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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
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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:
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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.
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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:
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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:
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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:
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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.
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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
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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:
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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:
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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:
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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.
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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
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DENMARK
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NETHERLANDS
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TUNISIA
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PORTUGAL
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GREECE
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PORTUGAL
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ETHIOPIA
ISRAEL
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UKRAINE
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BELGIUM
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BELGIUM
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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
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NETHERLANDS
LEBANON
USA
PHILIPPINES
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SPAIN
USA
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UK
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USA
INDIA
UK
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SAUDI ARABIA
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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