Ian P M Tomlinson

Publications (77)755.9 Total impact

• Source

  Available from: Vincent Peter Collins

  Article: Genomic profiling identifies discrete deletions associated with translocations in glioblastoma multiforme.

  Paul J Mulholland, Heike Fiegler, Chiara Mazzanti, Patricia Gorman, Peter Sasieni, Joanna Adams, Tania A Jones, Jane W Babbage, Radost Vatcheva, Koichi Ichimura, Philip East, Chrysanthos Poullikas, V Peter Collins, Nigel P Carter, Ian P M Tomlinson, Denise Sheer
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  ABSTRACT: Glioblastoma multiforme is the most common tumor arising in the central nervous system. Patients with these tumors have limited treatment options and their disease is invariably fatal. Molecularly targeted agents offer the potential to improve patient treatment, however the use of these will require a fuller understanding of the genetic changes in these complex tumors. In this study, we identify copy number changes in a series of glioblastoma multiforme tumors and cell lines by applying high-resolution microarray comparative genomic hybridization. Molecular cytogenetic characterization of the cell lines revealed that copy number changes define translocation breakpoints. We focused on chromosome 6 and further characterized three regions of copy number change associated with translocations including a discrete deletion involving IGF2R, PARK2, PACRG and QKI and an unbalanced translocation involving POLH, GTPBP2 and PTPRZ1.
  Cell cycle (Georgetown, Tex.) 05/2006; 5(7):783-91. · 5.36 Impact Factor
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  Available from: Sanna Siltanen

  Article: EPHB2 germline variants in patients with colorectal cancer or hyperplastic polyposis.

  Antti Kokko, Päivi Laiho, Rainer Lehtonen, Sanna Korja, Luis G Carvajal-Carmona, Heikki Järvinen, Jukka-Pekka Mecklin, Charis Eng, Johanna Schleutker, Ian P M Tomlinson, Pia Vahteristo, Lauri A Aaltonen
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  ABSTRACT: Ephrin receptor B2 (EPHB2) has recently been proposed as a novel tumor suppressor gene in colorectal cancer (CRC). Inactivation of the gene has been shown to correlate with progression of colorectal tumorigenesis, and somatic mutations have been reported in both colorectal and prostate tumors. Here we have analyzed the EPHB2 gene for germline alterations in 101 individuals either with 1) CRC and a personal or family history of prostate cancer (PC), or 2) intestinal hyperplastic polyposis (HPP), a condition associated with malignant degeneration such as serrated adenoma and CRC. Four previously unknown missense alterations were observed, which may be associated with the disease phenotype. Two of the changes, I361V and R568W, were identified in Finnish CRC patients, but not in over 300 Finnish familial CRC or PC patients or more than 200 population-matched healthy controls. The third change, D861N, was observed in a UK HPP patient, but not in additional 40 UK HPP patients or in 200 UK healthy controls. The fourth change R80H, originally identified in a Finnish CRC patient, was also found in 1/106 familial CRC patients and in 9/281 healthy controls and is likely to be a neutral polymorphism. We detected novel germline EPHB2 alterations in patients with colorectal tumors. The results suggest a limited role for these EPHB2 variants in colon tumor predisposition. Further studies including functional analyses are needed to confirm this.
  BMC Cancer 02/2006; 6:145. · 3.01 Impact Factor
• Article: Deletion at chromosome band 20p12.1 in colorectal cancer revealed by high resolution array comparative genomic hybridization.

