Dr Jean-Baptiste Cazier

Research Area: Bioinformatics & Stats (inc. Modelling and Computational Biology)
Technology Exchange: Bioinformatics, Chromosome mapping, Computational biology, Medical statistics and Statistical genetics
Keywords: Bioinformatics, Statistical Genetics, Metabonomic, Whole Genome Sequencing, High-Throughput-Sequencing, Genotyping, Expression, NMR and Cancer, Cardio-Vascular, Central Nervous System, Immunological disorder

I am interested in evaluating, developing and applying new statistical and computational methods to Genetic research, essentially in Cancer and Cardiovascular diseases. For many years I have been collaborating with Prof Ian Tomlinson's group (at WTCHG since 2008) to perform Genome-Wide Association, Linkage and Copy Number Variation studies of Colorectal Cancer. We have also been studying population stratification and admixture mapping in order to perform more accurate analysis across heterogeneous cohorts. This led us to successfully identify many genomic susceptibility variants conferring higher risk of Colorectal Cancer.

More recently I have been increasingly collaborating with Prof Chris Holmes' group (Statistics Department and WTCHG) to match the new problems and datasets to the latest statistical methods for both Copy Number Variation and Population Genetics.

Furthermore a significant part of my work is dedicated to Metabonomics with Prof. Dominique Gauguier 's lab in the FGENTCard project. We are studying the gene-environment interaction using rat- and mouse-models, by following the variation of their metabonome. Their metabolite spectra are measured in collaboration with Marc-Emmanuel Dumas, at the Ecole Normale Supérieure de Lyon, and Prof Jeremy Nicholson at Imperial College, London.

Finally I collaborate with other scientists in various cancers and neurologic diseases.

This broad range of work sometimes leads to the development of interactive tools such as the Genome Recurrent Event ViEwer (GREVE)

My current research interests focus essentially on Cancer Genetics, Population Genetics, Copy Number Variation and Metabonomics using technologies from High-Throughput Sequencing to SNP-array or NMR.

You can access further links at my private page.

Name Department Institution Country
Prof Ian Tomlinson Wellcome Trust Centre for Human Genetics Oxford University UK
Prof Chris Holmes Department of Statistics, University of Oxford UK
Prof Dominique Gauguier Wellcome Trust Centre for Human Genetics Oxford University UK
Dr Julian C Knight Wellcome Trust Centre for Human Genetics Oxford University UK
Dr Dianne Newbury Wellcome Trust Centre for Human Genetics Oxford University UK
Prof Pierre Zalloua School of Medicine Lebanese American University Lebanon
Prof Jotun hein Department of Statistics University of Oxford UK
Dr Marc-Emmanuel Dumas Department of Surgery & Cancer Imperial College UK
Prof Andrew Silver Institute Cell Molecular Science, Queen Mary University, London UK
Dr Clara Ruiz Ponte Fundación Pública Galega de Medicina Xenómica. Universite Santiago de Compostela Spain
Dr Jorg hager Genetics Core Nestle Institute of Health Sciences Switzerland
Dr Jude Fitzgibbon Molecular Oncology Unit Queen Mary University, London UK

Holt R, Sykes NH, Conceição IC, Cazier JB, Anney RJ, Oliveira G, Gallagher L, Vicente A, Monaco AP, Pagnamenta AT. 2012. CNVs leading to fusion transcripts in individuals with autism spectrum disorder. Eur J Hum Genet, Read abstract | Read more

There is strong evidence that rare copy number variants (CNVs) have a role in susceptibility to autism spectrum disorders (ASDs). Much research has focused on how CNVs mediate a phenotypic effect by altering gene expression levels. We investigated an alternative mechanism whereby CNVs combine the 5' and 3' ends of two genes, creating a 'fusion gene'. Any resulting mRNA with an open reading frame could potentially alter the phenotype via a gain-of-function mechanism. We examined 2382 and 3096 rare CNVs from 996 individuals with ASD and 1287 controls, respectively, for potential to generate fusion transcripts. There was no increased burden in individuals with ASD; 122/996 cases harbored at least one rare CNV of this type, compared with 179/1287 controls (P=0.89). There was also no difference in the overall frequency distribution between cases and controls. We examined specific examples of such CNVs nominated by case-control analysis and a candidate approach. Accordingly, a duplication involving REEP1-POLR1A (found in 3/996 cases and 0/1287 controls) and a single occurrence CNV involving KIAA0319-TDP2 were tested. However, no fusion transcripts were detected by RT-PCR. Analysis of additional samples based on cell line availability resulted in validation of a MAPKAPK5-ACAD10 fusion transcript in two probands. However, this variant was present in controls at a similar rate and is unlikely to influence ASD susceptibility. In summary, although we find no evidence that fusion-gene generating CNVs lead to ASD susceptibility, discovery of a MAPKAPK5-ACAD10 transcript with an estimated frequency of ∼1/200 suggests that gain-of-function mechanisms should be considered in future CNVs studies.European Journal of Human Genetics advance online publication, 2 May 2012; doi:10.1038/ejhg.2012.73. Hide abstract

