Publications by authors named "Sara E Dobbins"

38 Publications

Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9.

BMC Cardiovasc Disord 2019 10 29;19(1):240. Epub 2019 Oct 29.

Department Primary Care & Population Health, University College London, London, UK.

Background: We characterised the phenotypic consequence of genetic variation at the PCSK9 locus and compared findings with recent trials of pharmacological inhibitors of PCSK9.

Methods: Published and individual participant level data (300,000+ participants) were combined to construct a weighted PCSK9 gene-centric score (GS). Seventeen randomized placebo controlled PCSK9 inhibitor trials were included, providing data on 79,578 participants. Results were scaled to a one mmol/L lower LDL-C concentration.

Results: The PCSK9 GS (comprising 4 SNPs) associations with plasma lipid and apolipoprotein levels were consistent in direction with treatment effects. The GS odds ratio (OR) for myocardial infarction (MI) was 0.53 (95% CI 0.42; 0.68), compared to a PCSK9 inhibitor effect of 0.90 (95% CI 0.86; 0.93). For ischemic stroke ORs were 0.84 (95% CI 0.57; 1.22) for the GS, compared to 0.85 (95% CI 0.78; 0.93) in the drug trials. ORs with type 2 diabetes mellitus (T2DM) were 1.29 (95% CI 1.11; 1.50) for the GS, as compared to 1.00 (95% CI 0.96; 1.04) for incident T2DM in PCSK9 inhibitor trials. No genetic associations were observed for cancer, heart failure, atrial fibrillation, chronic obstructive pulmonary disease, or Alzheimer's disease - outcomes for which large-scale trial data were unavailable.

Conclusions: Genetic variation at the PCSK9 locus recapitulates the effects of therapeutic inhibition of PCSK9 on major blood lipid fractions and MI. While indicating an increased risk of T2DM, no other possible safety concerns were shown; although precision was moderate.
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http://dx.doi.org/10.1186/s12872-019-1187-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6820948PMC
October 2019

Mutational processes contributing to the development of multiple myeloma.

Blood Cancer J 2019 08 6;9(8):60. Epub 2019 Aug 6.

Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.

To gain insight into multiple myeloma (MM) tumorigenesis, we analyzed the mutational signatures in 874 whole-exome and 850 whole-genome data from the CoMMpass Study. We identified that coding and non-coding regions are differentially dominated by distinct single-nucleotide variant (SNV) mutational signatures, as well as five de novo structural rearrangement signatures. Mutational signatures reflective of different principle mutational processes-aging, defective DNA repair, and apolipoprotein B editing complex (APOBEC)/activation-induced deaminase activity-characterize MM. These mutational signatures show evidence of subgroup specificity-APOBEC-attributed signatures associated with MAF translocation t(14;16) and t(14;20) MM; potentially DNA repair deficiency with t(11;14) and t(4;14); and aging with hyperdiploidy. Mutational signatures beyond that associated with APOBEC are independent of established prognostic markers and appear to have relevance to predicting high-risk MM.
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http://dx.doi.org/10.1038/s41408-019-0221-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6684612PMC
August 2019

Identification of recurrent noncoding mutations in B-cell lymphoma using capture Hi-C.

Blood Adv 2019 01;3(1):21-32

Division of Genetics and Epidemiology and.

The identification of driver mutations is fundamental to understanding oncogenesis. Although genes frequently mutated in B-cell lymphoma have been identified, the search for driver mutations has largely focused on the coding genome. Here we report an analysis of the noncoding genome using whole-genome sequencing data from 117 patients with B-cell lymphoma. Using promoter capture Hi-C data in naive B cells, we define -regulatory elements, which represent an enriched subset of the noncoding genome in which to search for driver mutations. Regulatory regions were identified whose mutation significantly alters gene expression, including copy number variation at -regulatory elements targeting , , and , and single nucleotide variants in a -regulatory element for We also show the commonality of pathways targeted by coding and noncoding mutations, exemplified by , which regulates Notch signaling, a pathway important in lymphomagenesis and whose expression is associated with patient survival. This study provides an enhanced understanding of lymphomagenesis and describes the advantages of using chromosome conformation capture to decipher noncoding mutations relevant to cancer biology.
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http://dx.doi.org/10.1182/bloodadvances.2018026419DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6325301PMC
January 2019

Promoter capture Hi-C-based identification of recurrent noncoding mutations in colorectal cancer.

Nat Genet 2018 10 17;50(10):1375-1380. Epub 2018 Sep 17.

Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.

