Genetics and tumor genomics in familial colorectal cancer
Middeldorp, J.W.
Citation
Middeldorp, J. W. (2010, October 14). Genetics and tumor genomics in familial colorectal cancer. Retrieved from https://hdl.handle.net/1887/16041
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Genetics and Tumor Genomics in
Familial Colorectal Cancer
Genetics and Tumor Genomics in Familial Colorectal Cancer
©2010 Anneke Middeldorp
Printing: Ipskamp Drukkers Layout cover: Ipskamp Drukkers
The studies described in this thesis were performed at the Department of Pathology and the Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands.
The research described in this thesis was financially supported by the Dutch Cancer Society (UL2005-3247) and the NutsOhra Foundation (SNO-T-07-092).
The printing of this thesis was financially supported by the Dutch Cancer Society, Stichting Nationaal Fonds tegen Kanker - voor onderzoek naar reguliere en alternatieve therapieën, and the J.E. Jurriaanse Stichting.
Genetics and Tumor Genomics in Familial Colorectal Cancer
Proefschrift
ter verkrijging van
de graad van Doctor aan de Universiteit Leiden, op gezag van Rector Magnificus prof.mr. P.F. van der Heijden,
volgens besluit van het College voor Promoties te verdedigen op donderdag 14 oktober 2010
klokke 15.00 uur
door
Janneke Willemijn Middeldorp
geboren te Deventer
in 1980
Promotiecommissie
Promotores: Prof. dr. H. Morreau Prof. dr. P. Devilee
Copromotores: Dr. T. van Wezel Dr. J. Wijnen
Overige leden: Dr. F.J. Hes
Prof. dr. N.C. Hoogerbrugge (Radboud University Medical Center) Prof. dr. G.A. Meijer (VU Medical Center)
Contents
Aims and outline of this thesis Chapter 1
General Introduction Chapter 2
A procedure for the detection of linkage with high density SNP arrays in a large pedigree with colorectal cancer
BMC Cancer (2007) 7:6 Chapter 3
Comprehensive Genetic Analysis of Seven Large Families with Mismatch Repair Proficient Colorectal Cancer
Genes, Chromosomes and Cancer (2010) 49:539-548 Chapter 4
Enrichment of Low Penetrance Susceptibility Loci in a Dutch Familial Colorectal Cancer Cohort
Cancer, Epidemiology, Biomarkers & Prevention (2009) 18(11):3062-3067 Chapter 5
High frequency of copy-neutral LOH in MUTYH-associated polyposis carcinomas
Journal of Pathology (2008) 216(1):25-31 Chapter 6
Increased frequency of 20q gain and copy-neutral LOH in mismatch repair proficient familial colorectal carcinomas
Submitted Chapter 7
Genome-Wide Allelic State Analysis on Flow-Sorted Tumor Fractions Provides an Accurate Measure of Chromosomal Aberrations
Cancer Research (2008) 68(24):10333-10340 Chapter 8
Concluding Remarks and Future Perspectives Chapter 9
Summary
Nederlandse samenvatting Curriculum vitae
List of publications
7 9 45
51
63
71
81
99
109
125127 131137 139
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Aims and outline of this thesis
The aim of the work described in this thesis was to identify novel genes that predispose to colorectal cancer (CRC). Colorectal cancer is one of the most common malignancies in the Western world. The lifetime risk in the Netherlands for developing CRC is about 6%, with a 5-year survival of about 55%. The risk of CRC can be increased both by genetic and environ- mental factors. In twin studies it was estimated that in up to 30% of all CRC cases inherited predisposition plays a role. However, only 6% of all cases is explained by the known syn- dromes, like Lynch syndrome, Familial Adenomatous Polyposis (FAP) and MUTYH-associat- ed polyposis (MAP). In the remaining familial cases the underlying genetics remain elusive. In the cases that show a strong familial history of CRC, a high penetrance genetic factor can be expected to be responsible for the increased CRC risk. In other cases with a less strong family history but with an early onset of the disease, the increased cancer risk might be explained by common genetic variants, each conferring a small CRC risk. It is of great importance to identify both the low and high risk factors, because this knowledge can aid in obtaining further insight in the etiology of the disease. Moreover, identifying high risk factors will aid in identify- ing individuals at significant increased risk for CRC. These individuals can then be offered a regular screening of their colon to detect precursor lesions, and thereby prevent the disease from developing into a malignant lesion.
Chapter 1 provides a general introduction in the genetic and environmental factors that influ- ence the risk of CRC. Moreover, genetic loci that have been identified to possibly harbor a high risk gene are discussed as well as low level risk loci that have been identified. Colorectal tumorigenesis is briefly discussed and the genetic en genomic instability seen in colorectal tumors is described, both for sporadic and familial tumors. Finally, new fields in CRC research, prevention, and treatment are reviewed.
Different approaches were used to identify novel genetic factors predisposing to CRC. These approaches can be broadly divided into germ-line genetic approaches and somatic genomic approaches. Chapter 2 and 3 describe the germ-line approach to identify genetic loci har- boring high or moderate penetrance risk factors. Linkage analysis was used in large families affected with CRC. The linkage scan was performed using 10K SNP arrays. With this high number of markers and large pedigrees the computational burden of the linkage analysis was high. The procedure we developed to handle this complexity is described in Chapter 2. The results of the linkage analysis in seven large CRC families are described in Chapter 3.
In the search for low risk factors we replicated the association of six loci, identified in large ge- nome-wide association studies, in a Dutch clinical-based cohort of 995 familial CRC patients.
We studied the possible association of these loci with several clinico-pathological parameters.
The results of this study are described in Chapter 4.
The third approach we used was to study the genomic profile of the tumors familial CRC pa- tients develop. With profiling the tumors from patients with familial CRC we aimed on one side at stratifying the different families based on the genomic profile of their tumors and moreover,
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we aimed at identifying a locus that is frequently affected in these tumors indicating that there might be a gene important for the development of the disease located in that region. To prop- erly interpret the profile of the tumors from patients with an unknown cause of their increased CRC predisposition, we first generated the profile for known CRC syndromes. The results of the profiling of tumors from patients with MUTYH-associated polyposis are described in Chapter 5. We also studied the profile of tumors from Lynch syndrome patients in the context of another PhD thesis. For the familial cases with unknown cause we studied the profile of 30 tumors originating from 15 families (2 tumors per family were studied). The results of this study are described in Chapter 6. And in Chapter 7, an improved method for tumor profiling is described, with which the allelic state of the chromosomes can be determined.
In Chapter 8, all results described in this thesis are discussed and perspectives for future research are given. Chapter 9 provides a summary of this thesis.