  Eleanor J Davison, Patrick S Tarpey, Heike Fiegler, Ian P M Tomlinson, Nigel P Carter
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  ABSTRACT: Array comparative genomic hybridization (Array CGH) with tiling path resolution for a approximately 4.61 Mb region of chromosome band 20p12.1 has been used to investigate copy number loss in 48 colorectal cancer cell lines and 37 primary colorectal cancers. A recurrent deletion was detected in 55% of cell lines and 23% of primary cancers and the consensus minimum region of loss was identified as a approximately 190 kb section from 14.85 Mb to 15.04 Mb of chromosome 20. Two noncoding RNA genes located in the region, BA318C17.1 and DJ974N19.1, were investigated by mutation analysis and real-time PCR in colorectal cancer cell lines. Sequence changes in BA318C17.1 and reduced expression of both genes was detected, suggesting that the abrogation of these genes may play a role in colorectal tumorigenesis.
  Genes Chromosomes and Cancer 01/2006; 44(4):384-91. · 3.31 Impact Factor
• Article: Mitochondrial tumour suppressors: a genetic and biochemical update.

  Eyal Gottlieb, Ian P M Tomlinson
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  ABSTRACT: Since the discovery 5 years ago that the D-subunit of succinate dehydrogenase (SDHD) can behave as a classic tumour suppressor, other nuclear-encoded mitochondrial proteins (SDHB, SDHC and fumarate hydratase) have been implicated in tumour susceptibility. Mutations in these proteins are principally involved in familial predisposition to benign tumours, but the spectrum of inherited lesions is increasingly recognized to include malignant tumours, such as malignant phaeochromocytomas and renal cell carcinomas. Here we review recent advances in the field of mitochondrial tumour suppressors, the biochemical pathway that links mitochondrial dysfunction with tumorigenesis, and potential therapeutic approaches to these malignancies.
  Nature reviews. Cancer 12/2005; 5(11):857-66. · 37.54 Impact Factor
• Article: Missense mutations in fumarate hydratase in multiple cutaneous and uterine leiomyomatosis and renal cell cancer.

  N Afrina Alam, Simon Olpin, Andrew Rowan, David Kelsell, Irene M Leigh, Ian P M Tomlinson, Todd Weaver
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  ABSTRACT: Heterozygous germline mutations in fumarate hydratase (FH) predispose to the multiple cutaneous and uterine leiomyomatosis syndrome (MCUL), which, when co-existing with renal cancer, is also known as hereditary leiomyomatosis and renal cell cancer. Twenty-seven distinct missense mutations represent 68% of FH mutations reported in MCUL. Here we show that FH missense mutations significantly occurred in fully conserved residues and in residues functioning in the FH A-site, B-site, or subunit-interacting region. Of 24 distinct missense mutations, 13 (54%) occurred in the substrate-binding A-site, 4 (17%) in the substrate-binding B-site, and 7 (29%) in the subunit-interacting region. Clustering of missense mutations suggested the presence of possible mutational hotspots. FH functional assay of lymphoblastoid cell lines from 23 individuals with heterozygous FH missense mutations showed that A-site mutants had significantly less residual activity than B-site mutants, supporting data from Escherichia coli that the A-site is the main catalytic site. Missense FH mutations predisposing to renal cancer had no unusual features, and identical mutations were found in families without renal cancer, suggesting a role for genetic or environmental factors in renal cancer development in MCUL. That all missense FH mutations associating with MCUL/hereditary leiomyomatosis and renal cell cancer showed diminished FH enzymatic activity suggests that the tumor suppressor role of fumarate hydratase may relate to its enzymatic function.
  Journal of Molecular Diagnostics 11/2005; 7(4):437-43. · 3.58 Impact Factor
• Article: Tissue, cell and stage specificity of (epi)mutations in cancers.

  Oliver M Sieber, Simon R Tomlinson, Ian P M Tomlinson
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  ABSTRACT: Most (epi)mutations in cancers are specific to particular tumours or occur at specific stages of development, cell differentiation or tumorigenesis. Simple molecular mechanisms, such as tissue-restricted gene expression, seem to explain these associations only in rare cases. Instead, the specificity of (epi)mutations is probably due to the selection of a restricted spectrum of genetic changes by the cellular environment. In some cases, the resulting functional defects might be constrained to be neither too strong nor too weak for tumour growth to occur; that is, they lie within a 'window' that is permissive for tumorigenesis.
  Nature reviews. Cancer 09/2005; 5(8):649-55. · 37.54 Impact Factor
• Article: Evidence for an association between compound heterozygosity for germ line mutations in the hemochromatosis (HFE) gene and increased risk of colorectal cancer.