Efforts are being directed to systematically analyze the non-coding regions of the genome for cancer-driving mutations. cis-regulatory elements (CREs) represent a highly enriched subset of the non-coding regions of the genome in which to search for such mutations. Here we use high-throughput chromosome conformation capture techniques (Hi-C) for 19,023 promoter fragments to catalog the regulatory landscape of colorectal cancer in cell lines, mapping CREs and integrating these with whole-genome sequence and expression data from The Cancer Genome Atlas. We identify a recurrently mutated CRE interacting with the ETV1 promoter affecting gene expression. ETV1 expression influences cell viability and is associated with patient survival. We further refine our understanding of the regulatory effects of copy-number variations, showing that RASL11A is targeted by a previously identified enhancer amplification. This study reveals new insights into the complex genetic alterations driving tumor development, providing a paradigm for employing chromosome conformation capture to decipher non-coding CREs relevant to cancer biology.
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http://dx.doi.org/10.1038/s41588-018-0211-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6380472PMC
October 2018

Genome-wide association analysis identifies a meningioma risk locus at 11p15.5.

Neuro Oncol 2018 10;20(11):1485-1493

Division of Neuroepidemiology, Department of Neurological Surgery, University of California San Francisco, San Francisco, California, USA.

Background: Meningiomas are adult brain tumors originating in the meningeal coverings of the brain and spinal cord, with significant heritable basis. Genome-wide association studies (GWAS) have previously identified only a single risk locus for meningioma, at 10p12.31.

Methods: To identify a susceptibility locus for meningioma, we conducted a meta-analysis of 2 GWAS, imputed using a merged reference panel from the 1000 Genomes Project and UK10K data, with validation in 2 independent sample series totaling 2138 cases and 12081 controls.

Results: We identified a new susceptibility locus for meningioma at 11p15.5 (rs2686876, odds ratio = 1.44, P = 9.86 × 10-9). A number of genes localize to the region of linkage disequilibrium encompassing rs2686876, including RIC8A, which plays a central role in the development of neural crest-derived structures, such as the meninges.

Conclusions: This finding advances our understanding of the genetic basis of meningioma development and provides additional support for a polygenic model of meningioma.
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http://dx.doi.org/10.1093/neuonc/noy077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6176799PMC
October 2018

Whole-genome sequencing of multiple myeloma reveals oncogenic pathways are targeted somatically through multiple mechanisms.

Leukemia 2018 11 9;32(11):2459-2470. Epub 2018 Apr 9.

Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.

Multiple myeloma (MM) is a biologically heterogeneous malignancy, however, the mechanisms underlying this complexity are incompletely understood. We report an analysis of the whole-genome sequencing of 765 MM patients from CoMMpass. By employing promoter capture Hi-C in naïve B-cells, we identify cis-regulatory elements (CREs) that represent a highly enriched subset of the non-coding genome in which to search for driver mutations. We identify regulatory regions whose mutation significantly alters the expression of genes as candidate non-coding drivers, including copy number variation (CNV) at CREs of MYC and single-nucleotide variants (SNVs) in a PAX5 enhancer. To better inform the interplay between non-coding driver mutations with other driver mechanisms, and their respective roles in oncogenic pathways, we extended our analysis identifying coding drivers in 40 genes, including 11 novel candidates. We demonstrate the same pathways can be targeted by coding and non-coding mutations; exemplified by IRF4 and PRDM1, along with BCL6 and PAX5, genes that are central to plasma cell differentiation. This study reveals new insights into the complex genetic alterations driving MM development and an enhanced understanding of oncogenic pathways.
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http://dx.doi.org/10.1038/s41375-018-0103-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6224406PMC
November 2018

Genetic Predisposition to Multiple Myeloma at 5q15 Is Mediated by an ELL2 Enhancer Polymorphism.

Cell Rep 2017 Sep;20(11):2556-2564

Division of Genetics and Epidemiology, The Institute of Cancer Research, Surrey SM2 5NG, UK; Division of Molecular Pathology, The Institute of Cancer Research, Surrey SM2 5NG, UK. Electronic address:

Multiple myeloma (MM) is a malignancy of plasma cells. Genome-wide association studies have shown that variation at 5q15 influences MM risk. Here, we have sought to decipher the causal variant at 5q15 and the mechanism by which it influences tumorigenesis. We show that rs6877329 G > C resides in a predicted enhancer element that physically interacts with the transcription start site of ELL2. The rs6877329-C risk allele is associated with reduced enhancer activity and lowered ELL2 expression. Since ELL2 is critical to the B cell differentiation process, reduced ELL2 expression is consistent with inherited genetic variation contributing to arrest of plasma cell development, facilitating MM clonal expansion. These data provide evidence for a biological mechanism underlying a hereditary risk of MM at 5q15.
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http://dx.doi.org/10.1016/j.celrep.2017.08.062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5608969PMC
September 2017

Search for rare protein altering variants influencing susceptibility to multiple myeloma.

