good justification for the effort. Relevant publications: 1. Hovestadt, V. and Jones, D.T.W. et al., …,and Radlwimmer, B.*, Pfister, S.M.* ,Lichter, P.* (2014). Decoding the regulatory landscape of medulloblastoma using DNA methylation sequencing. Nature 510(7506):537-541. 2. 3. 4. 5. Witt H, Mack SC, Ryzhova M, Bender S, Sill M, Isserlin R, Benner A, Hielscher T, Milde T, Remke M, et al: Delineation of two clinically and molecularly distinct subgroups of posterior fossa ependymoma. Cancer Cell 2011, 20:143-157. Hovestadt V, Remke M, Kool M, Pietsch T, Northcott PA, Fischer R, Cavalli FM, Ramaswamy V, Zapatka M, Reifenberger G, et al: Robust molecular subgrouping and copy-number profiling of medulloblastoma from small amounts of archival tumour material using high-density DNA methylation arrays. Acta Neuropathol 2013, 125:913-916. D. Sturm, H. Witt, V. Hovestadt, D. Khuong Quang, D. Jones, C. Konermann, E. Pfaff, M. Sill, S. Bender, M. Kool, N. Becker, M. Zucknick, T. Hielscher, X. Liu, A. Fontebasso, M. Rizhova, M. Tönjes, S. Albrecht, K. Jacob, M. Wolter, M. Ebinger, M. Schuhmann, T. van Meter, M. Frühwald, H. Hauch, A. Pekrun, B. Radlwimmer, T. Niehues, G. von Komorowski, M. Dürken, A. Kulozik, J. Madden, A. Donson, N. Foreman, R. Drissi, M. Fouladi, W. Scheurlen, A. von Deimling, C. Monoranu, W. Roggendorf, C. Herold-Mende, A. Unterberg, C. Kramm, J. Felsberg, C. Hartmann, T. Milde, O. Witt, A. Lindroth, J. Schwartzentruber, D. Faury, A. Fleming, M. Zakrzewska, P. Liberski, K. Zakrzewski, M. Zapatka, P. Hauser, M. Garami, A. Klekner, L. Bognar, S. Morrissy, F. Cavalli, M. Taylor, P. van Sluis, J. Koster, R. Volckmann, T. Mikkelsen, K. Aldape, G. Reifenberger, V. Collins, J. Majewski, A. Korshunov, M. Ryzhova, V. Hovestadt, S. Bender, D. Sturm, D. Capper, J. Meyer, D. Schrimpf, M. Kool, P. Northcott, O. Zheludkova, T. Milde, O. Witt, A. Kulozik, G. Reifenberger, N. Jabado, A. Perry, P. Lichter, A. von Deimling, S. Pfister, D. W. Jones, Integrated analysis of pediatric glioblastoma reveals a subset of biologically favorable tumors with associated molecular prognostic markers. Acta Neuropathol 129, 669-678 (2015); published online Epub2015/05/01 (10.1007/s00401-015-1405-4). The molecular pathology of soft tissue sarcomas Matt van de Rijn (USA) In this talk I will present the use of a molecular approach to the diagnosis of sarcoma. Sarcomas are malignant tumors that originate from connective tissue cells such as muscle cells, fibroblasts and adipocytes. The disease is rare with approximately 11,000 new cases per year in the United States for soft tissue tumors and approximately 3,000 new cases per year for bone sarcomas. Within this group of tumors there are over 50 distinct diagnostic entities. As a result most clinicians only rarely see cases for each subtype leading to unfamiliarity with treatment options but also with diagnostic classifications. Accurate diagnosis is of course a prerequisite for appropriate therapy and this is especially the case when one considers that novel targeted therapies are continuously being developed. The classification of sarcomas has been based on the morphologic recognition of the different appearances of these tumors and has been supported by immunohistochemistry studies in the past decades. More recently it has been recognized that on a molecular level, two broad categories of sarcoma can be identified. One group of sarcomas is characterized by highly complex genetic abnormalities in which to date no specific patterns can be identified. Members of this category include leiomyosarcomas, undifferentiated pleomorphic sarcomas and malignant peripheral nerve sheath tumors. The second group of sarcomas has simple genetic changes that consist of chromosomal translocations, gene amplifications, and oncogenic mutations. Many of these simple genetic changes are actually relevant to the diagnosis of these tumor types as they occur specifically in only one tumor type. In addition they form the basis for much of the targeted therapy approaches that are in practice or are being developed. Specific chromosomal translocations have been identified for more than 30 soft tissue sarcomas and this number can be expected to increase. It is not cost effective to maintain a set of individual diagnostic tests (either by RTPCR or by FISH) for these rare disease in a CLIA-approved manner in diagnostic molecular laboratories. A number of NGS-based approaches have recently been developed that allow for the use of a single test to detect multiple translocations. References: 1. 