The Genetics and Molecular Alterations of Pancreatic Cancer

177 Pages·2015·13.89 MB·English

The Genetics and Molecular Alterations
of Pancreatic Cancer
by
Roeland Frederik de Wilde
De_Wilde.indd 1 5-8-2015 15:14:09
The Genetics and Molecular Alterations of Pancreatic Cancer
Thesis, Faculty of Medicine, University Medical Center Utrecht, Utrecht University, the Netherlands
Proefschrift, faculteit Geneeskunde, Universitair Medisch Centrum Utrecht, Universiteit Utrecht
© Roeland Frederik de Wilde 2015
ISBN/EAN: 978-94-6233-064-1
The research described in this thesis was financially supported by:
Stichting Prof. Michaël-van Vloten Fonds, afdeling Pathologie UMC Utrecht, VSBfonds, Stichting Dr. Hendrik Muller’s
Vaderlandsch Fonds, Prins Bernhard Cultuurfonds (Klok Korsmit Tacke Fonds), Lisa Waller Hayes Foundation.
Publication of this thesis was financially supported by:
Chirurgisch Fonds Heelkunde UMC Utrecht, afdeling Pathologie UMC Utrecht, afdeling Heelkunde Jeroen Bosch
Ziekenhuis, ABN AMRO Bank N.V., BGP Products B.V., ChipSoft B.V., Jeroen Bosch Academie, Olympus Nederland
B.V., Takeda Nederland B.V.
Displayed on the cover:
“1807, Friedland” by Ernest Meissonier (French, Lyons, 1815-1891, Paris), The Metropolitan Museum of Art
(New York (NY), USA), gift of Henry Hilton 1887, available online: http://www.metmuseum.org/collection/the-
collection-online/search/437052
About the cover:
Inspired by dr. Frans Gerard (Fred) de Wilde (1903-1999), my grandfather who was a pharmacist in Bussum,
expert on Dutch military history and uniforms, and author of ‘De uniformen van het Nederlandse leger ten tijde
van de Bataafse Republiek en het Koninkrijk Holland 1795-1810’ (DE BATAAFSCHE LEEUW, Amsterdam 1999,
ISBN 90 6707 501 9). The front of the cover symbolizes the battle we fight against pancreatic cancer in order to
offer patients a better perspective.
Cover design: Nicole Nijhuis, Gildeprint
Lay out: Textcetera, The Hague, the Netherlands
Printed by: Gildeprint, Enschede, the Netherlands
De_Wilde.indd 2 5-8-2015 15:14:09
The Genetics and Molecular Alterations
of Pancreatic Cancer
Genetische en Moleculaire Afwijkingen in het Pancreascarcinoom
(met een samenvatting in het Nederlands)
Proefschrift
ter verkrijging van de graad van doctor
aan de Universiteit Utrecht
op gezag van de rector magnificus, prof.dr. G.J. van der Zwaan,
ingevolge het besluit van het college voor promoties
in het openbaar te verdedigen op
donderdag 17 september 2015 des middags te 4.15 uur
door
Roeland Frederik de Wilde
geboren op 26 augustus 1984 te ’s-Gravenhage
De_Wilde.indd 3 5-8-2015 15:14:09
Promotoren: Prof.dr. I.H.M. Borel Rinkes
Prof.dr. G.J.A. Offerhaus
Prof.dr. M.R. Vriens
Copromotor: Dr. I.Q. Molenaar
De_Wilde.indd 4 5-8-2015 15:14:09
Voor Wiesje en mijn ouders
De_Wilde.indd 5 5-8-2015 15:14:09
De_Wilde.indd 6 5-8-2015 15:14:09
CONTENT
Chapter 1 General introduction and outline of the thesis 11
Chapter 2 Impact of nationwide centralization of pancreaticoduodenectomy on
hospital mortality 21
British Journal of Surgery 2012; 99: 404-410
Part I Neoplasms of the Exocrine Pancreas 32
Chapter 3 Reporting precursors to invasive pancreatic cancer: pancreatic
intraepithelial neoplasia, intraductal neoplasms and mucinous cystic
neoplasm 33
Diagnostic Histopathology 2011; 18(1): 17-30
Chapter 4 Very long-term survival following resection for pancreatic cancer is
not explained by commonly mutated genes:
results of whole-exome sequencing analysis 57
Clinical Cancer Research 2015; 21(8):1944-1950
Chapter 5 Analysis of LKB1 mutations and other molecular alterations in
pancreatic acinar cell carcinoma 77
Modern Pathology 2011; 24(9):1229-1236
Part II Neoplasms of the Endocrine Pancreas 90
Chapter 6 Well-differentiated pancreatic neuroendocrine tumors: from genetics
to therapy 91
Nature Reviews Gastroenterology & Hepatology 2012; 9(4):199-208
Chapter 7 DAXX/ATRX, MEN1 and mTOR pathway genes are frequently altered in
pancreatic neuroendocrine tumors 111
Science 2011; 331(6021):1199-1203
Chapter 8 Altered telomeres in tumors with ATRX and DAXX mutations 127
Science 2011; 333(6041):425
Chapter 9 Loss of ATRX or DAXX expression and concomitant acquisition of the
alternative lengthening of telomeres phenotype are late events in a
small subset of MEN-1 syndrome pancreatic neuroendocrine tumors 141
Modern Pathology 2012; 25(7):1033-1039
7
De_Wilde.indd 7 5-8-2015 15:14:09
CONTENT
Part III Summary, Discussion and Concluding Remarks 152
Chapter 10 Summary, discussion and concluding remarks 153
Chapter 11 Summary in Dutch (Samenvatting in het Nederlands) 163
Part IV Appendices 170
Chapter 12 List of abbreviations 173
Review committee 177
Acknowledgements (Dankwoord) 179
List of publications 185
Curriculum vitae auctoris 189
8
De_Wilde.indd 8 5-8-2015 15:14:09
De_Wilde.indd 9 5-8-2015 15:14:09
Chapter 1
De_Wilde.indd 10 5-8-2015 15:14:09