Christiaan Klijn
Christiaan Klijn
- T
- +31 20 5122004
- E
- C.N.Klijn@tudelft.nl
1066 CX Amsterdam
The Netherlands
Christiaan Klijn is a PhD student working in three groups, at both the Netherlands Cancer Institute (Jos Jonkers and Lodewyk Wessels groups) and the Delft University of Technology (Marcel Reinders group). He studied at the Delft University and the University of Leiden, earning a masters degree in Life Science & Technology. During his masters' thesis and the first few months of his PhD project he laid the foundation for the KC-SMART (Kernel Convolution: a Statistical Method for Aberrant Region deTection) method. KC-SMART is a way to determine which regions in tumor DNA are significantly more often gained or lost. Knowing which regions are frequently gained or lost might point to cancer genes, and several candidates have been identified from mouse models for cancer. His PhD project extends this effort and has as a goal to find and functionally validate cancer genes using genome-wide analyses and 'wet' laboratory techniques. KC-SMART is now available for the popular statistical analysis software R as a package in the bioconductor bioinformatics environment.
Recently his research has focussed on relational analysis of cancer DNA copy number data as well as next generation sequencing methods.
Research Highlights
Somatic structural rearrangements in genetically engineered mouse mammary tumors
This project reports on the first paired-end sequencing of tumors from genetically engineered mouse models of cancer to determine how faithfully these models recapitulate the landscape of somatic rearrangements found in human tumors. These were models of Trp53-mutated breast cancer, Brca1- and Brca2-associated hereditary breast cancer, and E-cadherin (Cdh1) mutated lobular breast cancer.
It is shown that although Brca1- and Brca2-deficient mouse mammary tumors have a defect in the homologous recombination pathway, there is no apparent difference in the type or frequency of somatic rearrangements found in these cancers when compared to other mouse mammary cancers, and tumors from all genetic backgrounds showed evidence of microhomology-mediated repair and non-homologous end-joining processes. Importantly, mouse mammary tumors were found to carry fewer structural rearrangements than human mammary cancers and expressed in-frame fusion genes. Like the fusion genes found in human mammary tumors, these were not recurrent. One mouse tumor was found to contain an internal deletion of exons of the Lrp1b gene, which led to a smaller in-frame transcript. We found internal in-frame deletions in the human ortholog of this gene in a significant number (4.2%) of human cancer cell lines.
Paired-end sequencing of mouse mammary tumors revealed that they display significant heterogeneity in their profiles of somatic rearrangement but, importantly, fewer rearrangements than cognate human mammary tumors, probably because these cancers have been induced by strong driver mutations engineered into the mouse genome. Both human and mouse mammary cancers carry expressed fusion genes and conserved homozygous deletions.Related publications
People involved
Christiaan Klijn, Lodewyk WesselsKC-SMART: Finding Significantly Recurrent Copy Number Changes
DNA copy number changes are a hallmark of tumor genomes. Cancers are prone to directed and random gain and loss of DNA. In this study we developed a method to separate the frequently occurring DNA copy number changes in a group of tumor samples from the random copy number changes. We do this in a statistically sound, unbiased manner which does not require any additional pre-processing of the data except for normalization. In addition, since we make use of a Gaussian kernel convolution frame work we are able to analyse the data in a scale space which allows for more in-depth discovery of important genomic locations of copy number change.
This work, KCsmart, is available as a package in the popular bioinformatics package Bioconductor for the statistical programming language R.