Prof Ian Tomlinson
|Research Area:||Genetics and Genomics|
|Technology Exchange:||Chromosome mapping, Immunohistochemistry, SNP typing, Transcript profiling and Transgenesis|
|Scientific Themes:||Cancer Biology and Genetics & Genomics|
|Keywords:||Cancer genetics, Population genetics, Colorectal, Renal, Mouse models and Pseudo-hypoxia|
- The identification of genes that predispose to colorectal and other cancers
- Functional genetics of colorectal tumorigenesis, with emphasis on the relative importance of selection and genomic instability.
- Genetic changes and mechanisms of tumorigenesis in renal tumours.
|Prof Jenny Taylor||Wellcome Trust Centre for Human Genetics||University of Oxford||United Kingdom|
|Prof Chris Holmes||Wellcome Trust Centre for Human Genetics||University of Oxford||United Kingdom|
|Dr Jean-Baptiste Cazier||Wellcome Trust Centre for Human Genetics||University of Oxford||United Kingdom|
|Prof Simon Leedham||Wellcome Trust Centre for Human Genetics||University of Oxford||United Kingdom|
|Prof David Kerr CBE FMedSci FRCP (RDM)||Nuffield Division of Clinical Laboratory Sciences||University of Oxford||United Kingdom|
|Dr Rachel Midgley (RDM)||Oncology||University of Oxford||United Kingdom|
|Prof Jonathan M Grimes||Structural Biology||University of Oxford||United Kingdom|
Cancers with chromosomal instability (CIN) are held to be aneuploid/polyploid with multiple large-scale gains/deletions, but the processes underlying CIN are unclear and different types of CIN might exist. We investigated colorectal cancer cell lines using array-comparative genomic hybridization (CGH) for copy number changes and single-copy number polymorphism (SNP) microarrays for allelic loss (LOH). Many array-based CGH changes were not found by LOH because they did not cause true reduction-to-homozygosity. Conversely, many regions of SNP-LOH occurred in the absence of copy number change, comprising an average per cell line of 2 chromosomes with complete LOH; 1-2 terminal regions of LOH (mitotic recombination); and 1 interstitial region of LOH. SNP-LOH detected many novel changes, representing possible locations of uncharacterized tumor suppressor loci. Microsatellite unstable (MSI+) lines infrequently showed gains/deletions or whole-chromosome LOH, but their near-diploid karyotypes concealed mitotic recombination frequencies similar to those of MSI- lines. We analyzed p53 and chromosome 18q (SMAD4) in detail, including mutation screening. Almost all MSI- lines showed LOH and/or deletion of p53 and 18q; some near-triploid lines had acquired three independent changes at these loci. We found consistent results in primary colorectal cancers. Overall, the distributions of mitotic recombination and whole-chromosome LOH in the MSI- cell lines differed significantly from random, with some lines having much higher than expected levels of these changes. Moreover, lines with more LOH changes had significantly fewer copy number changes. These data suggest that CIN is not synonymous with copy number change and some cancers have a specific tendency to whole-chromosome deletion and regain or to mitotic recombination. Hide abstract
The nuclear-encoded Krebs cycle enzymes, fumarate hydratase (FH) and succinate dehydrogenase (SDHB, -C and -D), act as tumour suppressors. Germline mutations in FH predispose individuals to leiomyomas and renal cell cancer (HLRCC), whereas mutations in SDH cause paragangliomas and phaeochromocytomas (HPGL). In this study, we have shown that FH-deficient cells and tumours accumulate fumarate and, to a lesser extent, succinate. SDH-deficient tumours principally accumulate succinate. In situ analyses showed that these tumours also have over-expression of hypoxia-inducible factor 1alpha (HIF1alpha), activation of HIF1alphatargets (such as vascular endothelial growth factor) and high microvessel density. We found no evidence of increased reactive oxygen species in our cells. Our data provide in vivo evidence to support the hypothesis that increased succinate and/or fumarate causes stabilization of HIF1alpha a plausible mechanism, inhibition of HIF prolyl hydroxylases, has previously been suggested by in vitro studies. The basic mechanism of tumorigenesis in HPGL and HLRCC is likely to be pseudo-hypoxic drive, just as it is in von Hippel-Lindau syndrome. Hide abstract
