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1.  Diagnosis of pertussis using nasopharyngeal IgA and polymerase chain reaction in specimens from outpatients in Australia 
We assessed IgA antibodies and polymerase chain reaction (PCR) for diagnosis of pertussis in nasopharyngeal aspiration (NPA) samples from outpatients in Australia.
  A total of 1700 patients (849 adults, 851 children) from Western Australia and the Northern Territory fulfilled the laboratory case definition for pertussis between 2004 and 2013: 732 specimens were positive by NPA IgA alone, 559 by PCR alone, and 409 by both tests. Overall, 968 cases (56.8%) were positive by PCR and 1141 cases (67.2%) by IgA [p < 0.00025]. Among pediatric patients, PCR was positive in 524 (61.3%) and IgA in 569 (67%). In 849 adult cases, the respective proportions were 52.3% and 67.4% [p < 0.00025].
  The duration of cough in 507 patients was shorter in 262 pediatric cases (mean, 2.51 weeks; standard deviation [SD], 2.25) than 245 adult patients (3.27 weeks; SD, 2.79) [p = 0.0009]. PCR positivity showed a season-dependent variance (range, 5.6 to 85.9%) and peaked in the second week (71.7%) of illness. IgA antibodies peaked in the fifth week (89.5%) postinfection, and the positivity rate for NPA IgA was less variable (range, 38.3–97.2%).
  Nasopharyngeal Bordetella pertussis-specific IgA antibodies are valuable in diagnosis of pertussis in Australia. Reliance on PCR alone misses a significant proportion of pertussis cases, especially those with a delayed presentation.
PMCID: PMC4271813  PMID: 25544889
IgA; nasopharyngeal aspirate; PCR; pertussis; serology
2.  Genome sequencing of normal cells reveals developmental lineages and mutational processes 
Nature  2014;513(7518):422-425.
The somatic mutations present in the genome of a cell have been accumulated over the lifetime of a multicellular organism. These mutations can provide insights into the developmental lineage tree1, the number of divisions each cell has undergone and the mutational processes that have been operative2. Here, we conducted whole genome sequencing of clonal lines3 derived from multiple tissues of healthy mice. Using somatic base substitutions, we reconstructed the early cell divisions of each animal demonstrating the contributions of embryonic cells to adult tissues. Differences were observed between tissues in the numbers and types of mutations accumulated by each cell, which likely reflect differences in the number of cell divisions they have undergone and varying contributions of different mutational processes. If somatic mutation rates are similar to those in mice, the results indicate that precise insights into development and mutagenesis of normal human cells will be possible.
PMCID: PMC4227286  PMID: 25043003
3.  Association of a germline copy number polymorphism of APOBEC3A and APOBEC3B with burden of putative APOBEC-dependent mutations in breast cancer 
Nature genetics  2014;46(5):487-491.
The somatic mutations in a cancer genome are the aggregate outcome of one or more mutational processes operative through the life of the cancer patient1-3. Each mutational process leaves a characteristic mutational signature determined by the mechanisms of DNA damage and repair that constitute it. A role was recently proposed for the APOBEC family of cytidine deaminases in generating particular genome-wide mutational signatures1,4 and a signature of localized hypermutation called kataegis1,4. A germline copy number polymorphism involving APOBEC3A and APOBEC3B, which effectively deletes APOBEC3B5, has been associated with a modest increased risk of breast cancer6-8. Here, we show that breast cancers in carriers of the deletion show more mutations of the putative APOBEC-dependent genome-wide signatures than cancers in non-carriers. The results suggest that the APOBEC3A/3B germline deletion allele confers cancer susceptibility through increased activity of APOBEC-dependent mutational processes, although the mechanism by which this occurs remains unknown.
PMCID: PMC4137149  PMID: 24728294
4.  OncoCis: annotation of cis-regulatory mutations in cancer 
Genome Biology  2014;15(10):485.
Whole genome sequencing has enabled the identification of thousands of somatic mutations within non-coding genomic regions of individual cancer samples. However, identification of mutations that potentially alter gene regulation remains a major challenge. Here we present OncoCis, a new method that enables identification of potential cis-regulatory mutations using cell type-specific genome and epigenome-wide datasets along with matching gene expression data. We demonstrate that the use of cell type-specific information and gene expression can significantly reduce the number of candidate cis-regulatory mutations compared with existing tools designed for the annotation of cis-regulatory SNPs. The OncoCis webserver is freely accessible at
Electronic supplementary material
The online version of this article (doi:10.1186/s13059-014-0485-0) contains supplementary material, which is available to authorized users.