Diawara M, Gan X, Cazier JB, Mott R, Calderari S, Gauguier D. 2012. Regulation of microARN expression deteremined by systematic sequencing in obesity induced by a diet rich in fat DIABETES & METABOLISM, 38 pp. A62-A62.

Ghassibe-Sabbagh M, Platt DE, Youhanna S, Abchee AB, Stewart K, Badro DA, Haber M, Salloum AK et al. 2012. Genetic and environmental influences on total plasma homocysteine and its role in coronary artery disease risk. Atherosclerosis, 222 (1), pp. 180-186. Read abstract | Read more

Elevated levels of total plasma homocysteine are a risk factor for atherosclerotic disease. Hide abstract

Knight SJ, Yau C, Clifford R, Timbs AT, Sadighi Akha E, Dréau HM, Burns A, Ciria C et al. 2012. Quantification of subclonal distributions of recurrent genomic aberrations in paired pre-treatment and relapse samples from patients with B-cell chronic lymphocytic leukemia. Leukemia, Read abstract | Read more

Genome-wide array approaches and sequencing analyses are powerful tools for identifying genetic aberrations in cancers, including leukemias and lymphomas. However, the clinical and biological significance of such aberrations and their subclonal distribution are poorly understood. Here, we present the first genome-wide array based study of pre-treatment and relapse samples from patients with B-cell chronic lymphocytic leukemia (B-CLL) that uses the computational statistical tool OncoSNP. We show that quantification of the proportion of copy number alterations (CNAs) and copy neutral loss of heterozygosity regions (cnLOHs) in each sample is feasible. Furthermore, we (i) reveal complex changes in the subclonal architecture of paired samples at relapse compared with pre-treatment, (ii) provide evidence supporting an association between increased genomic complexity and poor clinical outcome (iii) report previously undefined, recurrent CNA/cnLOH regions that expand or newly occur at relapse and therefore might harbor candidate driver genes of relapse and/or chemotherapy resistance. Our findings are likely to impact on future therapeutic strategies aimed towards selecting effective and individually tailored targeted therapies.Leukemia advance online publication, 14 February 2012; doi:10.1038/leu.2012.13. Hide abstract

Fernandez-Rozadilla C, Cazier JB, Moreno V, Crous-Bou M, Guinó E, Durán G, Lamas MJ, López R et al. 2012. Pharmacogenomics in colorectal cancer: a genome-wide association study to predict toxicity after 5-fluorouracil or FOLFOX administration. Pharmacogenomics J, Read abstract | Read more

The development of genotyping technologies has allowed for wider screening for inherited causes of variable outcomes following drug administration. We have performed a genome-wide association study (GWAS) on 221 colorectal cancer (CRC) patients that had been treated with 5-fluorouracil (5-FU), either alone or in combination with oxaliplatin (FOLFOX). A validation set of 791 patients was also studied. Seven SNPs (rs16857540, rs2465403, rs10876844, rs10784749, rs17626122, rs7325568 and rs4243761) showed evidence of association (pooled P-values 0.020, 9.426E-03, 0.010, 0.017, 0.042, 2.302E-04, 2.803E-03) with adverse drug reactions (ADRs). This is the first study to explore the genetic basis of inter-individual variation in toxicity responses to the administration of 5-FU or FOLFOX in CRC patients on a genome-wide scale.The Pharmacogenomics Journal advance online publication, 7 February 2012; doi:10.1038/tpj.2012.2. Hide abstract

Cazier JB, Kaisaki PJ, Argoud K, Blaise BJ, Veselkov K, Ebbels TM, Tsang T, Wang Y et al. 2012. Untargeted metabolome quantitative trait locus mapping associates variation in urine glycerate to mutant glycerate kinase. J Proteome Res, 11 (2), pp. 631-642. Read abstract | Read more