Oncotarget 2017 May;8(22):36203-36210

The Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.

The genetic basis underlying the inherited risk of developing multiple myeloma (MM) is largely unknown. To examine the impact of rare protein altering variants on the risk of developing MM we analyzed high-coverage exome sequencing data on 513 MM cases and 1,569 healthy controls, performing both single variant and gene burden tests. We did not identify any recurrent coding low-frequency alleles (1-5%) with moderate effect that were statistically associated with MM. In a gene burden analysis we did however identify a promising relationship between variation in the marrow kinetochore microtubule stromal gene KIF18A, which plays a role in control mitotic chromosome positioning dynamics, and risk of MM (P =3.6x10-6). Further analysis showed KIF18A displays a distinct pattern of expression across molecular subgroups of MM as well as being associated with patient survival. Our results inform future study design and provide a resource for contextualizing the impact of candidate MM susceptibility genes.
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http://dx.doi.org/10.18632/oncotarget.15874DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5482649PMC
May 2017

CanVar: A resource for sharing germline variation in cancer patients.

F1000Res 2016 5;5:2813. Epub 2016 Dec 5.

Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK; Division of Molecular Pathology, The Institute of Cancer Research, London, UK.

The advent of high-throughput sequencing has accelerated our ability to discover genes predisposing to disease and is transforming clinical genomic sequencing. In both contexts knowledge of the spectrum and frequency of genetic variation in the general population and in disease cohorts is vital to the interpretation of sequencing data. While population level data is becoming increasingly available from publicly accessible sources, as exemplified by The Exome Aggregation Consortium (ExAC), the availability of large-scale disease-specific frequency information is limited. These data are of particular importance to contextualise findings from clinical mutation screens and small gene discovery projects. This is especially true for cancer, which is typified by a number of hereditary predisposition syndromes.  Although mutation frequencies in tumours are available from resources such as Cosmic and The Cancer Genome Atlas, a similar facility for germline variation is lacking. Here we present the Cancer Variation Resource (CanVar) an online database which has been developed using the ExAC framework to provide open access to germline variant frequency data from the sequenced exomes of cancer patients. In its first release, CanVar catalogues the exomes of 1,006 familial early-onset colorectal cancer (CRC) patients sequenced at The Institute of Cancer Research. It is anticipated that CanVar will host data for additional cancers, providing a resource for others studying cancer predisposition and an example of how the research community can utilise the ExAC framework to share sequencing data.
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http://dx.doi.org/10.12688/f1000research.10058.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5200944PMC
December 2016

Validation of Recently Proposed Colorectal Cancer Susceptibility Gene Variants in an Analysis of Families and Patients-a Systematic Review.

Gastroenterology 2017 01 3;152(1):75-77.e4. Epub 2016 Oct 3.

Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK; Division of Pathology, The Institute of Cancer Research, London, UK. Electronic address:

High-throughput sequencing analysis has accelerated searches for genes associated with risk for colorectal cancer (CRC); germline mutations in NTHL1, RPS20, FANCM, FAN1, TP53, BUB1, BUB3, LRP6, and PTPN12 have been recently proposed to increase CRC risk. We attempted to validate the association between variants in these genes and development of CRC in a systematic review of 11 publications, using sequence data from 863 familial CRC cases and 1604 individuals without CRC (controls). All cases were diagnosed at an age of 55 years or younger and did not carry mutations in an established CRC predisposition gene. We found sufficient evidence for NTHL1 to be considered a CRC predisposition gene-members of 3 unrelated Dutch families were homozygous for inactivating p.Gln90Ter mutations; a Canadian woman with polyposis, CRC, and multiple tumors was reported to be heterozygous for the inactivating NTHL1 p.Gln90Ter/c.709+1G>A mutations; and a man with polyposis was reported to carry p.Gln90Ter/p.Gln287Ter; whereas no inactivating homozygous or compound heterozygous mutations were detected in controls. Variants that disrupted RPS20 were detected in a Finnish family with early-onset CRC (p.Val50SerfsTer23), a 39-year old individual with metachronous CRC (p.Leu61GlufsTer11 mutation), and a 41-year-old individual with CRC (missense p.Val54Leu), but not in controls. We therefore found published evidence to support the association between variants in NTHL1 and RPS20 with CRC, but not of other recently reported CRC susceptibility variants. We urge the research community to adopt rigorous statistical and biological approaches coupled with independent replication before making claims of pathogenicity.
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http://dx.doi.org/10.1053/j.gastro.2016.09.041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5860724PMC
January 2017

Undefined familial colorectal cancer and the role of pleiotropism in cancer susceptibility genes.