PMCID: PMC4224696  PMID: 25298093
5.  Constitutional and somatic rearrangement of chromosome 21 in acute lymphoblastic leukaemia 
Nature  2014;508(7494):98-102.
Changes in gene dosage are a major driver of cancer, engineered from a finite, but increasingly well annotated, repertoire of mutational mechanisms1. This can potentially generate correlated copy number alterations across hundreds of linked genes, as exemplified by the 2% of childhood acute lymphoblastic leukemia (ALL) with recurrent amplification of megabase regions of chromosome 21 (iAMP21)2,3. We used genomic, cytogenetic and transcriptional analysis, coupled with novel bioinformatic approaches, to reconstruct the evolution of iAMP21 ALL. We find that individuals born with the rare constitutional Robertsonian translocation between chromosomes 15 and 21, rob(15;21)(q10;q10)c, have ~2700-fold increased risk of developing iAMP21 ALL compared to the general population. In such cases, amplification is initiated by a chromothripsis event involving both sister chromatids of the Robertsonian chromosome, a novel mechanism for cancer predisposition. In sporadic iAMP21, breakage-fusion-bridge cycles are typically the initiating event, often followed by chromothripsis. In both sporadic and rob(15;21)c-associated iAMP21, the final stages frequently involve duplications of the entire abnormal chromosome. The end-product is a derivative of chromosome 21 or the rob(15;21)c chromosome with gene dosage optimised for leukemic potential, showing constrained copy number levels over multiple linked genes. Thus, dicentric chromosomes may be an important precipitant of chromothripsis, as we show rob(15;21)c to be constitutionally dicentric and breakage-fusion-bridge cycles generate dicentric chromosomes somatically. Furthermore, our data illustrate that several cancer-specific mutational processes, applied sequentially, can co-ordinate to fashion copy number profiles over large genomic scales, incrementally refining the fitness benefits of aggregated gene dosage changes.
PMCID: PMC3976272  PMID: 24670643
6.  Recurrent PTPRB and PLCG1 mutations in angiosarcoma 
Nature genetics  2014;46(4):376-379.
Angiosarcoma is an aggressive malignancy that arises spontaneously or secondarily to ionising radiation or chronic lymphoedema1. Previous work has identified aberrant angiogenesis, including occasional somatic mutations in angiogenesis signalling genes, as a key driver of angiosarcoma1. Here, we employed whole genome, exome, and targeted sequencing to study the somatic changes underpinning primary and secondary angiosarcoma. We identified recurrent mutations in two genes, PTPRB and PLCG1, which are intimately linked to angiogenesis. The endothelial phosphatase PTPRB, a negative regulator of vascular growth factor tyrosine kinases, harboured predominantly truncating mutations in 10/39 (26%) tumours. PLCG1, a signal transducer of tyrosine kinases, presented with a recurrent, likely activating R707Q missense variant in 3/34 cases (9%). Overall, 15/39 (38%) tumours harboured at least one driver mutation in angiogenesis signalling genes. Our findings inform and reinforce current therapeutic efforts to target angiogenesis signalling in angiosarcoma.
PMCID: PMC4032873  PMID: 24633157
7.  Ability of bone graft substitutes to support the osteoprogenitor cells: An in-vitro study 
World Journal of Stem Cells  2014;6(4):497-504.
AIM: To compare seven commercially available bone graft substitutes (BGS) in terms of these properties and without using any additional biological growth factors.
METHODS: Porcine osteoprogenitor cells were loaded on seven commercially available BGS and allowed to proliferate for one week followed by osteogenic induction. Staining for live/dead cells as well as scanning electron microscopy (SEM) was carried out to determine viability and cellular binding. Further outcome measures included alkaline phosphatase (ALP) assays with normalisation for DNA content to quantify osteogenic potential. Negative and positive control experiments were carried out in parallel to validate the results.