  James P Robinson, Victoria L Johnson, Pauline A Rogers, Richard S Houlston, Earmonn R Maher, D Timothy Bishop, D Gareth R Evans, Huw J W Thomas, Ian P M Tomlinson, Andrew R J Silver
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  ABSTRACT: Whereas a recent study reported an increased risk of colorectal cancer associated with any HFE germ line mutation (C282Y or H63D), other investigators have concluded there is no increased risk, or that any increase is dependent on polymorphisms in HFE-interacting genes such as the transferrin receptor (TFR). We have established the frequency of HFE mutations in colorectal cancer patients (n = 327) with a family history of the disease and randomly selected controls (n = 322); this design increases greatly the study's power. Genotyping for the TRF S142G polymorphism was also conducted on a large proportion of the study group. Using PCR, restriction enzyme mapping, sequencing followed by data analysis with Fisher's exact test and logistic regression, we show that the presence of any HFE mutation (Y282 or D63) was not associated with colorectal cancer risk (P = 0.57). In contrast, individuals compound heterozygous for both mutations (15 cases versus 5 controls) had thrice the odds of developing colorectal cancer (odds ratio, 3.03; 95% confidence interval, 1.06-8.61) compared with those with a single mutation. This finding did not quite reach statistical significance after allowing for multiple post hoc testing (P(observed) = 0.038 versus P = 0.025, with Bonferonni correction). Overall, our data indicate that individuals with a single HFE mutation, C282Y or H63D, are unlikely predisposed to develop colorectal cancer. However, risk of colorectal cancer might be increased by compound heterozygosity for the HFE mutations in the small number of subjects studied. TFR gene polymorphism was not an independent risk factor and did not modify the disease risk associated with HFE mutation.
  Cancer Epidemiology Biomarkers &amp Prevention 07/2005; 14(6):1460-3. · 4.12 Impact Factor
• Article: Mutations of the PU.1 Ets domain are specifically associated with murine radiation-induced, but not human therapy-related, acute myeloid leukaemia.

  Nirosha Suraweera, Emmy Meijne, John Moody, Luis G Carvajal-Carmona, Kazuko Yoshida, Patrick Pollard, Jude Fitzgibbon, Andrew Riches, Theo van Laar, Rene Huiskamp, Andrew Rowan, Ian P M Tomlinson, Andrew Silver
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  ABSTRACT: Murine radiation-induced acute myeloid leukaemia (AML) is characterized by loss of one copy of chromosome 2. Previously, we positioned the critical haematopoietic-specific transcription factor PU.1 within a minimally deleted region. We now report a high frequency (>65%) of missense mutation at codon 235 in the DNA-binding Ets domain of PU.1 in murine AML. Earlier studies, outside the context of malignancy, determined that conversion of arginine 235 (R235) to any other amino-acid residue leads to ablation of DNA-binding function and loss of expression of downstream targets. We show that mutation of R235 does not lead to protein loss, and occurs specifically in those AMLs showing loss of one copy of PU.1 (P=0.001, Fisher's exact test). PU.1 mutations were not found in the coding region, UTRs or promoter of human therapy-related AMLs. Potentially regulatory elements upstream of PU.1 were located but no mutations found. In conclusion, we have identified the cause of murine radiation-induced AML and have shown that loss of one copy of PU.1, as a consequence of flanking radiation-sensitive fragile domains on chromosome 2, and subsequent R235 conversion are highly specific to this mouse model. Such a mechanism does not operate, or is extremely rare, in human AML.
  Oncogene 06/2005; 24(22):3678-83. · 6.37 Impact Factor
• Article: Allelic loss studies do not provide evidence for the "endometriosis-as-tumor" theory.