Fam Cancer 2016 10;15(4):593-9

Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.

Although family history is a major risk factor for colorectal cancer (CRC) a genetic diagnosis cannot be obtained in over 50 % of familial cases when screened for known CRC cancer susceptibility genes. The genetics of undefined-familial CRC is complex and recent studies have implied additional clinically actionable mutations for CRC in susceptibility genes for other cancers. To clarify the contribution of non-CRC susceptibility genes to undefined-familial CRC we conducted a mutational screen of 114 cancer susceptibility genes in 847 patients with early-onset undefined-familial CRC and 1609 controls by analysing high-coverage exome sequencing data. We implemented American College of Medical Genetics and Genomics standards and guidelines for assigning pathogenicity to variants. Globally across all 114 cancer susceptibility genes no statistically significant enrichment of likely pathogenic variants was shown (6.7 % cases 57/847, 5.3 % controls 85/1609; P = 0.15). Moreover there was no significant enrichment of mutations in genes such as TP53 or BRCA2 which have been proposed for clinical testing in CRC. In conclusion, while we identified genes that may be considered interesting candidates as determinants of CRC risk warranting further research, there is currently scant evidence to support a role for genes other than those responsible for established CRC syndromes in the clinical management of familial CRC.
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http://dx.doi.org/10.1007/s10689-016-9914-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5010824PMC
October 2016

Rare disruptive mutations and their contribution to the heritable risk of colorectal cancer.

Nat Commun 2016 06 22;7:11883. Epub 2016 Jun 22.

Division of Genetics and Epidemiology, The Institute of Cancer Research, London SM2 5NG, UK.

Colorectal cancer (CRC) displays a complex pattern of inheritance. It is postulated that much of the missing heritability of CRC is enshrined in high-impact rare alleles, which are mechanistically and clinically important. In this study, we assay the impact of rare germline mutations on CRC, analysing high-coverage exome sequencing data on 1,006 early-onset familial CRC cases and 1,609 healthy controls, with additional sequencing and array data on up to 5,552 cases and 6,792 controls. We identify highly penetrant rare mutations in 16% of familial CRC. Although the majority of these reside in known genes, we identify POT1, POLE2 and MRE11 as candidate CRC genes. We did not identify any coding low-frequency alleles (1-5%) with moderate effect. Our study clarifies the genetic architecture of CRC and probably discounts the existence of further major high-penetrance susceptibility genes, which individually account for >1% of the familial risk. Our results inform future study design and provide a resource for contextualizing the impact of new CRC genes.
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http://dx.doi.org/10.1038/ncomms11883DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4917884PMC
June 2016

TCF12 is mutated in anaplastic oligodendroglioma.

Nat Commun 2015 Jun 12;6:7207. Epub 2015 Jun 12.

Division of Genetics and Epidemiology, The Institute of Cancer Research, Sutton, Surrey SM2 5NG, UK.

Anaplastic oligodendroglioma (AO) are rare primary brain tumours that are generally incurable, with heterogeneous prognosis and few treatment targets identified. Most oligodendrogliomas have chromosomes 1p/19q co-deletion and an IDH mutation. Here we analysed 51 AO by whole-exome sequencing, identifying previously reported frequent somatic mutations in CIC and FUBP1. We also identified recurrent mutations in TCF12 and in an additional series of 83 AO. Overall, 7.5% of AO are mutated for TCF12, which encodes an oligodendrocyte-related transcription factor. Eighty percent of TCF12 mutations identified were in either the bHLH domain, which is important for TCF12 function as a transcription factor, or were frameshift mutations leading to TCF12 truncated for this domain. We show that these mutations compromise TCF12 transcriptional activity and are associated with a more aggressive tumour type. Our analysis provides further insights into the unique and shared pathways driving AO.
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http://dx.doi.org/10.1038/ncomms8207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4490400PMC
June 2015

A new GWAS and meta-analysis with 1000Genomes imputation identifies novel risk variants for colorectal cancer.

Sci Rep 2015 May 20;5:10442. Epub 2015 May 20.

Department of Preventive Medicine, University of Southern California, Los Angeles, CA, USA.