RESULTS: Live/dead and SEM imaging showed higher viability and attachment with β-tricalcium phosphate (β-TCP) than with other BGS (P < 0.05). The average ALP activity in nmol/mL (normalised value for DNA content in nmol/μg DNA) per sample was 657.58 (132.03) for β-TCP, 36.22 (unable to normalise) for calcium sulphate, 19.93 (11.39) for the Hydroxyapatite/Tricalcium Phosphate composite, 14.79 (18.53) for polygraft, 13.98 (8.15) for the highly porous β-Tricalcium Phosphate, 5.56 (10.0) for polymers, and 3.82 (3.8) for Hydroxyapatite.
CONCLUSION: Under the above experimental conditions, β-TCP was able to maintain better the viability of osteoprogenitor cells and allow proliferation and differentiation (P < 0.05).
PMCID: PMC4172679  PMID: 25258672
Bone graft; Bone graft substitute; Osteoprogenitor cells; Fracture healing; Bone
8.  Association Between Red and Processed Meat Intake and Mortality Among Colorectal Cancer Survivors 
Journal of Clinical Oncology  2013;31(22):2773-2782.
Red and processed meat intake is convincingly associated with colorectal cancer (CRC) incidence, but its impact on prognosis after CRC diagnosis is unknown. We examined associations of red and processed meat consumption, self-reported before and after cancer diagnosis, with all-cause and cause-specific mortality among men and women with invasive, nonmetastatic CRC.
Patients and Methods
Participants in the Cancer Prevention Study II Nutrition Cohort reported information on diet and other factors at baseline in 1992-1993, 1999, and 2003. Participants with a verified CRC diagnosis after baseline and up to June 30, 2009, were observed for mortality through December 31, 2010.
Among 2,315 participants diagnosed with CRC, 966 died during follow-up (413 from CRC and 176 from cardiovascular disease [CVD]). In multivariable-adjusted Cox proportional hazards regression models, red and processed meat intake before CRC diagnosis was associated with higher risks of death as a result of all causes (top v bottom quartile, relative risk [RR], 1.29; 95% CI, 1.05 to 1.59; Ptrend = .03) and from CVD (RR, 1.63; 95% CI, 1.00 to 2.67; Ptrend = .08) but not CRC (RR, 1.09; 95% CI, 0.79 to 1.51; Ptrend = 0.54). Although red and processed meat consumption after CRC diagnosis was not associated with mortality, survivors with consistently high (median or higher) intakes before and after diagnosis had a higher risk of CRC-specific mortality (RR, 1.79; 95% CI, 1.11 to 2.89) compared with those with consistently low intakes.
This study suggests that greater red and processed meat intake before diagnosis is associated with higher risk of death among patients with nonmetastatic CRC.
PMCID: PMC3718877  PMID: 23816965
9.  Fibroblastic growth factor receptor 1 amplification in osteosarcoma is associated with poor response to neo-adjuvant chemotherapy 
Cancer Medicine  2014;3(4):980-987.
Osteosarcoma, the most common primary bone sarcoma, is a genetically complex disease with no widely accepted biomarker to allow stratification of patients for treatment. After a recent report of one osteosarcoma cell line and one tumor exhibiting fibroblastic growth factor receptor 1 (FGFR1) gene amplification, the aim of this work was to assess the frequency of FGFR1 amplification in a larger cohort of osteosarcoma and to determine if this biomarker could be used for stratification of patients for treatment. About 352 osteosarcoma samples from 288 patients were analyzed for FGFR1 amplification by interphase fluorescence in situ hybridization. FGFR1 amplification was detected in 18.5% of patients whose tumors revealed a poor response to chemotherapy, and no patients whose tumors responded well to therapy harbored this genetic alteration. FGFR1 amplification is present disproportionately in the rarer histological variants of osteosarcoma. This study provides a rationale for inclusion of patients with osteosarcoma in clinical trials using FGFR kinase inhibitors.
PMCID: PMC4303166  PMID: 24861215
Amplification; FGFR; FGFR1; FISH; genetics; osteosarcoma; polysomy
Science (New York, N.Y.)  2014;343(6169):437-440.
Canine transmissible venereal tumor (CTVT) is the oldest known somatic cell lineage. It is a transmissible cancer that propagates naturally in dogs. We sequenced the genomes of two CTVT tumors and found that CTVT has acquired 1.9 million somatic substitution mutations and bears evidence of exposure to ultraviolet light. CTVT is remarkably stable and lacks subclonal heterogeneity despite thousands of rearrangements, copy number changes and retrotransposon insertions. More than 10,000 genes carry non-synonymous variants and 646 genes have been lost. CTVT first arose in a dog with low genomic heterozygosity that may have lived approximately 11,000 years ago. The cancer spawned by this individual dispersed across continents approximately 500 years ago. Our results provide a genetic identikit of an ancient dog and demonstrate the robustness of mammalian somatic cells to survive for millennia despite a massive mutation burden.