  Amanda H Prowse, Giannoulis Fakis, Sanjiv Manek, Michael Churchman, Sarah Edwards, Andrew Rowan, Philippe Koninckx, Stephen Kennedy, Ian P M Tomlinson
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  ABSTRACT: To identify consistent genetic changes in endometriosis samples to determine whether endometriosis lesions are true neoplasms. We analyzed ovarian endometriosis lesions for loss of heterozygosity (LOH) at 12 loci of potential importance (D9S1870, D9S265, D9S270, D9S161, D11S29, D1S199, D8S261, APOA2, PTCH, TP53, D10S541, and D10S1765), including some at which genetic changes were previously reported in endometriosis. Molecular biology laboratory in a university hospital department. Seventeen women with ovarian endometriosis. Laser capture microdissection to separate the endometriotic epithelium, the adjacent endometriotic stroma, and surrounding normal ovarian stromal tissue, followed by DNA extraction and polymerase chain reaction amplification of polymorphic microsatellite markers. Fluorescence-based quantitation for the LOH analysis. We identified LOH in only one lesion at one locus (D8S261). Our data do not support the hypothesis that ovarian endometriosis is a true neoplasm.
  Fertility and Sterility 05/2005; 83 Suppl 1:1134-43. · 3.56 Impact Factor
• Article: Dercum's Disease

  Noel C. Wortham, Ian P.M. Tomlinson
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  ABSTRACT: Dercum's disease (adiposis dolorosa, lipomatosis dolorosa morbus Dercum), is a rare disorder resulting in painful fatty deposits around the upper legs, trunk, and upper arms. The portrait painted of Dercum's disease is very complicated, with many other disorders seen associated with the disease. There are no clear pathological mechanisms known, although it is suspected that there is either a metabolic or autoimmune component involved. Here, the authors review the literature to date, including some information from their own studies. In particular, the authors will look at the different strands of evidence pointing to the pathological mechanism of the disorder.
  SKINmed 04/2005; 4(3):157 - 162.
• Article: Clinical features of multiple cutaneous and uterine leiomyomatosis: an underdiagnosed tumor syndrome.

  N Afrina Alam, Ella Barclay, Andrew J Rowan, Jonathan P Tyrer, Eduardo Calonje, Sanjiv Manek, David Kelsell, Irene Leigh, Simon Olpin, Ian P M Tomlinson
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  ABSTRACT: To investigate the clinical features of the multiple cutaneous and uterine leiomyomatosis (MCUL) syndrome, including the hereditary leiomyomatosis and renal cell cancer syndrome. A case series of patients with multiple skin leiomyomas solicited via a circular letter to dermatologists. Research institute. A total of 108 affected individuals, including 46 probands and 62 affected relatives. The proportion of probands with underlying fumarate hydratase (FH) mutations, the penetrance of FH mutations, and clinicopathologic features of MCUL. Forty-one (89%) of 46 probands with multiple skin leiomyomas had evidence of germline FH mutations, which were highly penetrant. All 26 male mutation carriers had skin leiomyomas. Of 67 women with FH mutations, 46 (69%) had both skin and uterine leiomyomas; 10 (15%) had only skin leiomyomas; 5 (7%) had only uterine leiomyomas; and 6 (9%) were clinically unaffected. Patients presented with skin leiomyomas at a mean age of 24 years and had a mean of 25 lesions. Forty-one individuals (89%) reported painful lesions, particularly in response to cold or trauma. Fibroids were histologically unremarkable, highly symptomatic, and associated with a high risk of early hysterectomy. One individual had a very aggressive collecting duct renal cancer. The G354R FH mutation predisposed patients to uterine fibroids without skin leiomyomas (P = .03). Many patients with skin leiomyomas had not previously presented for medical attention. Fibroids were rarely recognized as cases of MCUL. Highly penetrant FH mutations underlie MCUL. Increased clinical awareness is important because of the associated risk of severe uterine fibroids and, in some cases, aggressive renal cancer.
  Archives of Dermatology 03/2005; 141(2):199-206. · 3.89 Impact Factor
• Article: Analysis of ovarian cancer cell lines using array-based comparative genomic hybridization.