With successes of genome-wide association studies, molecular phenotyping systems are developed to identify genetically determined disease-associated biomarkers. Genetic studies of the human metabolome are emerging but exclusively apply targeted approaches, which restricts the analysis to a limited number of well-known metabolites. We have developed novel technical and statistical methods for systematic and automated quantification of untargeted NMR spectral data designed to perform robust and accurate quantitative trait locus (QTL) mapping of known and previously unreported molecular compounds of the metabolome. For each spectral peak, six summary statistics were calculated and independently tested for evidence of genetic linkage in a cohort of F2 (129S6xBALB/c) mice. The most significant evidence of linkages were obtained with NMR signals characterizing the glycerate (LOD10-42) at the mutant glycerate kinase locus, which demonstrate the power of metabolomics in quantitative genetics to identify the biological function of genetic variants. These results provide new insights into the resolution of the complex nature of metabolic regulations and novel analytical techniques that maximize the full utilization of metabolomic spectra in human genetics to discover mappable disease-associated biomarkers. Hide abstract

Vernes SC, Oliver PL, Spiteri E, Lockstone HE, Puliyadi R, Taylor JM, Ho J, Mombereau C et al. 2011. Foxp2 regulates gene networks implicated in neurite outgrowth in the developing brain. PLoS Genet, 7 (7), pp. e1002145. Read abstract | Read more

Forkhead-box protein P2 is a transcription factor that has been associated with intriguing aspects of cognitive function in humans, non-human mammals, and song-learning birds. Heterozygous mutations of the human FOXP2 gene cause a monogenic speech and language disorder. Reduced functional dosage of the mouse version (Foxp2) causes deficient cortico-striatal synaptic plasticity and impairs motor-skill learning. Moreover, the songbird orthologue appears critically important for vocal learning. Across diverse vertebrate species, this well-conserved transcription factor is highly expressed in the developing and adult central nervous system. Very little is known about the mechanisms regulated by Foxp2 during brain development. We used an integrated functional genomics strategy to robustly define Foxp2-dependent pathways, both direct and indirect targets, in the embryonic brain. Specifically, we performed genome-wide in vivo ChIP-chip screens for Foxp2-binding and thereby identified a set of 264 high-confidence neural targets under strict, empirically derived significance thresholds. The findings, coupled to expression profiling and in situ hybridization of brain tissue from wild-type and mutant mouse embryos, strongly highlighted gene networks linked to neurite development. We followed up our genomics data with functional experiments, showing that Foxp2 impacts on neurite outgrowth in primary neurons and in neuronal cell models. Our data indicate that Foxp2 modulates neuronal network formation, by directly and indirectly regulating mRNAs involved in the development and plasticity of neuronal connections. Hide abstract

Tomlinson IP, Carvajal-Carmona LG, Dobbins SE, Tenesa A, Jones AM, Howarth K, Palles C, Broderick P et al. 2011. Multiple common susceptibility variants near BMP pathway loci GREM1, BMP4, and BMP2 explain part of the missing heritability of colorectal cancer. PLoS Genet, 7 (6), pp. e1002105. Read abstract | Read more

Genome-wide association studies (GWAS) have identified 14 tagging single nucleotide polymorphisms (tagSNPs) that are associated with the risk of colorectal cancer (CRC), and several of these tagSNPs are near bone morphogenetic protein (BMP) pathway loci. The penalty of multiple testing implicit in GWAS increases the attraction of complementary approaches for disease gene discovery, including candidate gene- or pathway-based analyses. The strongest candidate loci for additional predisposition SNPs are arguably those already known both to have functional relevance and to be involved in disease risk. To investigate this proposition, we searched for novel CRC susceptibility variants close to the BMP pathway genes GREM1 (15q13.3), BMP4 (14q22.2), and BMP2 (20p12.3) using sample sets totalling 24,910 CRC cases and 26,275 controls. We identified new, independent CRC predisposition SNPs close to BMP4 (rs1957636, P = 3.93×10(-10)) and BMP2 (rs4813802, P = 4.65×10(-11)). Near GREM1, we found using fine-mapping that the previously-identified association between tagSNP rs4779584 and CRC actually resulted from two independent signals represented by rs16969681 (P = 5.33×10(-8)) and rs11632715 (P = 2.30×10(-10)). As low-penetrance predisposition variants become harder to identify-owing to small effect sizes and/or low risk allele frequencies-approaches based on informed candidate gene selection may become increasingly attractive. Our data emphasise that genetic fine-mapping studies can deconvolute associations that have arisen owing to independent correlation of a tagSNP with more than one functional SNP, thus explaining some of the apparently missing heritability of common diseases. Hide abstract

Villanueva P, Newbury DF, Jara L, De Barbieri Z, Mirza G, Palamino HM, Fernández MA, Cazier J-B, Monaco AP, Palomino H. 2011. Genome-wide analysis of genetic susceptibility to language impairment in an isolated Chilean population European Journal of Human Genetics, 19 (6), pp. 687-695.