PMCID: PMC3918581  PMID: 24458646
11.  Inactivating CUX1 mutations promote tumorigenesis 
Nature genetics  2013;46(1):10.1038/ng.2846.
A major challenge for cancer genetics is to determine which low frequency somatic mutations are drivers of tumorigenesis. Here we interrogate the genomes of 7,651 diverse human cancers to identify novel drivers and find inactivating mutations in the homeodomain transcription factor CUX1 (cut-like homeobox 1) in ~1-5% of tumors. Meta-analysis of CUX1 mutational status in 2,519 cases of myeloid malignancies reveals disruptive mutations associated with poor survival, highlighting the clinical significance of CUX1 loss. In parallel, we validate CUX1 as a bona fide tumor suppressor using mouse transposon-mediated insertional mutagenesis and Drosophila cancer models. We demonstrate that CUX1 deficiency activates phosphoinositide 3-kinase (PI3K) signaling through direct transcriptional downregulation of the PI3K inhibitor PIK3IP1 (phosphoinositide-3-kinase interacting protein 1), leading to increased tumor growth, while exposing susceptibility to PI3K-AKT inhibition. Thus, our complementary approaches identify CUX1 as a new pan-driver of tumorigenesis and uncover a potential strategy for treating CUX1-mutant tumors.
PMCID: PMC3874239  PMID: 24316979
12.  Long-term functional results and isokinetic strength evaluation after arthroscopic tenotomy of the long head of biceps tendon 
The objective of this study is to evaluate the biomechanical function of the upper arm after arthroscopic long head of biceps (LHB) tenotomy at long-term follow-up.
Materials and Methods:
Twenty-five male subjects ranging from 30 to 63 years old were evaluated at a mean follow-up of 7.0 years after tenotomy. Bilateral isokinetic testing was performed to obtain peak torque values, as well as total work done throughout the full range of elbow flexion and supination.
Magnetic resonance imaging scans revealed nine unrecognized LHB ruptures in the contralateral arm, leaving 16 subjects to complete the testing protocol. The mean quickDASH score was 8.1 (standard error [SE] 2.5). The mean oxford elbow score was 97.9 (SE 1.6). The tenotomy arm recorded a decrease in peak flexion torque of 7.0% (confidence interval [CI] 1.2-12.8), and a decrease in the peak supination torque of 9.1% (CI 1.8-16.4) relative to the contralateral arm. The total work carried out through the full range of joint motion was reduced in elbow flexion by 5.1% (CI −1.3-11.4) and in forearm supination by 5.7% (CI-2.4-13.9).
Maximum strength in elbow flexion and forearm supination is significantly reduced compared with the contralateral arm. However, this impairment is partially compensated for by relatively greater strength sustained through the latter stages of joint motion. This results in comparable total work measurements between the tenotomised and contralateral side, potentially accounting for ongoing high levels of patient satisfaction and clinical function in the long term after LHB tenotomy.
Level of Evidence IV:
Case series without comparison group.
PMCID: PMC4168656  PMID: 25258498
Biceps tenotomy; isokinetic strength; long-term
13.  Genome-Wide Diet-Gene Interaction Analyses for Risk of Colorectal Cancer 
PLoS Genetics  2014;10(4):e1004228.
Dietary factors, including meat, fruits, vegetables and fiber, are associated with colorectal cancer; however, there is limited information as to whether these dietary factors interact with genetic variants to modify risk of colorectal cancer. We tested interactions between these dietary factors and approximately 2.7 million genetic variants for colorectal cancer risk among 9,287 cases and 9,117 controls from ten studies. We used logistic regression to investigate multiplicative gene-diet interactions, as well as our recently developed Cocktail method that involves a screening step based on marginal associations and gene-diet correlations and a testing step for multiplicative interactions, while correcting for multiple testing using weighted hypothesis testing. Per quartile increment in the intake of red and processed meat were associated with statistically significant increased risks of colorectal cancer and vegetable, fruit and fiber intake with lower risks. From the case-control analysis, we detected a significant interaction between rs4143094 (10p14/near GATA3) and processed meat consumption (OR = 1.17; p = 8.7E-09), which was consistently observed across studies (p heterogeneity = 0.78). The risk of colorectal cancer associated with processed meat was increased among individuals with the rs4143094-TG and -TT genotypes (OR = 1.20 and OR = 1.39, respectively) and null among those with the GG genotype (OR = 1.03). Our results identify a novel gene-diet interaction with processed meat for colorectal cancer, highlighting that diet may modify the effect of genetic variants on disease risk, which may have important implications for prevention.