  Maryou B K Lambros, Heike Fiegler, Angela Jones, Patricia Gorman, Rebecca R Roylance, Nigel P Carter, Ian P M Tomlinson
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  ABSTRACT: In this study, 23 ovarian cancer cell lines were screened using array-comparative genomic hybridization (aCGH) based on large-insert clones at about 1 Mb density from throughout the genome. The most frequent recurrent changes at the level of the chromosome arm were loss of chromosome 4 or 4q, loss of 18q and gain of 20 or 20q; other recurrent changes included losses of 6q, 8p, 9p, 11p, 15q, 16q, 17p, and 22q, and gain of 7q. Losses of 4q and 18q occurred together more often than expected. Evidence was found for two types of ovarian cancer, one typically near-triploid and characterized by a generally higher frequency of chromosomal changes (especially losses of 4p, 4q, 13q, 15q, 16p, 16q, 18p and 18q), and the other typically near-diploid/tetraploid and with fewer changes overall, but with relatively high frequencies of 9p loss, 9q gain, and 20p gain. Multiple novel changes (amplifications, homozygous deletions, discrete regions of gain or loss, small overlapping regions of change and frequently changed clones) were also detected, each of which might indicate the locations of oncogenes or tumour suppressor loci. For example, at least two regions of amplification on chromosome 11q13, one including cyclin D1 and the other the candidate oncogene PAK1, were found. Amplification on 11q22 near the progesterone receptor gene and a cluster of matrix metalloproteinase loci was also detected. Other potential oncogenes, which mapped to regions found by this study, included cyclin E and PIK3C2G. Candidate tumour suppressor genes in regions of loss included CDKN2C, SMAD4-interacting protein and RASSF2.
  The Journal of Pathology 02/2005; 205(1):29-40. · 6.32 Impact Factor
• Article: Array-CGH analysis of microsatellite-stable, near-diploid bowel cancers and comparison with other types of colorectal carcinoma.

  Angela M Jones, Eleanor J Douglas, Sarah Er Halford, Heike Fiegler, Patricia A Gorman, Rebecca R Roylance, Nigel P Carter, Ian P M Tomlinson
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  ABSTRACT: Microsatellite-stable, near-diploid (MSI-CIN-) colorectal carcinomas have been reported, but it is not clear as to whether these tumours form a discrete group or represent one end of the distribution of MSI-CIN+ cancers. In order to address this question, we screened 23 MSI-CIN- colorectal cancers for gains and losses using array-based comparative genomic hybridization (aCGH) based on large-insert clones at about 1 Mb density. We compared our findings with those from a small set of MSI+CIN+ cancers, and with our reported data from MSI-CIN+ and MSI+CIN- cancers. We found no evidence of any form of genomic instability in MSI-CIN- cancers. At the level of the chromosome arm, the MSI-CIN- cancers had significantly fewer gains and losses than MSI-CIN+ tumours, but more than the MSI+CIN- and MSI+CIN+ lesions. The chromosomal-scale changes found in MSI-CIN- cancers generally involved the same sites as those in MSI-CIN+ tumours, and in both cancer groups, the best predictor of a specific change was the total number of such changes in that tumour. A few chromosomal-scale changes did, however, differ between the MSI-CIN- and MSI-CIN+ pathways. MSI-CIN- cancers showed: low frequencies of gain of 9p and 19p; infrequent loss of 5q and a high frequency of 20p gain. Overall, our data suggested that the MSI-CIN- group is heterogeneous, one type of MSI-CIN- cancer having few (< or =6) chromosomal-scale changes and the other with more (> or =10) changes resembling MSI-CIN+ cancers. At the level of individual clones, frequent and/or discrete gains or losses were generally located within regions of chromosomal-scale changes in both MSI-CIN- and MSI-CIN+ cancers, and fewer losses and gains were present in MSI-CIN- than MSI-CIN+ tumours. No changes by clone, which were specific to the MSI-CIN- cancers, were found. In addition to indicating differences among the cancer groups, our results also detected over 50 sites (amplifications, potential homozygous deletion and gains or losses which extended over only a few megabases) which might harbour uncharacterized oncogenes or tumour suppressor loci. In conclusion, our data support the suggestion that some MSI-CIN- carcinomas form a qualitatively different group from the other cancer types, and also suggest that the MSI-CIN- group is itself heterogeneous.
  Oncogene 01/2005; 24(1):118-29. · 6.37 Impact Factor
• Article: Myh deficiency enhances intestinal tumorigenesis in multiple intestinal neoplasia (ApcMin/+) mice.