Villanueva P, Newbury DF, Jara L, De Barbieri Z, Mirza G, Palomino HM, Fernández MA, Cazier JB, Monaco AP, Palomino H. 2011. Genome-wide analysis of genetic susceptibility to language impairment in an isolated Chilean population. Eur J Hum Genet, 19 (6), pp. 687-695. Read abstract | Read more

Specific language impairment (SLI) is an unexpected deficit in the acquisition of language skills and affects between 5 and 8% of pre-school children. Despite its prevalence and high heritability, our understanding of the aetiology of this disorder is only emerging. In this paper, we apply genome-wide techniques to investigate an isolated Chilean population who exhibit an increased frequency of SLI. Loss of heterozygosity (LOH) mapping and parametric and non-parametric linkage analyses indicate that complex genetic factors are likely to underlie susceptibility to SLI in this population. Across all analyses performed, the most consistently implicated locus was on chromosome 7q. This locus achieved highly significant linkage under all three non-parametric models (max NPL = 6.73, P = 4.0 × 10(-11)). In addition, it yielded a HLOD of 1.24 in the recessive parametric linkage analyses and contained a segment that was homozygous in two affected individuals. Further, investigation of this region identified a two-SNP haplotype that occurs at an increased frequency in language-impaired individuals (P = 0.008). We hypothesise that the linkage regions identified here, in particular that on chromosome 7, may contain variants that underlie the high prevalence of SLI observed in this isolated population and may be of relevance to other populations affected by language impairments. Hide abstract

Saade S, Cazier JB, Ghassibe-Sabbagh M, Youhanna S, Badro DA, Kamatani Y, Hager J, Yeretzian JS et al. 2011. Large scale association analysis identifies three susceptibility loci for coronary artery disease. PLoS One, 6 (12), pp. e29427. Read abstract | Read more

Genome wide association studies (GWAS) and their replications that have associated DNA variants with myocardial infarction (MI) and/or coronary artery disease (CAD) are predominantly based on populations of European or Eastern Asian descent. Replication of the most significantly associated polymorphisms in multiple populations with distinctive genetic backgrounds and lifestyles is crucial to the understanding of the pathophysiology of a multifactorial disease like CAD. We have used our Lebanese cohort to perform a replication study of nine previously identified CAD/MI susceptibility loci (LTA, CDKN2A-CDKN2B, CELSR2-PSRC1-SORT1, CXCL12, MTHFD1L, WDR12, PCSK9, SH2B3, and SLC22A3), and 88 genes in related phenotypes. The study was conducted on 2,002 patients with detailed demographic, clinical characteristics, and cardiac catheterization results. One marker, rs6922269, in MTHFD1L was significantly protective against MI (OR=0.68, p=0.0035), while the variant rs4977574 in CDKN2A-CDKN2B was significantly associated with MI (OR=1.33, p=0.0086). Associations were detected after adjustment for family history of CAD, gender, hypertension, hyperlipidemia, diabetes, and smoking. The parallel study of 88 previously published genes in related phenotypes encompassed 20,225 markers, three quarters of which with imputed genotypes The study was based on our genome-wide genotype data set, with imputation across the whole genome to HapMap II release 22 using HapMap CEU population as a reference. Analysis was conducted on both the genotyped and imputed variants in the 88 regions covering selected genes. This approach replicated HNRNPA3P1-CXCL12 association with CAD and identified new significant associations of CDKAL1, ST6GAL1, and PTPRD with CAD. Our study provides evidence for the importance of the multifactorial aspect of CAD/MI and describes genes predisposing to their etiology. Hide abstract

Cazier J-B, Tomlinson I. 2010. General lessons from large-scale studies to identify human cancer predisposition genes (Journal of Pathology (2010) 220, (255-262)) Journal of Pathology, 220 (5), pp. 618-618.