2. 3. Taylor et al. Advances in sarcoma genomics and new therapeutic targets. Nature Reviews, 2011, 541-557 West et al. A landscape effect in tenosynovial giant-cell tumor from activation of CSF1 expression by a translocation in a minority of tumor cells. Proceedings National Academy of Sciences, 2006, 103: 690-5 Tap et al. Structure-guided targeting of the CSF1 receptor in tenosynovial giant cell tumor. New England Journal of Medicine, 2015, in press The molecular pathology of gastrointestinal stromal tumors Brian Rubin (USA) This lecture will focus on more recent developments related to gastrointestinal stromal tumor. (GIST). GISTs were originally thought to harbor either KIT or platelet-derived growth factor receptor A (PDGFRA) mutations only, which are targeted by KIT and PDFRA inhibitors such as imatinib mesylate therapeutically. However, more recent discoveries have highlighted additional, less common oncogenic driver mutations including NF1, BRAF and succinate dehydrogenase (SDH) mutations. Some of these newly discovered mutations are germline mutations which further complicate GIST patient management. Genotyping GISTs has become more important since not all genotypes respond equally to FDA-approved tyrosine kinase inhibitors. Because it is apparent that GIST is comprised of a family of related cancers driven by different oncogenic mechanisms, GIST has become a paradigm for personalized cancer therapy. Recent developments in GIST immunohistochemistry (IHC) demonstrate how IHC can be used to diagnose GIST and screen for specific GIST mutations. DOG1 is particularly useful in the diagnosis of KIT IHC negative GIST including those GISTs with PDGFRA mutations, which can also potentially be identified by PDGFRA immunohistochemistry. SDHB immunohistochemistry is useful in characterizing GISTs with SDHA-D mutations while SDHA immunohistochemistry is able to identify SDHA mutant GISTs. References: 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. Hirota S, Isozaki K, Moriyama Y, Hashimoto K, Nishida T, Ishiguro S, et al. Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science. 1998;279:577-80. Corless CL, Barnett CM, Heinrich MC. Gastrointestinal stromal tumours: origin and molecular oncology. Nat Rev Cancer. 2011;11:865-78. Heinrich MC, Corless CL, Duensing A, McGreevey L, Chen CJ, Joseph N, et al. PDGFRA activating mutations in gastrointestinal stromal tumors. Science. 2003;299:708-10. Nishida T, Hirota S, Taniguchi M, Hashimoto K, Isozaki K, Nakamura H, et al. Familial gastrointestinal stromal tumours with germline mutation of the KIT gene. Nat Genet. 1998;19:323-4. Hostein I, Faur N, Primois C, Boury F, Denard J, Emile JF, et al. BRAF mutation status in gastrointestinal stromal tumors. Am J Clin Pathol. 2010;133:141-8. Gill AJ. Succinate dehydrogenase (SDH) and mitochondrial driven neoplasia. Pathology. 2012;44:28592. Pasini B, McWhinney SR, Bei T, Matyakhina L, Stergiopoulos S, Muchow M, et al. Clinical and molecular genetics of patients with the Carney-Stratakis syndrome and germline mutations of the genes coding for the succinate dehydrogenase subunits SDHB, SDHC, and SDHD. Eur J Hum Genet. 2008;16:79-88. Haller F, Moskalev EA, Faucz FR, Barthelmess S, Wiemann S, Bieg M, et al. Aberrant DNA hypermethylation of SDHC: a novel mechanism of tumor development in Carney triad. Endocr Relat Cancer. 2014;21:567-77. Doyle LA, Nelson D, Heinrich MC, Corless CL, Hornick JL. Loss of succinate dehydrogenase subunit B (SDHB) expression is limited to a distinctive subset of gastric wild-type gastrointestinal stromal tumours: a comprehensive genotype-phenotype correlation study. Histopathology. 2012. Gaal J, Stratakis CA, Carney JA, Ball ER, Korpershoek E, Lodish MB, et al. SDHB immunohistochemistry: a useful tool in the diagnosis of Carney-Stratakis and Carney triad gastrointestinal stromal tumors. Mod Pathol. 