  Oliver M Sieber, Kimberley M Howarth, Christina Thirlwell, Andrew Rowan, Nikki Mandir, Robert A Goodlad, Ashfaq Gilkar, Bradley Spencer-Dene, Gordon Stamp, Victoria Johnson, Andrew Silver, Hanjing Yang, Jeffrey H Miller, Mohammad Ilyas, Ian P M Tomlinson
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  ABSTRACT: Monoallelic APC and biallelic MYH (homolog of Escherichia coli mutY) germ-line mutations are independently associated with a strong predisposition to colorectal adenomas and carcinoma in humans. Whereas mice heterozygous for mutant Apc develop intestinal tumors, mice homozygous for mutant Myh do not show increased tumor susceptibility. We analyzed the phenotype of Apc(Min/+)/Myh(-/-) mice and found that they developed significantly more adenomas in the small intestine than did Apc(Min/+)/Myh(+/+) or Apc(Min/+)/Myh(+/-) mice (median 231 versus 151 versus 152). In the large bowel, Apc(Min/+)/Myh(-/-) mice showed significant increases in the number of aberrant crypt foci. In addition, Apc(Min/+)/Myh(-/-) mice developed an increased number of mammary tumors. Molecular analyses suggested that at least 19% of intestinal tumors from Apc(Min/+)/Myh(-/-) mice had acquired intragenic Apc mutations rather than allelic loss. Consistent with a defect in base excision repair, three intragenic Apc mutations in polyps without allelic loss from Apc(Min/+)/Myh(-/-) mice were shown to be G:C to T:A transversions which resulted in termination codons; no such mutations were found in polyps from Apc(Min/+)/Myh(+/+) or Apc(Min/+)/Myh(+/-) mice. Tumors from Apc(Min/+)/Myh(+/-) mice harbored neither somatic mutations nor allelic loss at Myh. Thus, homozygous, but not heterozygous, Myh deficiency enhanced intestinal tumorigenesis in Apc(Min/+) mice. The excess small-bowel adenomas in Apc(Min/+)/Myh(-/-) mice, therefore, appear to be a model of MYH-associated polyposis in humans.
  Cancer Research 01/2005; 64(24):8876-81. · 7.86 Impact Factor
• Source

  Available from: Jennifer L Wilding

  Article: Multiple rare variants in different genes account for multifactorial inherited susceptibility to colorectal adenomas.

  Nicola S Fearnhead, Jennifer L Wilding, Bruce Winney, Susan Tonks, Sylvia Bartlett, David C Bicknell, Ian P M Tomlinson, Neil J McC Mortensen, Walter F Bodmer
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  ABSTRACT: Clear-cut inherited Mendelian traits, such as familial adenomatous polyposis or hereditary nonpolyposis colorectal cancer, account for <4% of colorectal cancers. Another 20% of all colorectal cancers are thought to occur in individuals with a significant inherited multifactorial susceptibility to colorectal cancer that is not obviously familial. Incompletely penetrant, comparatively rare missense variants in the adenomatous polyposis coli gene, which is responsible for familial adenomatous polyposis, have been described in patients with multiple colorectal adenomas. These variants represent a category of variation that has been suggested, quite generally, to account for a substantial fraction of such multifactorial inherited susceptibility. The aim of this study was to explore this rare variant hypothesis for multifactorial inheritance by using multiple colorectal adenomas as the model. Patients with multiple adenomas were screened for germ-line variants in a panel of candidate genes. Germ-line DNA was obtained from 124 patients with between 3 and 100 histologically proven synchronous or metachronous adenomatous polyps. All patients were tested for the adenomatous polyposis coli variants I1307K and E1317Q, and variants were also sought in AXIN1 (axin), CTNNB1 (beta-catenin), and the mismatch repair genes hMLH1 and hMSH2. The control group consisted of 483 random controls. Thirty of 124 (24.9%) patients carried potentially pathogenic germ-line variants as compared with 55 ( approximately 12%) of the controls. This overall difference is highly significant, suggesting that many rare variants collectively contribute to the inherited susceptibility to colorectal adenomas.
  Proceedings of the National Academy of Sciences 12/2004; 101(45):15992-7. · 9.68 Impact Factor
• Article: Array comparative genomic hybridization analysis of colorectal cancer cell lines and primary carcinomas.