Genome-wide association studies (GWAS) of colorectal cancer (CRC) have identified 23 susceptibility loci thus far. Analyses of previously conducted GWAS indicate additional risk loci are yet to be discovered. To identify novel CRC susceptibility loci, we conducted a new GWAS and performed a meta-analysis with five published GWAS (totalling 7,577 cases and 9,979 controls of European ancestry), imputing genotypes utilising the 1000 Genomes Project. The combined analysis identified new, significant associations with CRC at 1p36.2 marked by rs72647484 (minor allele frequency [MAF] = 0.09) near CDC42 and WNT4 (P = 1.21 × 10(-8), odds ratio [OR] = 1.21 ) and at 16q24.1 marked by rs16941835 (MAF = 0.21, P = 5.06 × 10(-8); OR = 1.15) within the long non-coding RNA (lncRNA) RP11-58A18.1 and ~500 kb from the nearest coding gene FOXL1. Additionally we identified a promising association at 10p13 with rs10904849 intronic to CUBN (MAF = 0.32, P = 7.01 × 10(-8); OR = 1.14). These findings provide further insights into the genetic and biological basis of inherited genetic susceptibility to CRC. Additionally, our analysis further demonstrates that imputation can be used to exploit GWAS data to identify novel disease-causing variants.
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http://dx.doi.org/10.1038/srep10442DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4438486PMC
May 2015

Genetic diagnosis of high-penetrance susceptibility for colorectal cancer (CRC) is achievable for a high proportion of familial CRC by exome sequencing.

J Clin Oncol 2015 Feb 5;33(5):426-32. Epub 2015 Jan 5.

All authors: Institute of Cancer Research, London, United Kingdom.

Purpose: Knowledge of the contribution of high-penetrance susceptibility to familial colorectal cancer (CRC) is relevant to the counseling, treatment, and surveillance of CRC patients and families.

Patients And Methods: To quantify the impact of germline mutation to familial CRC, we sequenced the mismatch repair genes (MMR) APC, MUTYH, and SMAD4/BMPR1A in 626 early-onset familial CRC cases ascertained through a population-based United Kingdom national registry. In addition, we evaluated the contribution of mutations in the exonuclease domain (exodom) of POLE and POLD1 genes that have recently been reported to confer CRC risk.

Results: Overall mutations (pathogenic, likely pathogenic) in MMR genes make the highest contribution to familial CRC (10.9%). Mutations in the other established CRC genes account for 3.3% of cases. POLE/POLD1 exodom mutations were identified in three patients with family histories consistent with dominant transmission of CRC. Collectively, mutations in the known genes account for 14.2% of familial CRC (89 of 626 cases; 95% CI = 11.5, 17.2).

Conclusion: A genetic diagnosis is feasible in a high proportion of familial CRC. Mainstreaming such analysis in clinical practice should enable the medical management of patients and their families to be optimized. Findings suggest CRC screening of POLE and POLD1 mutation carriers should be comparable to that afforded to those at risk of HNPCC. Although the risk of CRC associated with unexplained familial CRC is in general moderate, in some families the risk is substantive and likely to be the consequence of unidentified genes, as exemplified by POLE and POLD1. Our findings have utility in the design of genetic analyses to identify such novel CRC risk genes.
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http://dx.doi.org/10.1200/JCO.2014.56.5689DOI Listing
February 2015

Identification of susceptibility loci for colorectal cancer in a genome-wide meta-analysis.

Hum Mol Genet 2014 Sep 15;23(17):4729-37. Epub 2014 Apr 15.

Molecular and Population Genetics, Division of Genetics and Epidemiology, Institute of Cancer Research, Sutton, Surrey SM2 5NG, UK

To identify common variants influencing colorectal cancer (CRC) risk, we performed a meta-analysis of five genome-wide association studies, comprising 5626 cases and 7817 controls of European descent. We conducted replication of top ranked single nucleotide polymorphisms (SNPs) in additional series totalling 14 037 cases and 15 937 controls, identifying a new CRC risk locus at 10q24.2 [rs1035209; odds ratio (OR) = 1.13, P = 4.54 × 10(-11)]. We also performed meta-analysis of our studies, with previously published data, of several recently purported CRC risk loci. We failed to find convincing evidence for a previously reported genome-wide association at rs11903757 (2q32.3). Of the three additional loci for which evidence of an association in Europeans has been previously described we failed to show an association between rs59336 (12q24.21) and CRC risk. However, for the other two SNPs, our analyses demonstrated new, formally significant associations with CRC. These are rs3217810 intronic in CCND2 (12p13.32; OR = 1.19, P = 2.16 × 10(-10)) and rs10911251 near LAMC1 (1q25.3; OR = 1.09, P = 1.75 × 10(-8)). Additionally, we found some evidence to support a relationship between, rs647161, rs2423297 and rs10774214 and CRC risk originally identified in East Asians in our European datasets. Our findings provide further insights into the genetic and biological basis of inherited genetic susceptibility to CRC.
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http://dx.doi.org/10.1093/hmg/ddu177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4133584PMC
September 2014

Common variation at 3q26.2, 6p21.33, 17p11.2 and 22q13.1 influences multiple myeloma risk.