2011;24:147-51. Janeway KA, Kim SY, Lodish M, Nose V, Rustin P, Gaal J, et al. Defects in succinate dehydrogenase in gastrointestinal stromal tumors lacking KIT and PDGFRA mutations. Proc Natl Acad Sci U S A. 2011;108:314-8. Miettinen M, Wang ZF, Sarlomo-Rikala M, Osuch C, Rutkowski P, Lasota J. Succinate dehydrogenasedeficient GISTs: a clinicopathologic, immunohistochemical, and molecular genetic study of 66 gastric GISTs with predilection to young age. Am J Surg Pathol. 2011;35:1712-21. Wagner AJ, Remillard SP, Zhang YX, Doyle LA, George S, Hornick JL. Loss of expression of SDHA predicts SDHA mutations in gastrointestinal stromal tumors. Mod Pathol. 2013;26:289-94. Killian JK, Kim SY, Miettinen M, Smith C, Merino M, Tsokos M, et al. Succinate dehydrogenase mutation underlies global epigenomic divergence in gastrointestinal stromal tumor. Cancer Discov. 2013;3:648-57. Nannini M, Astolfi A, Urbini M, Indio V, Santini D, Heinrich MC, et al. Integrated genomic study of quadruple-WT GIST (KIT/PDGFRA/SDH/RAS pathway wild-type GIST). BMC Cancer. 2014;14:685. Pantaleo MA, Nannini M, Corless CL, Heinrich MC. Quadruple wild-type (WT) GIST: defining the subset of GIST that lacks abnormalities of KIT, PDGFRA, SDH, or RAS signaling pathways. Cancer Med. 2014. 17. Medeiros F, Corless CL, Duensing A, Hornick JL, Oliveira AM, Heinrich MC, et al. KIT-negative gastrointestinal stromal tumors: proof of concept and therapeutic implications. Am J Surg Pathol. 2004;28:889-94. 18. Espinosa I, Lee CH, Kim MK, Rouse BT, Subramanian S, Montgomery K, et al. A novel monoclonal antibody against DOG1 is a sensitive and specific marker for gastrointestinal stromal tumors. Am J Surg Pathol. 2008;32:210-8. 19. West RB, Corless CL, Chen X, Rubin BP, Subramanian S, Montgomery K, et al. The novel marker, DOG1, is expressed ubiquitously in gastrointestinal stromal tumors irrespective of KIT or PDGFRA mutation status. Am J Pathol. 2004;165:107-13. 20. Agaimy A, Otto C, Braun A, Geddert H, Schaefer IM, Haller F. Value of epithelioid morphology and PDGFRA immunostaining pattern for prediction of PDGFRA mutated genotype in gastrointestinal stromal tumors (GISTs). Int J Clin Exp Pathol. 2013;6:1839-46. 21. Miettinen M, Killian JK, Wang ZF, Lasota J, Lau C, Jones L, et al. Immunohistochemical loss of succinate dehydrogenase subunit A (SDHA) in gastrointestinal stromal tumors (GISTs) signals SDHA germline mutation. Am J Surg Pathol. 2013;37:234-40. 22. Rubin BP, Hornick JL. Mesenchymal Tumors of the Gastrointestinal Tract. In: Hornick JL, editor. Practical Soft Tissue Pathology: A Diagnostic Approach. Philadelphia: Elsevier; 2013. p. 437-74. 23. Rubin BP, Heinrich MC. Genotyping and immunohistochemistry of gastrointestinal stromal tumors: An update. Semin Diagn Pathol. 201515:S0740-2570. 24. Killian JK, Miettinen M, Walker RL, Wang Y, Zhu YJ, Waterfall JJ, Noyes N, Retnakumar P, Yang Z, Smith WI Jr, Killian MS, Lau CC, Pineda M, Walling J, Stevenson H, Smith C, Wang Z, Lasota J, Kim SY, Boikos SA, Helman LJ, Meltzer PS. Recurrent epimutation of SDHC in gastrointestinal stromal tumors. Sci Transl Med. 2014;6:268ra177. The molecular pathology of leukaemias Tim Somervaille (UK) Introduction Haematological malignancies are a highly diverse set of cancers involving multiple blood lineages with variable outcomes and therapeutic approaches. The talk will briefly survey the great range of molecular pathologies in blood cancers (which have been uncovered through approaches such as karyotyping and more recently next generation sequencing) before focusing on the specific mechanisms of oncogenic transformation of three of the most common oncogenes in acute myeloid leukaemia: PML-RARA, AML1-ETO and PML-RARA. Publications that may be of interest J T Lynch, W J Harris and T C P Somervaille (2012). LSD1 inhibition: a therapeutic strategy in cancer? Expert Opinion in Therapeutic Targets 16:1239-49. W J Harris, X Huang, J T Lynch, G J Spencer, J R Hitchin, Y Li, F Ciceri, J G Blaser, B F Greystoke, A M Jordan, C J Miller, D J Ogilvie and T C P Somervaille (2012). The histone demethylase KDM1A sustains the oncogenic potential of MLL-AF9 leukemia stem cells. Cancer Cell 21:473-487. T C P Somervaille and M L Cleary (2010). Grist for the MLL: how do MLL oncogenic fusion proteins generate leukemia stem cells? International Journal of Hematology 91:735-741. T C P Somervaille and M L Cleary (2006). Identification and characterization of leukemia stem cells in murine MLL-AF9 acute myeloid leukemia. Cancer Cell 10: 257-268. The molecular pathology of bone tumours Judith Bovee (the Netherlands) Professor Judith V.M.G. Bovée is a clinician scientist at the Department of Pathology, LUMC, with a special focus on bone and soft tissue tumours. Her aim is to crosslink patient care (diagnostic pathology of bone and soft tissue tumours) with basic research (elucidating the molecular events underlying sarcoma development and progression) in order to establish improved diagnosis, prognosis and treatment for patients with bone and soft tissue tumours. Abstract Bone tumours are considered difficult by most pathologists, as they are rare, have overlapping morphology, need radiological correlation, and the usefullness of immunohistochemistry is limited. Therefore, conventional morphology is still the cornerstone of the diagnosis. Over the past decade, more knowledge has become available on the molecular background of bone tumours. In sarcomas, we recognize three molecular classes of bone tumours. First, tumors with deregulated transcription, which is usually due to a translocation in which the fusion product acts as an aberrant transcription factor, include for instance Ewing sarcoma. Second, deregulated signalling can be caused by specific amplification (e.g. MDM2 in low grade osteosarcoma), specific gene mutation (e.g. GNAS mutation in fibrous dysplasia) or a translocation causing a promotor swab leading to upregulation of a specific gene (e.g. USP6 rearrangement in aneurysmal bone cyst or GRM1 rearrangement in chondromyxoid fibroma). Third, the largest subgroup includes sarcomas with genetic instability and complex karyotypes. These include osteosarcoma and high grade chondrosarcoma. Technical advancements including next generation sequencing have revealed many new genetic alterations in rare bone tumours over the past few years, which helps us to understand their histogenesis, may assist in the differential diagnosis and may provide targets for novel therapeutic strategies. Further reading: Molecular pathology and its diagnostic use in bone tumors. Szuhai K, Cleton-Jansen AM, Hogendoorn PCW, Bovée JVMG Cancer Genet. 2012 May;205(5):193-204. doi: 10.1016/j.cancergen.2012.04.001. Somatic mosaic IDH1 and IDH2 mutations are associated with enchondroma and spindle cell hemangioma in Ollier disease and Maffucci syndrome. Pansuriya TC, van Eijk R, d'Adamo P, van Ruler MA, Kuijjer ML, Oosting J, Cleton-Jansen AM, van Oosterwijk JG, Verbeke SL, Meijer D, van Wezel T, Nord KH, Sangiorgi L, Toker B, Liegl-Atzwanger B, San-Julian M, Sciot R, Limaye N, Kindblom LG, Daugaard S, Godfraind C, Boon LM, Vikkula M, Kurek KC, Szuhai K, French PJ, Bovée JVMG Nat Genet. 2011 Nov 6;43(12):1256-61. doi: 10.1038/ng.1004. GRM1 is upregulated through gene fusion and promoter swapping in chondromyxoid fibroma. Nord KH, Lilljebjörn H, Vezzi F, Nilsson J, Magnusson L, Tayebwa J, de Jong D, Bovée JVMG, Hogendoorn PCW, Szuhai K. Nat Genet. 2014 May;46(5):474-7. doi: 10.1038/ng.2927. Epub 2014 Mar 23. Distinct H3F3A and H3F3B driver mutations define chondroblastoma and giant cell tumor of bone. Behjati S, Tarpey PS, Presneau N, Scheipl S, Pillay N, Van Loo P, Wedge DC, Cooke SL, Gundem G, Davies H, Nik-Zainal S, Martin S, McLaren S, Goody V, Robinson B, Butler A, Teague JW, Halai D, Khatri B, Myklebost O, Baumhoer D, Jundt G, Hamoudi R, Tirabosco R, Amary MF, Futreal PA, Stratton MR, Campbell PJ, Flanagan AM. Nat Genet. 2013 Dec;45(12):1479-82. doi: 10.1038/ng.2814. Epub 2013 Oct 27. Erratum in: Nat Genet. 