Cazier JB, Tomlinson I. 2010. General lessons from large-scale studies to identify human cancer predisposition genes. J Pathol, 220 (2), pp. 255-262. Read abstract | Read more

There are now about 100 genes known to cause Mendelian inherited cancer syndromes, but these only explain a minor part of the familial clustering of the common cancers. The increased familial relative risk of cancer in the general population must largely involve genes of low- or moderate-penetrance. Until recently, attempts to identify cancer predisposition genes with low penetrance had proved similarly unrewarding. However, in the past 2 years, developments in this area have been rapid. In particular, the 'common disease-common variant' model of predisposition has come to the fore. In this model, alleles of high frequency (typically > 10%) and low penetrance (typically < two-fold increased lifetime risk) contribute substantially to susceptibility to the common human diseases, including cancers. Many common risk alleles for cancer have been found by genome-wide association studies (GWASs) in the form of tagging SNPs, although identification of the disease-causing variants generally remains a difficult problem. The 'common disease-common variant' model has recently been criticized by proponents of a 'common disease-rare variant' model. In fact, the conflict between the models is false and a more continuous approach, bounded only by technical limitations and sample sizes, appears to be more appropriate. In this review, we summarize the general findings from cancer GWASs and their problems, and discuss the issues of finding rarer variants and other forms of cancer-predisposing variation, such as copy number polymorphisms. Hide abstract

Houlston RS, Cheadle J, Dobbins SE, Tenesa A, Jones AM, Howarth K, Spain SL, Broderick P et al. 2010. Meta-analysis of three genome-wide association studies identifies susceptibility loci for colorectal cancer at 1q41, 3q26.2, 12q13.13 and 20q13.33 NAT GENET, 42 (11), pp. 973-U89. | Read more

Spain SL, Cazier JB, CORGI Consortium,, Houlston R, Carvajal-Carmona L, Tomlinson I. 2009. Colorectal cancer risk is not associated with increased levels of homozygosity in a population from the United Kingdom. Cancer Res, 69 (18), pp. 7422-7429. Read abstract | Read more

Genome-wide association studies have identified several common single nucleotide polymorphisms (SNP) associated with an increased risk of colorectal cancer (CRC), although they have failed to identify any recessively acting alleles that contribute to disease risk. However, two recent studies have suggested that inbreeding and runs of homozygosity (ROH) increase the risk of developing cancer, perhaps by exposing recessive alleles as a result of autozygosity. To examine these results in a relatively large case-control series, we analyzed samples from a cohort in the United Kingdom comprising 921 colorectal tumor cases and 929 controls. Individuals were genotyped using a 550,000 tagging SNP panel. Additionally, we identified from these SNPs a set of approximately 30,000 SNPs in low pairwise linkage disequilibrium. To determine whether homozygosity was associated with CRC, we performed multiple tests to assess homozygosity at individual SNPs and ROHs in cases and controls. No association was found between CRC and (i) homozygosity at any individual SNP, (ii) overall homozygosity or level of inbreeding, (iii) total length or number of ROHs per individual, or (iv) a ROH at any particular genomic location. In conclusion, our results from a large case-control series do not replicate those of previous studies and suggest that homozygosity/autozygosity is not a major risk factor for CRC in an outbred population. Hide abstract

Houlston RS, Webb E, Broderick P, Pittman AM, Di Bernardo MC, Lubbe S, Chandler I, Vijayakrishnan J et al. 2008. Meta-analysis of genome-wide association data identifies four new susceptibility loci for colorectal cancer NAT GENET, 40 (12), pp. 1426-1435. | Read more

Houlston RS, Webb E, Broderick P, Pittman AM, Di Bernardo MC, Lubbe S, Chandler I, Vijayakrishnan J et al. 2008. Meta-analysis of genome-wide association data identifies four new susceptibility loci for colorectal cancer. Nat Genet, 40 (12), pp. 1426-1435. Read abstract | Read more

Genome-wide association (GWA) studies have identified multiple loci at which common variants modestly influence the risk of developing colorectal cancer (CRC). To enhance power to identify additional loci with similar effect sizes, we conducted a meta-analysis of two GWA studies, comprising 13,315 individuals genotyped for 38,710 common tagging SNPs. We undertook replication testing in up to eight independent case-control series comprising 27,418 subjects. We identified four previously unreported CRC risk loci at 14q22.2 (rs4444235, BMP4; P = 8.1 x 10(-10)), 16q22.1 (rs9929218, CDH1; P = 1.2 x 10(-8)), 19q13.1 (rs10411210, RHPN2; P = 4.6 x 10(-9)) and 20p12.3 (rs961253; P = 2.0 x 10(-10)). These findings underscore the value of large sample series for discovery and follow-up of genetic variants contributing to the etiology of CRC. Hide abstract

Tomlinson IPM, Webb E, Carvajal-Carmona L, Broderick P, Howarth K, Pittman AM, Spain S, Lubbe S et al. 2008. A genome-wide association study identifies colorectal cancer susceptibility loci on chromosomes 10p14 and 8q23.3 NAT GENET, 40 (5), pp. 623-630. | Read more