BACKGROUND: Germ-line mutations in the base-excision-repair gene MYH have been associated with recessive inheritance of multiple colorectal adenomas. Tumors from affected persons displayed excess somatic transversions of a guanine-cytosine pair to a thymine-adenine pair (G:C-->T:A) in the APC gene. METHODS: We screened for germ-line MYH mutations in 152 patients with multiple (3 to 100) colorectal adenomas and 107 APC-mutation-negative probands with classic familial adenomatous polyposis (>100 adenomas). Subgroups were analyzed for changes in the related genes MTH1 and OGG1. Adenomas were tested for somatic APC mutations. RESULTS: Six patients with multiple adenomas and eight patients with polyposis had biallelic germline MYH variants. Missense and protein-truncating mutations were found, and the spectrums of mutations were very similar in the two groups of patients. In the tumors of carriers of biallelic mutations, all somatic APC mutations were G:C-->T:A transversions. In the group with multiple adenomas, about one third of patients with more than 15 adenomas had biallelic MYH mutations. In the polyposis group, no patient with biallelic MYH mutations had severe disease (>1000 adenomas), but three had extracolonic disease. No clearly pathogenic MTH1 or OGG1 mutations were identified. CONCLUSIONS: Germ-line MYH mutations predispose persons to a recessive phenotype, multiple adenomas, or polyposis coli. For patients with about 15 or more colorectal adenomas--especially if no germ-line APC mutation has been identified and the family history is compatible with recessive inheritance--genetic testing of MYH is indicated for diagnosis and calculation of the level of risk in relatives. Clinical care of patients with biallelic MYH mutations should be similar to that of patients with classic or attenuated familial adenomatous polyposis. Hide abstract
BMP signalling and cancer susceptibility
We have found that genetic variation in the bone morphogenetic (BMP) signalling pathway are, despite the pathway’s name, the most important in predicting the risk of bowel cancer in the general population. However, there remain contradictions regarding the role of BMP signalling, specifically that different, yet apparently functionally similar, BMP ligands have been reported as having opposing effects on bowel cancer risk. More generally, BMP pathway activity may have different influences on ...
Identifying drivers of papillary renal carcinogenesis
In collaboration with the Swanton group at the Cancer Research UK London Research Institute, we have recently sequenced the genomes and exomes of kidney cancers of the papillary type. This has shown, surprisingly, that the major somatic mutations driving this cancer’s growth are copy number gains of chromosomes 7, 16 and 17 rather than mutations of individual genes, which seem to be the drivers of most cancers. Often, although importantly not always, the whole chromosome is gained in the kidney ...
Tracking the evolution of gastrointestinal tumours in time and space
In some families with bowel and/or uterine cancer, we have recently identified inherited mutations in two genes, POLE and POLD1, that encode the major polymerases. These enzymes copy the DNA in almost all our cells when they divide, but rather than preventing DNA replication, the POLE and POLD1 mutations affect proofreading, such that there is a 100-fold increase in the rate of somatic base substitutions. One major issue is why mutations expected to have ubiquitous effects specifically cause ...
Disruption of intestinal morphogen signalling initiates colorectal cancer from cells outside of the crypt base stem cell niche
Colorectal cancer (CRC) remains a common and important health problem affecting more than 39,000 people/year in the UK. Recent molecular stratification has revealed considerable disease heterogeneity and defined multiple CRC sub-types, each with a morphologically distinct precursor lesion and unique pathogenic molecular pathway. By investigating some of these human CRC subtypes we have shown that carcinogenesis can result from disruption of the microenvironmental control of intestinal stem ...