2014 Mar;46(3):316. The molecular pathology of central nervous system tumours Pieter Wesseling (the Netherlands) Prof. Dr. Pieter Wesseling is a pathologist/neuropathologist and full professor in Neuro-oncological Pathology at both Radboud University Nijmegen Medical Centre, Nijmegen and VU University Medical Center Amsterdam. Recent publications: Overcoming the blood-brain tumor barrier for effective glioblastoma treatment. van Tellingen O, Yetkin-Arik B, de Gooijer MC, Wesseling P, Wurdinger T, de Vries HE. Drug Resist Updat. 2015 Mar 6. pii: S1368-7646(15)00012-6. doi: 10.1016/j.drup.2015.02.002. [Epub ahead of print] Review. Identification of a novel MET mutation in high-grade glioma resulting in an auto-active intracellular protein. Navis AC, van Lith SA, van Duijnhoven SM, de Pooter M, Yetkin-Arik B, Wesseling P, Hendriks WJ, Venselaar H, Timmer M, van Cleef P, van Bergen En Henegouwen P, Best MG, Wurdinger TD, Tops BB, Leenders WP. Acta Neuropathol. 2015 Apr 11. [Epub ahead of print] Increase in Both CD14-Positive and CD15-Positive Myeloid-Derived Suppressor Cell Subpopulations in the Blood of Patients With Glioma But Predominance of CD15-Positive Myeloid-Derived Suppressor Cells in Glioma Tissue. Gielen PR, Schulte BM, Kers-Rebel ED, Verrijp K, Petersen-Baltussen HM, Ter Laan M, Wesseling P, Adema GJ. J Neuropathol Exp Neurol. 2015 May;74(5):390-400. doi: 10.1097/NEN.0000000000000183. Landscape of chromosomal copy number aberrations in gangliogliomas and dysembryoplastic neuroepithelial tumours. Prabowo AS, van Thuijl HF, Scheinin I, Sie D, van Essen HF, Iyer AM, Spliet WG, Ferrier CH, van Rijen PC, Veersema TJ, Thom M, Schouten-van Meeteren AY, Reijneveld JC, Ylstra B, Wesseling P, Aronica E. Neuropathol Appl Neurobiol. 2015 Mar 12. doi: 10.1111/nan.12235. [Epub ahead of print] Whole-genome copy-number analysis identifies new leads for chromosomal aberrations involved in the oncogenesis and metastastic behavior of uveal melanomas. van Engen-van Grunsven AC, Baar MP, Pfundt R, Rijntjes J, Küsters-Vandevelde HV, Delbecq AL, Keunen JE, Klevering JB, Wesseling P, Blokx WA, Groenen PJ. Melanoma Res. 2015 Mar 9. [Epub ahead of print] Evolution of DNA repair defects during malignant progression of low-grade gliomas after temozolomide treatment. van Thuijl HF, Mazor T, Johnson BE, Fouse SD, Aihara K, Hong C, Malmström A, Hallbeck M, Heimans JJ, Kloezeman JJ, Stenmark-Askmalm M, Lamfers ML, Saito N, Aburatani H, Mukasa A, Berger MS, Söderkvist P, Taylor BS, Molinaro AM, Wesseling P, Reijneveld JC, Chang SM, Ylstra B, Costello JF. Acta Neuropathol. 2015 Apr;129(4):597-607. doi: 10.1007/s00401-015-1403-6. Epub 2015 Feb 28. Liquid biopsies in patients with diffuse glioma. Best MG, Sol N, Zijl S, Reijneveld JC, Wesseling P, Wurdinger T. Acta Neuropathol. 2015 Feb 27. [Epub ahead of print] IDH mutation status and role of WHO grade and mitotic index in overall survival in grade II-III diffuse gliomas. Olar A, Wani KM, Alfaro-Munoz KD, Heathcock LE, van Thuijl HF, Gilbert MR, Armstrong TS, Sulman EP, Cahill DP, Vera-Bolanos E, Yuan Y, Reijneveld JC, Ylstra B, Wesseling P, Aldape KD. Acta Neuropathol. 2015 Apr;129(4):585-96. doi: 10.1007/s00401-015-1398-z. Epub 2015 Feb 21. Primary melanocytic tumors of the central nervous system: a review with focus on molecular aspects. Küsters-Vandevelde HV, Küsters B, van Engen-van Grunsven AC, Groenen PJ, Wesseling P, Blokx WA. Brain Pathol. 2015 Mar;25(2):209-26. doi: 10.1111/bpa.12241. The molecular pathology of non-Hodgkin lymphomas Andrew C. Wotherspoon (UK) Non-Hodgkin lymphoma is a broad collection of lymphoid malignancies that comprises over 40 different entities, some of which have distinct sub-types. The current WHO classification recognises each entity on the basis of distinct clinico-pathological features and attempts, where possible, to relate the entity to a specific stage in B cell development. Molecular features are becoming more central to the assessment of lymphoid malignancies. At the most basic level molecular studies are used in equivocal cases to confirm the presence of neoplasia by demonstrating clonality and to assign cell lineage through examination of immunoglobulin heavy and light chain T cell receptor genes. A proportion of lymphomas are characterised by specific balanced chromosomal translocations. These may either involve the immunoglobulin