Tomlinson IP, Webb E, Carvajal-Carmona L, Broderick P, Howarth K, Pittman AM, Spain S, Lubbe S et al. 2008. A genome-wide association study identifies colorectal cancer susceptibility loci on chromosomes 10p14 and 8q23.3. Nat Genet, 40 (5), pp. 623-630. Read abstract | Read more

To identify colorectal cancer (CRC) susceptibility alleles, we conducted a genome-wide association study. In phase 1, we genotyped 550,163 tagSNPs in 940 familial colorectal tumor cases (627 CRC, 313 high-risk adenoma) and 965 controls. In phase 2, we genotyped 42,708 selected SNPs in 2,873 CRC cases and 2,871 controls. In phase 3, we evaluated 11 SNPs showing association at P < 10(-4) in a joint analysis of phases 1 and 2 in 4,287 CRC cases and 3,743 controls. Two SNPs were taken forward to phase 4 genotyping (10,731 CRC cases and 10,961 controls from eight centers). In addition to the previously reported 8q24, 15q13 and 18q21 CRC risk loci, we identified two previously unreported associations: rs10795668, located at 10p14 (P = 2.5 x 10(-13) overall; P = 6.9 x 10(-12) replication), and rs16892766, at 8q23.3 (P = 3.3 x 10(-18) overall; P = 9.6 x 10(-17) replication), which tags a plausible causative gene, EIF3H. These data provide further evidence for the 'common-disease common-variant' model of CRC predisposition. Hide abstract

Jaeger E, Webb E, Howarth K, Carvajal-Carmona L, Rowan A, Broderick P, Walther A, Spain S et al. 2008. Common genetic variants at the CRAC1 (HMPS) locus on chromosome 15q13.3 influence colorectal cancer risk. Nat Genet, 40 (1), pp. 26-28. Read abstract | Read more

We mapped a high-penetrance gene (CRAC1; also known as HMPS) associated with colorectal cancer (CRC) in the Ashkenazi population to a 0.6-Mb region on chromosome 15 containing SCG5 (also known as SGNE1), GREM1 and FMN1. We hypothesized that the CRAC1 locus harbored low-penetrance variants that increased CRC risk in the general population. In a large series of colorectal cancer cases and controls, SNPs near GREM1 and SCG5 were strongly associated with increased CRC risk (for rs4779584, P = 4.44 x 10(-14)). Hide abstract

Dixon-McIver A, East P, Mein CA, Cazier JB, Molloy G, Chaplin T, Andrew Lister T, Young BD, Debernardi S. 2008. Distinctive patterns of microRNA expression associated with karyotype in acute myeloid leukaemia. PLoS One, 3 (5), pp. e2141. Read abstract | Read more

Acute myeloid leukaemia (AML) is the most common acute leukaemia in adults; however, the genetic aetiology of the disease is not yet fully understood. A quantitative expression profile analysis of 157 mature miRNAs was performed on 100 AML patients representing the spectrum of known karyotypes common in AML. The principle observation reported here is that AMLs bearing a t(15;17) translocation had a distinctive signature throughout the whole set of genes, including the up regulation of a subset of miRNAs located in the human 14q32 imprinted domain. The set included miR-127, miR-154, miR-154*, miR-299, miR-323, miR-368, and miR-370. Furthermore, specific subsets of miRNAs were identified that provided molecular signatures characteristic of the major translocation-mediated gene fusion events in AML. Analysis of variance showed the significant deregulation of 33 miRNAs across the leukaemic set with respect to bone marrow from healthy donors. Fluorescent in situ hybridisation analysis using miRNA-specific locked nucleic acid (LNA) probes on cryopreserved patient cells confirmed the results obtained by real-time PCR. This study, conducted on about a fifth of the miRNAs currently reported in the Sanger database (microrna.sanger.ac.uk), demonstrates the potential for using miRNA expression to sub-classify cancer and suggests a role in the aetiology of leukaemia. Hide abstract

Paulsson K, Cazier JB, Macdougall F, Stevens J, Stasevich I, Vrcelj N, Chaplin T, Lillington DM, Lister TA, Young BD. 2008. Microdeletions are a general feature of adult and adolescent acute lymphoblastic leukemia: Unexpected similarities with pediatric disease. Proc Natl Acad Sci U S A, 105 (18), pp. 6708-6713. Read abstract | Read more