  Eleanor J Douglas, Heike Fiegler, Andrew Rowan, Sarah Halford, David C Bicknell, Walter Bodmer, Ian P M Tomlinson, Nigel P Carter
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  ABSTRACT: Array comparative genomic hybridization, with a genome-wide resolution of approximately 1 Mb, has been used to investigate copy number changes in 48 colorectal cancer (CRC) cell lines and 37 primary CRCs. The samples were divided for analysis according to the type of genomic instability that they exhibit, microsatellite instability (MSI) or chromosomal instability (CIN). Consistent copy number changes were identified, including gain of chromosomes 20, 13, and 8q and smaller regions of amplification such as chromosome 17q11.2-q12. Loss of chromosome 18q was a recurrent finding along with deletion of discrete regions such as chromosome 4q34-q35. The overall pattern of copy number change was strikingly similar between cell lines and primary cancers with a few obvious exceptions such as loss of chromosome 6 and gain of chromosomes 15 and 12p in the former. A greater number of aberrations were detected in CIN+ than MSI+ samples as well as differences in the type and extent of change reported. For example, loss of chromosome 8p was a common event in CIN+ cell lines and cancers but was often found to be gained in MSI+ cancers. In addition, the target of amplification on chromosome 8q appeared to differ, with 8q24.21 amplified frequently in CIN+ samples but 8q24.3 amplification a common finding in MSI+ samples. A number of genes of interest are located within the frequently aberrated regions, which are likely to be of importance in the development and progression of CRC.
  Cancer Research 08/2004; 64(14):4817-25. · 7.86 Impact Factor
• Article: MSI-low, a real phenomenon which varies in frequency among cancer types.

  Sarah E R Halford, Elinor J Sawyer, Maryou B Lambros, Patricia Gorman, Nicola D Macdonald, Ian C Talbot, William D Foulkes, Cheryl E Gillett, Diana M Barnes, Lars A Akslen, Kwok Lee, Ian J Jacobs, Andrew M Hanby, Trivadi S Ganesan, Helga B Salvesen, Walter F Bodmer, Ian P M Tomlinson, Rebecca R Roylance
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  ABSTRACT: This study assessed whether low-level microsatellite instability (MSI-L) is a phenomenon specific to colorectal cancers or is also present in other tumour types. Breast (grade III ductal and lobular), endometrial and ovarian carcinomas, as well as colorectal cancers, were analysed for MSI-L using eight microsatellite markers. The markers were selected from a panel that had previously been shown to be sensitive for the detection of MSI-L in colorectal cancers. It was found that MSI-L was present in 30 of 87 (35%) colorectal cancers, 2 of 59 (3%) grade III breast carcinomas, 1 of 35 (3%) lobular breast cancers, 16 of 50 (32%) endometrial cancers, and 9 of 34 (26%) ovarian cancers. These results suggest that MSI-L is a very rare occurrence in breast carcinomas, but does occur as a real phenomenon in colorectal, endometrial, and ovarian carcinomas, which are all part of the hereditary non-polyposis colon cancer (HNPCC) syndrome. PCR artefact was also found to masquerade as MSI-L; criteria for the assessment of MSI-L are suggested to eliminate this problem.
  The Journal of Pathology 12/2003; 201(3):389-94. · 6.32 Impact Factor
• Article: Carcinogenesis in MYH-associated polyposis follows a distinct genetic pathway.