or T cell receptor genes as a result of recombination errors or be translocations that result in the production of novel chimeric proteins. In some cases the presence of a translocation, while characteristic of the lymphoma entity, is insufficient for full malignant transformation and results in a subclinical pre-neoplastic proliferation that only evolves into overt lymphoma following subsequent genetic hits. More recently gene profiling studies have identified specific mutations that are highly associated with some specific lymphoma entities that previously had no specific genetic marker. These are frequently not entirely disease specific but, in the correct histological context can be diagnostically helpful. With the development of new agents that can be used to specifically target intra-cellular signalling pathways detection of specific mutations is likely to become an important component of routine diagnostic assessment in the evaluation of some lymphoid malignancies. As with some solid tumours subsets of single entities can be shown to harbour specific mutations that render the tumour sensitive to novel non-chemotherapeutic agents that target various pathways, particularly the B cell receptor (BCR) signalling pathway in B cell lymphoma and NF-κB activation. Finally, genetic data can be important in the prognostication and prediction of future behaviour in some lymphoma types. The presence of specific mutation may indicate a higher risk of transformation while other genetic changes can be used to predict the likelihood of response to specific chemotherapies. Over the last few years genetic studies have enhanced our understanding of lymphoma pathogenesis and behaviour and more sophisticated genetic testing is beginning to be introduced in the routine assessment of these proliferations. Additional reading: B-cell receptor signalling in diffuse large B cell lymphoma. Young RM, Shaffer AL 3rd, Phelan JD, Staudt LM. Semin Hematol 2015; 52:77-85 B-cell receptor signalling as a driver of lymphoma development and evolution. Niemann CU, Wiestner A. Semin Cancer Biol 2013; 23: 410-421 B cell receptor signalling in chronic lymphocytic leukaemia. Burger JA, Chiorazzi N. Trends Immunol 2013; 34: 592-601 Pathologic importance and therapeutic implications of NF-κB in lymphoid malignancies. Lim KH, Yang Y, Staudt LM. Immunol Rev 2012; 246: 359-378 Molecular testing in clinical practice: European perspective Andreas Jung (Germany) [email protected] With the understanding of the molecular mechanisms underlying traits of cell biology it was possible to design and develop drugs that interfere with essential hallmarks of cancer cells. Moreover, scenarios could be defined in which these drugs work or do not work. These scenarios are defined by the activation state of molecules in the signalling pathway and this activation state is defined by mutations of the molecule. Therefore, these molecules indicate if the drug will work in an individual patient and have been named biomarker. Thus, a biomarker defines if a targeted therapy will work in an individual patient (personalized medicine). The first example of a targeted therapy was Trastuzumab which is used for the treatment of mamma carcinoma if they are characterized by high expression of the surface receptor Her2 (human EGFR 2) which is determined by immunohistochemistry and/ or FiSH (Fluorescence in situ hybridization). With the advent of targeted anti-EGFR for metastastic colorectal cancer (mCRC) the mutation of the frequently mutated KRAS or NRAS molecules (RAS) were identified as biomarkers.1-7 When RAS molecules are activated they activate the EGFR/ RAS/ RAF/ MAPK signalling pathway downstream of the receptor level so that the inactivation of the EGFR by the drugs (cetuximab, panitumumab) is useless. Therefore, the mutational status of the RAS genes of the level of DNA has to be determined with the help of molecular methods without having any histomorphological correlate at hand any more. Moreover, the result of the test results in the determination of the therapy of an individual patient which influences the outcome in terms of overall survival (OS) thus the life-span of the patient.8,9 Clearly, the test has to be valid and reliable. In general two ways can be approached: 1. In one system, which is the American way used by the FDA (food and drug Administration), a single test which was used in the clinical approval study is used for the detection of mutations. 