We present here a genome-wide map of abnormalities found in diagnostic samples from 45 adults and adolescents with acute lymphoblastic leukemia (ALL). A 500K SNP array analysis uncovered frequent genetic abnormalities, with cryptic deletions constituting half of the detected changes, implying that microdeletions are a characteristic feature of this malignancy. Importantly, the pattern of deletions resembled that recently reported in pediatric ALL, suggesting that adult, adolescent, and childhood cases may be more similar on the genetic level than previously thought. Thus, 70% of the cases displayed deletion of one or more of the CDKN2A, PAX5, IKZF1, ETV6, RB1, and EBF1 genes. Furthermore, several genes not previously implicated in the pathogenesis of ALL were identified as possible recurrent targets of deletion. In total, the SNP array analysis identified 367 genetic abnormalities not corresponding to known copy number polymorphisms, with all but two cases (96%) displaying at least one cryptic change. The resolution level of this SNP array study is the highest used to date to investigate a malignant hematologic disorder. Our findings provide insights into the leukemogenic process and may be clinically important in adult and adolescent ALL. Most importantly, we report that microdeletions of key genes appear to be a common, characteristic feature of ALL that is shared among different clinical, morphological, and cytogenetic subgroups. Hide abstract

Gupta M, Raghavan M, Gale RE, Chelala C, Allen C, Molloy G, Chaplin T, Linch DC, Cazier JB, Young BD. 2008. Novel regions of acquired uniparental disomy discovered in acute myeloid leukemia. Genes Chromosomes Cancer, 47 (9), pp. 729-739. Read abstract | Read more

The acquisition of uniparental disomy (aUPD) in acute myeloid leukemia (AML) results in homozygosity for known gene mutations. Uncovering novel regions of aUPD has the potential to identify previously unknown mutational targets. We therefore aimed to develop a map of the regions of aUPD in AML. Here, we have analyzed a large set of diagnostic AML samples (n = 454) from young adults (age: 15-55 years) using genotype arrays. Acquired UPD was found in 17% of the samples with a nonrandom distribution particularly affecting chromosome arms 13q, 11p, and 11q. Novel recurrent regions of aUPD were uncovered at 2p, 17p, 2q, 17q, 1p, and Xq. Overall, aUPDs were observed across all cytogenetic risk groups, although samples with aUPD13q (5.4% of samples) belonged exclusively to the intermediate-risk group as defined by cytogenetics. All cases with a high FLT3-ITD level, measured previously, had aUPD13q covering the FLT3 gene. Significantly, none of the samples with FLT3-ITD(-)/FLT3-TKD(+) mutation exhibited aUPD13q. Of the 119 aUPDs observed, the majority (87%) were due to mitotic recombination while only 13% were due to nondisjunction. This study demonstrates aUPD is a frequent and significant finding in AML and pinpoints regions that may contain novel mutational targets. Hide abstract

Broderick P, Carvajal-Carmona L, Pittman AM, Webb E, Howarth K, Rowan A, Lubbe S, Spain S et al. 2007. A genome-wide association study shows that common alleles of SMAD7 influence colorectal cancer risk. Nat Genet, 39 (11), pp. 1315-1317. Read abstract | Read more

To identify risk variants for colorectal cancer (CRC), we conducted a genome-wide association study, genotyping 550,163 tag SNPs in 940 individuals with familial colorectal tumor (627 CRC, 313 advanced adenomas) and 965 controls. We evaluated selected SNPs in three replication sample sets (7,473 cases, 5,984 controls) and identified three SNPs in SMAD7 (involved in TGF-beta and Wnt signaling) associated with CRC. Across the four sample sets, the association between rs4939827 and CRC was highly statistically significant (P(trend) = 1.0 x 10(-12)). Hide abstract

Tomlinson I, Webb E, Carvajal-Carmona L, Broderick P, Kemp Z, Spain S, Penegar S, Chandler I et al. 2007. A genome-wide association scan of tag SNPs identifies a susceptibility variant for colorectal cancer at 8q24.21. Nat Genet, 39 (8), pp. 984-988. Read abstract | Read more