Nat Genet 2013 Oct 18;45(10):1221-1225. Epub 2013 Aug 18.

Newcastle Cancer Centre, Northern Institute for Cancer Research, Medical School, Newcastle University, Newcastle-upon-Tyne, UK.

To identify variants for multiple myeloma risk, we conducted a genome-wide association study with validation in additional series totaling 4,692 individuals with multiple myeloma (cases) and 10,990 controls. We identified four risk loci at 3q26.2 (rs10936599, P = 8.70 × 10(-14)), 6p21.33 (rs2285803, PSORS1C2, P = 9.67 × 10(-11)), 17p11.2 (rs4273077, TNFRSF13B, P = 7.67 × 10(-9)) and 22q13.1 (rs877529, CBX7, P = 7.63 × 10(-16)). These data provide further evidence for genetic susceptibility to this B-cell hematological malignancy, as well as insight into the biological basis of predisposition.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5053356PMC
http://dx.doi.org/10.1038/ng.2733DOI Listing
October 2013

Deciphering the genetic architecture of low-penetrance susceptibility to colorectal cancer.

Hum Mol Genet 2013 Dec 30;22(24):5075-82. Epub 2013 Jul 30.

Molecular and Population Genetics, Division of Genetics and Epidemiology, Institute of Cancer Research, Sutton, Surrey SM2 5NG, UK.

Recent genome-wide association studies (GWASs) have identified common variants at 16 autosomal regions influencing the risk of developing colorectal cancer (CRC). To decipher the genetic basis of the association signals at these loci, we performed a meta-analysis of data from five GWASs, totalling 5626 cases and 7817 controls, using imputation to recover un-typed genotypes. To enhance our ability to discover low-frequency risk variants, in addition to using 1000 Genomes Project data as a reference panel, we made use of high-coverage sequencing data on 253 individuals, 199 with early-onset familial CRC. For 13 of the regions, it was possible to refine the association signal identifying a smaller region of interest likely to harbour the functional variant. Our analysis did not provide evidence that any of the associations at the 16 loci being a consequence of synthetic associations rather than linkage disequilibrium with a common risk variant.
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http://dx.doi.org/10.1093/hmg/ddt357DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3836483PMC
December 2013

The silent mutational landscape of infant MLL-AF4 pro-B acute lymphoblastic leukemia.

Genes Chromosomes Cancer 2013 Oct 26;52(10):954-60. Epub 2013 Jul 26.

Molecular and Population Genetics, Division of Genetics and Epidemiology, Institute of Cancer Research, Sutton, Surrey, SM2 5NG, UK.

Over 90% of infants (< 1-year-old) diagnosed with leukemia have pro-B acute lymphoblastic leukemia (ALL) containing the MLL-AF4 fusion. When compared with other forms of paediatric ALL affecting later B-cell differentiation, MLL-AF4 pro-B is associated with a dismal prognosis with a typical 5-year disease-free survival of <20%. MLL-AF4 may be sufficient on its own for leukemogenesis or the gene-fusion product may alternatively predispose transformed cells to global genetic instability, enhancing the acquisition of additional key mutations. To gain insight into the genomic landscape of infant MLL-AF4 pro-B ALL we performed whole genome sequencing of diagnostic leukemic blasts and matched germline samples from three MLL-AF4 pro-B ALL infants. Our analysis revealed few somatic changes (copy number abnormalities, loss of heterozygosity, or single nucleotide variants), demonstrating that only a very small number of mutations are necessary to generate infant MLL-leukemia.
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http://dx.doi.org/10.1002/gcc.22090DOI Listing
October 2013

Developmental timing of mutations revealed by whole-genome sequencing of twins with acute lymphoblastic leukemia.

Proc Natl Acad Sci U S A 2013 Apr 8;110(18):7429-33. Epub 2013 Apr 8.

Molecular and Population Genetics, Division of Genetics and Epidemiology, Institute of Cancer Research, Sutton, Surrey SM2 5NG, United Kingdom.