2. In another system, which is the European way used by the EMA (European Medicines Agency) the final result is in the focus independent of the method which was used for the generation of the data. This way of analysis goes in parallel with checking the quality of the test system in use. Therefore, several External Quality Assurance (EQA) systems have been built in Europe to control the quality of molecular pathological detection. References: 1. 2. 3. 4. 5. 6. 7. 8. 9. Amado, R. G. et al. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol 26, 1626-1634 (2008). Bokemeyer, C. et al. Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol 27, 663-671 (2009). Douillard, J. Y. et al. Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study. J Clin Oncol 28, 4697-4705,(2010). Douillard, J.-Y. et al. Panitumumab–FOLFOX4 Treatment and RAS Mutations in Colorectal Cancer. New Engl J Med 369, 1023 (2013). Van Cutsem, E. et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med 360, 1408-1417 (2009). Van Cutsem, E. et al. Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status. J Clin Oncol 29, 2011-2019, (2011). Van Cutsem, E. et al. Fluorouracil, Leucovorin, and Irinotecan Plus Cetuximab Treatment and RAS Mutations in Colorectal Cancer. J Clin Oncol 33, 692-700, (2015). Heinemann, V. et al. FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial. Lancet Oncol 15, 1065-1075, (2014). Schwartzberg, L. S. et al. PEAK: A Randomized, Multicenter Phase II Study of Panitumumab Plus Modified Fluorouracil, Leucovorin, and Oxaliplatin (mFOLFOX6) or Bevacizumab Plus mFOLFOX6 in Patients With Previously Untreated, Unresectable, Wild-Type KRAS Exon 2 Metastatic Colorectal Cancer. J Clin Oncol, (2014). Massively-parallel sequencing Serena Nik-Zainal (UK) The recent increase in the speed of sequencing offered by modern sequencing technologies permits an unprecedented degree of exploration of the human genome. No longer are we restricted to PCR-defined fragments of protein-coding exons, we can now investigate all the genetic material in human cells. I explain the principles underlying massively-parallel sequencing giving some insight into the advances as well as the difficulties posed by processing of the enormous datasets generated by modern sequencing experiments. Cancer is the ultimate disorder of the genome, characterised by not just one or two mutations, but hundreds to thousands of acquired mutations that have been accrued through the development of a tumour. Utilising the extraordinary surge in scale as well as the digital nature of massively-parallel sequencing, I explain some of the recent highlights into tumour biology offered by these modern methods: cancer gene discovery, mutation signatures and cancer evolution. Further reading: Cancer genomics background http://www.ncbi.nlm.nih.gov/pubmed/19360079 Massively-parallel sequencing http://www.ncbi.nlm.nih.gov/pubmed/18987734 Impact of NGS: reviews http://www.ncbi.nlm.nih.gov/pubmed/24074859 http://www.ncbi.nlm.nih.gov/pubmed/23121054 Signatures of mutagenesis http://www.ncbi.nlm.nih.gov/pubmed/22608084 http://www.ncbi.nlm.nih.gov/pubmed/23945592 Cancer evolution http://www.ncbi.nlm.nih.gov/pubmed/22608083 http://www.ncbi.nlm.nih.gov/pubmed/22817890 Molecular Pathology Approach to Cancer 2015 Participants List Firstname Surname Country Email Sana Eltahir Ihsan Mohamed Mubark Omar Abdul Rahman Mohammad Martin Marta Valentin Samuel Anne Cristiane Stoyan Bettina Bart Hager Bechir Judith Brad Simonetta Joao Vesna Panagiotis Anne-Marie Bruno Erienne Jeroen Frederik Janine Eveline Naomi Erik Jan Carole Mohamed Zelalem Ayelet Ulrike Femke Marije Mª Carmen De La David Anthony J. Mariia Tatjana Koen Evelien Andreas Alexander Yoo Na Jan Charlotte Denis Natalja Jan Willem Bjorn Sushmitha Richard Abdalla Abdelhalim Ahmed Ali Mohamed Osman Alishlash Annous Arafa