Much of the variation in inherited risk of colorectal cancer (CRC) is probably due to combinations of common low risk variants. We conducted a genome-wide association study of 550,000 tag SNPs in 930 familial colorectal tumor cases and 960 controls. The most strongly associated SNP (P = 1.72 x 10(-7), allelic test) was rs6983267 at 8q24.21. To validate this finding, we genotyped rs6983267 in three additional CRC case-control series (4,361 affected individuals and 3,752 controls; 1,901 affected individuals and 1,079 controls; 1,072 affected individuals and 415 controls) and replicated the association, providing P = 1.27 x 10(-14) (allelic test) overall, with odds ratios (ORs) of 1.27 (95% confidence interval (c.i.): 1.16-1.39) and 1.47 (95% c.i.: 1.34-1.62) for heterozygotes and rare homozygotes, respectively. Analyses based on 1,477 individuals with colorectal adenoma and 2,136 controls suggest that susceptibility to CRC is mediated through development of adenomas (OR = 1.21, 95% c.i.: 1.10-1.34; P = 6.89 x 10(-5)). These data show that common, low-penetrance susceptibility alleles predispose to colorectal neoplasia. Hide abstract

Amundadottir LT, Sulem P, Gudmundsson J, Helgason A, Baker A, Agnarsson BA, Sigurdsson A, Benediktsdottir KR et al. 2006. A common variant associated with prostate cancer in European and African populations. Nat Genet, 38 (6), pp. 652-658. Read abstract | Read more

With the increasing incidence of prostate cancer, identifying common genetic variants that confer risk of the disease is important. Here we report such a variant on chromosome 8q24, a region initially identified through a study of Icelandic families. Allele -8 of the microsatellite DG8S737 was associated with prostate cancer in three case-control series of European ancestry from Iceland, Sweden and the US. The estimated odds ratio (OR) of the allele is 1.62 (P = 2.7 x 10(-11)). About 19% of affected men and 13% of the general population carry at least one copy, yielding a population attributable risk (PAR) of approximately 8%. The association was also replicated in an African American case-control group with a similar OR, in which 41% of affected individuals and 30% of the population are carriers. This leads to a greater estimated PAR (16%) that may contribute to higher incidence of prostate cancer in African American men than in men of European ancestry. Hide abstract

Stefansson H, Helgason A, Thorleifsson G, Steinthorsdottir V, Masson G, Barnard J, Baker A, Jonasdottir A et al. 2005. A common inversion under selection in Europeans. Nat Genet, 37 (2), pp. 129-137. Read abstract | Read more

A refined physical map of chromosome 17q21.31 uncovered a 900-kb inversion polymorphism. Chromosomes with the inverted segment in different orientations represent two distinct lineages, H1 and H2, that have diverged for as much as 3 million years and show no evidence of having recombined. The H2 lineage is rare in Africans, almost absent in East Asians but found at a frequency of 20% in Europeans, in whom the haplotype structure is indicative of a history of positive selection. Here we show that the H2 lineage is undergoing positive selection in the Icelandic population, such that carrier females have more children and have higher recombination rates than noncarriers. Hide abstract

Styrkarsdottir U, Cazier JB, Kong A, Rolfsson O, Larsen H, Bjarnadottir E, Johannsdottir VD, Sigurdardottir MS et al. 2003. Linkage of osteoporosis to chromosome 20p12 and association to BMP2. PLoS Biol, 1 (3), pp. E69. Read abstract | Read more

Osteoporotic fractures are a major cause of morbidity and mortality in ageing populations. Osteoporosis, defined as low bone mineral density (BMD) and associated fractures, have significant genetic components that are largely unknown. Linkage analysis in a large number of extended osteoporosis families in Iceland, using a phenotype that combines osteoporotic fractures and BMD measurements, showed linkage to Chromosome 20p12.3 (multipoint allele-sharing LOD, 5.10; p value, 6.3 x 10(-7)), results that are statistically significant after adjusting for the number of phenotypes tested and the genome-wide search. A follow-up association analysis using closely spaced polymorphic markers was performed. Three variants in the bone morphogenetic protein 2 (BMP2) gene, a missense polymorphism and two anonymous single nucleotide polymorphism haplotypes, were determined to be associated with osteoporosis in the Icelandic patients. The association is seen with many definitions of an osteoporotic phenotype, including osteoporotic fractures as well as low BMD, both before and after menopause. A replication study with a Danish cohort of postmenopausal women was conducted to confirm the contribution of the three identified variants. In conclusion, we find that a region on the short arm of Chromosome 20 contains a gene or genes that appear to be a major risk factor for osteoporosis and osteoporotic fractures, and our evidence supports the view that BMP2 is at least one of these genes. Hide abstract

Weren R, Venkatachalam R, Cazier J-B, Akkers R, Vreede L, Verwiel ETP, van Asseldonk M, Kamping EJ et al. 2012. High-resolution genomic profiling reveals KIAA1797/miR-491 as a novel candidate colorectal cancer susceptibility locus CELLULAR ONCOLOGY, 35 pp. S39-S40.