  Lara Lipton, Sarah E Halford, Victoria Johnson, Marco R Novelli, Angela Jones, Carole Cummings, Ella Barclay, Oliver Sieber, Amir Sadat, Marie-Luise Bisgaard, Shirley V Hodgson, Lauri A Aaltonen, Huw J W Thomas, Ian P M Tomlinson
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  ABSTRACT: Colorectal carcinomas develop according to particular genetic pathways, including the chromosomal instability (CIN+), microsatellite instability (MSI+) and MSI- CIN- routes. We have determined the genetic pathway in patients with MYH-associated polyposis (MAP), a syndrome of colorectal adenomas and cancer that results from defective base excision repair (BER). As in previous studies, MAP tumors showed a high frequency of G>T mutations in APC, in accordance with defective BER. We found that K-ras mutations were common in MAP tumors, all of the changes comprising conversion of the first guanine residue of codon 12 to thymidine (G12C, GGT>TGT). We found no BRAF mutations at the codon 599 hotspot or elsewhere in exon 14. Almost all of the MAP cancers were near-diploid (CIN-), and none was MSI+. A few p53 mutations were found, but these were not predominantly G>T changes. p53 overexpression was, however, frequent. No SMAD4 or TGFBIIR mutations were found. MAP tumors appear to follow a distinct genetic pathway, with some features of both the CIN and MSI pathways. BER deficiency is rarely accompanied by CIN or MSI. The spectrum of somatic mutations in MAP tumors reflects both selection and hypermutation to which certain guanine residues are particularly prone.
  Cancer Research 11/2003; 63(22):7595-9. · 7.86 Impact Factor
• Article: Contribution of the CHEK2 1100delC variant to risk of multiple colorectal adenoma and carcinoma.

  Lara Lipton, Christina Fleischmann, Oliver M Sieber, Huw J W Thomas, Shirley V Hodgson, Ian P M Tomlinson, Richard S Houlston
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  ABSTRACT: Aneuploidy is a characteristic of a subset of colorectal tumours. CHEK2 (also known as CHK2) is one of the cell cycle checkpoint genes coding for a family of proteins that sense damage in eukaryotic cells. Germline variation in CHEK2 has recently been shown to confer cancer susceptibility. Heterozygous mutations have been identified in patients with TP53-negative Li-Fraumeni syndrome. Furthermore, the CHEK2 1100delC variant carried by 1% of the population has been shown to act as a low penetrance allele for both breast and prostate cancers. To further our knowledge about the contribution of CHEK2 1100delC to cancer incidence we have analysed a series of 149 patients with multiple colorectal adenomas some of whom developed colorectal cancer. The CHEK2 1100delC allele was not over-represented in cases suggesting that this variant is not associated with an increased risk of colorectal disease.
  Cancer Letters 10/2003; 200(2):149-52. · 4.24 Impact Factor
• Article: Genomic instability--the engine of tumorigenesis?

  Oliver M Sieber, Karl Heinimann, Ian P M Tomlinson
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  ABSTRACT: Human cancers harbour numerous mutations and it has been proposed that these result from some form of inherent genomic instability. Some cancers have proven genomic instability or features that are indicative of this. Inherited cancer syndromes exist that are caused by deficient DNA repair or chromosomal integrity. By contrast, theoretical analysis and experimental data from sporadic colorectal tumours provide little general evidence of genomic instability in early lesions. These apparently conflicting data raise the question of whether or not genomic instability is necessary for driving tumour growth, and whether or not it is the usual initiating event in tumorigenesis.
  Nature reviews. Cancer 10/2003; 3(9):701-8. · 37.54 Impact Factor