Bak Barbosa Barsan Beck Benard Bentin Toaldo Bichev Bisig Bliek Bouchareb Memni Boughaba Bovee Bryan Buglioni Carvalho Cemerikic Martinovic Christopoulos Cleton-Jansen Costa Gomes de Cuba de Jong De Smet de Waard den Biezen Donner Dubbink Ferraro-Peyret Gadkarim Gebremedhin Harari Harms Hillen Hoogland Hoz Torres Huntsman Iafrate Inomistova Ivković-Kapicl Jacobs Jongeneel Jung Kabakov Kang Köster Kweldam Larsimont Leeuwis Leeuwis Lohman Malpe Gopal Marais SUDAN SUDAN EGYPT SUDAN UK LEBANON EGYPT DENMARK PORTUGAL USA NETHERLANDS NETHERLANDS NETHERLANDS BULGARIA SWITZERLAND NETHERLANDS TUNISIA ITALY NETHERLANDS USA ITALY PORTUGAL SERBIA GREECE NETHERLANDS PORTUGAL NETHERLANDS NETHERLANDS BELGIUM NETHERLANDS NETHERLANDS NETHERLANDS NETHERLANDS FRANCE SUDAN ETHIOPIA ISRAEL UK BELGIUM NETHERLANDS SPAIN CANADA USA UKRAINE SERBIA BELGIUM NETHERLANDS GERMANY RUSSIAN FEDERATION SOUTH KOREA NETHERLANDS NETHERLANDS BELGIUM NETHERLANDS NETHERLANDS NETHERLANDS INDIA UK [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] Firstname Surname Country Email Claudia Tatiana Santosh Kim Hans Mekhti Andra Serena Marcela Saskia Gordana Stefan Dave Janneke Souheil Jorge Abigail Tjitte Antonia Natalia Brian Emma Angela Pia Saphira Anne Archana Tim Ji-Ying Giorgio Maryvonne Bandar Yuan Raimo Erik Roanna Claudia Hester Anne Matt Marc Mari Jacob Jacqueline Dianne Lidiane Giuseppe Pieter Adele Andrew Caroline David Robin Ondrej Ilse Mateoiu Meier Menon Monkhorst Morreau Narimanov Neefjes-Borst Nik-Zainal Novotna Offerman Petrusevska Pfister Ploeg Quicken Raad Reis-Filho Remo Rijpkema Rizzuto Rodon Rubin Rutten Sanzone Satumalaij Schultheis Shivamurthy Somervaille Song Stanta Steenkamer Suliman Tang Tanzi Thunnissen Ueda Valverde Morales van Boven van Brussel van de Rijn van de Vijver van den Hout van der Laan van der Meij van Strijp Vieira Marins Viglietto Wesseling Wong Wotherspoon Wyss-Abulker Yick Yves Marie Zitek Zondervan SWEDEN GERMANY INDIA NETHERLANDS NETHERLANDS RUSSIAN FEDERATION NETHERLANDS UK CZECH REPUBLIC NETHERLANDS MACEDONIA GERMANY NETHERLANDS NETHERLANDS LEBANON USA PHILIPPINES NETHERLANDS ITALY SPAIN USA NETHERLANDS UK NETHERLANDS USA INDIA UK NETHERLANDS ITALY NETHERLANDS SAUDI ARABIA UK ITALY NETHERLANDS USA SPAIN NETHERLANDS NETHERLANDS USA NETHERLANDS NETHERLANDS NETHERLANDS NETHERLANDS NETHERLANDS BRAZIL ITALY NETHERLANDS SINGAPORE UK SWITZERLAND NETHERLANDS FRANCE CZECH REPUBLIC NETHERLANDS [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] Sponsors and Exhibitors We wish to express our appreciation for the significant support provided by sponsors at the 5th EACR - OECI Joint Training Course on Molecular Pathology Approach to Cancer. Their interest and enthusiasm for the course has enabled the organisers to provide an impressive scientific programme. Gold Sponsor Sponsors EACR Sustaining Members The European Association for Cancer Research gratefully acknowledges the organisations and companies that support the Association as Sustaining Members. Through Sustaining Membership, organisations and companies offer ongoing support to the EACR and provide the means for the Association to develop important initiatives. The EACR Conference Series is an important example of this. HETEROGENEITY HAPPENS Are You Ready to Make Sense of it? FFPE: Image-based selection on the DEPArrayTM System allows the identification and recovery of homogeneous tumor and stromal cell populations. The CellBrowserTM software enables to recover cells of interest selecting user-defined fluorescence criteria, DNA content and cell morphology. DIGITAL: DEPArrayTM technology uses dielectrophoresis-based array to sort at single cell level. This enables a precise recovery of target cells or cell groups, for subsequent molecular analysis. PRECISION: DEPArrayTM technology can sort and recover homogeneous pools of phenotypically identical cells from heterogeneous cells suspensions, obtained from disaggregated FFPE tissues allowing precise characterization of genomics quantitative traits from your tissue sections. RESOLVE SAMPLE HETEROGENEITY AND UNDERSTAND CANCER GENETICS w w w. s i l i c o n b i o s y s t e m s . c o m
© Copyright 2024