Acute lymphoblastic leukemia (ALL) is the major pediatric cancer. At diagnosis, the developmental timing of mutations contributing critically to clonal diversification and selection can be buried in the leukemia's covert natural history. Concordance of ALL in monozygotic, monochorionic twins is a consequence of intraplacental spread of an initiated preleukemic clone. Studying monozygotic twins with ALL provides a unique means of uncovering the timeline of mutations contributing to clonal evolution, pre- and postnatally. We sequenced the whole genomes of leukemic cells from two twin pairs with ALL to comprehensively characterize acquired somatic mutations in ALL, elucidating the developmental timing of all genetic lesions. Shared, prenatal, coding-region single-nucleotide variants were limited to the putative initiating lesions. All other nonsynonymous single-nucleotide variants were distinct between tumors and, therefore, secondary and postnatal. These changes occurred in a background of noncoding mutational changes that were almost entirely discordant in twin pairs and likely passenger mutations acquired during leukemic cell proliferation.
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http://dx.doi.org/10.1073/pnas.1221099110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3645544PMC
April 2013

The CCND1 c.870G>A polymorphism is a risk factor for t(11;14)(q13;q32) multiple myeloma.

Nat Genet 2013 May 17;45(5):522-525. Epub 2013 Mar 17.

German Cancer Research Center, Heidelberg, Germany.

A number of specific chromosomal abnormalities define the subgroups of multiple myeloma. In a meta-analysis of two genome-wide association studies of multiple myeloma including a total of 1,661 affected individuals, we investigated risk for developing a specific tumor karyotype. The t(11;14)(q13;q32) translocation in which CCND1 is placed under the control of the immunoglobulin heavy chain enhancer was strongly associated with the CCND1 c.870G>A polymorphism (P = 7.96 × 10(-11)). These results provide a model in which a constitutive genetic factor is associated with risk of a specific chromosomal translocation.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5056630PMC
http://dx.doi.org/10.1038/ng.2583DOI Listing
May 2013

Common variation near CDKN1A, POLD3 and SHROOM2 influences colorectal cancer risk.

Nat Genet 2012 May 27;44(7):770-6. Epub 2012 May 27.

Colon Cancer Genetics Group, Institute of Genetics and Molecular Medicine, University of Edinburgh and Medical Research Council (MRC) Human Genetics Unit, Edinburgh, UK.

We performed a meta-analysis of five genome-wide association studies to identify common variants influencing colorectal cancer (CRC) risk comprising 8,682 cases and 9,649 controls. Replication analysis was performed in case-control sets totaling 21,096 cases and 19,555 controls. We identified three new CRC risk loci at 6p21 (rs1321311, near CDKN1A; P = 1.14 × 10(-10)), 11q13.4 (rs3824999, intronic to POLD3; P = 3.65 × 10(-10)) and Xp22.2 (rs5934683, near SHROOM2; P = 7.30 × 10(-10)) This brings the number of independent loci associated with CRC risk to 20 and provides further insight into the genetic architecture of inherited susceptibility to CRC.
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http://dx.doi.org/10.1038/ng.2293DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4747430PMC
May 2012

Common variation at 3p22.1 and 7p15.3 influences multiple myeloma risk.

Nat Genet 2011 Nov 27;44(1):58-61. Epub 2011 Nov 27.

Molecular and Population Genetics, Division of Genetics and Epidemiology, Institute of Cancer Research, Surrey, UK.

To identify risk variants for multiple myeloma, we conducted a genome-wide association study of 1,675 individuals with multiple myeloma and 5,903 control subjects. We identified risk loci for multiple myeloma at 3p22.1 (rs1052501 in ULK4; odds ratio (OR) = 1.32; P = 7.47 × 10(-9)) and 7p15.3 (rs4487645, OR = 1.38; P = 3.33 × 10(-15)). In addition, we observed a promising association at 2p23.3 (rs6746082, OR = 1.29; P = 1.22 × 10(-7)). Our study identifies new genomic regions associated with multiple myeloma risk that may lead to new etiological insights.
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http://dx.doi.org/10.1038/ng.993DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5108406PMC
November 2011

Common variation at 10p12.31 near MLLT10 influences meningioma risk.

Nat Genet 2011 Jul 31;43(9):825-7. Epub 2011 Jul 31.

Section of Cancer Genetics, Institute of Cancer Research, Sutton, UK.

To identify susceptibility loci for meningioma, we conducted a genome-wide association study of 859 affected individuals (cases) and 704 controls with validation in two independent sample sets totaling 774 cases and 1,764 controls. We identified a new susceptibility locus for meningioma at 10p12.31 (MLLT10, rs11012732, odds ratio = 1.46, P(combined) = 1.88 × 10(-14)). This finding advances our understanding of the genetic basis of meningioma development.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5053355PMC
http://dx.doi.org/10.1038/ng.879DOI Listing
July 2011

Multiple common susceptibility variants near BMP pathway loci GREM1, BMP4, and BMP2 explain part of the missing heritability of colorectal cancer.

PLoS Genet 2011 Jun 2;7(6):e1002105. Epub 2011 Jun 2.

Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.

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.
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http://dx.doi.org/10.1371/journal.pgen.1002105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3107194PMC
June 2011

Chromosome 7p11.2 (EGFR) variation influences glioma risk.

Hum Mol Genet 2011 Jul 29;20(14):2897-904. Epub 2011 Apr 29.

Université Pierre et Marie Curie-Paris 6, Centre de Recherche de l’Institut du Cerveau et de la Moëlle épinière/UMR-S975, GH Pitié-Salpêtrière, 47 boulevard de l'Hôpital, Paris, France.

While gliomas are the most common primary brain tumors, their etiology is largely unknown. To identify novel risk loci for glioma, we conducted genome-wide association (GWA) analysis of two case-control series from France and Germany (2269 cases and 2500 controls). Pooling these data with previously reported UK and US GWA studies provided data on 4147 glioma cases and 7435 controls genotyped for 424 460 common tagging single-nucleotide polymorphisms. Using these data, we demonstrate two statistically independent associations between glioma and rs11979158 and rs2252586, at 7p11.2 which encompasses the EGFR gene (population-corrected statistics, P(c) = 7.72 × 10(-8) and 2.09 × 10(-8), respectively). Both associations were independent of tumor subtype, and were independent of EGFR amplification, p16INK4a deletion and IDH1 mutation status in tumors; compatible with driver effects of the variants on glioma development. These findings show that variation in 7p11.2 is a determinant of inherited glioma risk.
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http://dx.doi.org/10.1093/hmg/ddr192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3118762PMC
July 2011

Genome-wide association studies for detecting cancer susceptibility.

Br Med Bull 2011 18;97:27-46. Epub 2011 Jan 18.

Section of Cancer Genetics, Institute of Cancer Research, Surrey, UK.

Genome-wide association (GWA) studies search for genetic variants, across the entire genome, which display differences in frequencies between cases and controls. Studies in PubMed using the keywords 'genomewide association' and 'cancer' are reported together with selected literature. Since 2007, GWA studies have successfully yielded risk loci for most common cancers. Findings have provided insights into the biological basis of cancer susceptibility implicating previously unsuspected genes in tumourogenesis. The variants identified typically account for only a small proportion of the familial risk of cancer and thus their application for individual risk prediction is poor. Furthermore, the genotyped variants are unlikely to be directly causal and identifying the causal basis is a major challenge. Methodological developments are desirable to fully utilize existing data sets and to enable more complex models of inherited predisposition to be investigated. Annotation of low frequency variation coupled with next-generation sequencing is making the search for rare disease-causing variants a realistic prospect.
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http://dx.doi.org/10.1093/bmb/ldq038DOI Listing
May 2011

MHC variation and risk of childhood B-cell precursor acute lymphoblastic leukemia.

Blood 2011 Feb 8;117(5):1633-40. Epub 2010 Nov 8.

Section of Cancer Genetics, Institute of Cancer Research, Sutton, Surrey, United Kingdom.

A role for specific human leukocyte antigen (HLA) variants in the etiology of childhood acute lymphoblastic leukemia (ALL) has been extensively studied over the last 30 years, but no unambiguous association has been identified. To comprehensively study the relationship between genetic variation within the 4.5 Mb major histocompatibility complex genomic region and precursor B-cell (BCP) ALL risk, we analyzed 1075 observed and 8176 imputed single nucleotide polymorphisms and their related haplotypes in 824 BCP-ALL cases and 4737 controls. Using these genotypes we also imputed both common and rare alleles at class I (HLA-A, HLA-B, and HLA-C) and class II (HLA-DRB1, HLA-DQA1, and HLA-DQB1) HLA loci. Overall, we found no statistically significant association between variants and BCP-ALL risk. We conclude that major histocompatibility complex-defined variation in immune-mediated response is unlikely to be a major risk factor for BCP-ALL.
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http://dx.doi.org/10.1182/blood-2010-08-301598DOI Listing
February 2011