Author Summary
High intake of red and processed meat and low intake of fruits, vegetables and fiber are associated with a higher risk of colorectal cancer. We investigate if the effect of these dietary factors on colorectal cancer risk is modified by common genetic variants across the genome (total of about 2.7 million genetic variants), also known as gene-diet interactions. We included over 9,000 colorectal cancer cases and 9,000 controls that were not diagnosed with colorectal cancer. Our results provide strong evidence for a gene-diet interaction and colorectal cancer risk between a genetic variant (rs4143094) on chromosome 10p14 near the gene GATA3 and processed meat consumption (p = 8.7E-09). This genetic locus may have interesting biological significance given its location in the genome. Our results suggest that genetic variants may interact with diet and in combination affect colorectal cancer risk, which may have important implications for personalized cancer care and provide novel insights into prevention strategies.
PMCID: PMC3990510  PMID: 24743840
14.  Identification of Genetic Susceptibility Loci for Colorectal Tumors in a Genome-wide Meta-analysis 
Peters, Ulrike | Jiao, Shuo | Schumacher, Fredrick R. | Hutter, Carolyn M. | Aragaki, Aaron K. | Baron, John A. | Berndt, Sonja I. | Bézieau, Stéphane | Brenner, Hermann | Butterbach, Katja | Caan, Bette J. | Campbell, Peter T. | Carlson, Christopher S. | Casey, Graham | Chan, Andrew T. | Chang-Claude, Jenny | Chanock, Stephen J. | Chen, Lin S. | Coetzee, Gerhard A. | Coetzee, Simon G. | Conti, David V. | Curtis, Keith R. | Duggan, David | Edwards, Todd | Fuchs, Charles S. | Gallinger, Steven | Giovannucci, Edward L. | Gogarten, Stephanie M. | Gruber, Stephen B. | Haile, Robert W. | Harrison, Tabitha A. | Hayes, Richard B. | Henderson, Brian E. | Hoffmeister, Michael | Hopper, John L. | Hudson, Thomas J. | Hunter, David J. | Jackson, Rebecca D. | Jee, Sun Ha | Jenkins, Mark A. | Jia, Wei-Hua | Kolonel, Laurence N. | Kooperberg, Charles | Küry, Sébastien | Lacroix, Andrea Z. | Laurie, Cathy C. | Laurie, Cecelia A. | Le Marchand, Loic | Lemire, Mathieu | Levine, David | Lindor, Noralane M. | Liu, Yan | Ma, Jing | Makar, Karen W. | Matsuo, Keitaro | Newcomb, Polly A. | Potter, John D. | Prentice, Ross L. | Qu, Conghui | Rohan, Thomas | Rosse, Stephanie A. | Schoen, Robert E. | Seminara, Daniela | Shrubsole, Martha | Shu, Xiao-Ou | Slattery, Martha L. | Taverna, Darin | Thibodeau, Stephen N. | Ulrich, Cornelia M. | White, Emily | Xiang, Yongbing | Zanke, Brent W. | Zeng, Yi-Xin | Zhang, Ben | Zheng, Wei | Hsu, Li
Gastroenterology  2012;144(4):799-807.e24.
Heritable factors contribute to the development of colorectal cancer. Identifying the genetic loci associated with colorectal tumor formation could elucidate the mechanisms of pathogenesis.
We conducted a genome-wide association study that included 14 studies, 12,696 cases of colorectal tumors (11,870 cancer, 826 adenoma), and 15,113 controls of European descent. The 10 most statistically significant, previously unreported findings were followed up in 6 studies; these included 3056 colorectal tumor cases (2098 cancer, 958 adenoma) and 6658 controls of European and Asian descent.
Based on the combined analysis, we identified a locus that reached the conventional genome-wide significance level at less than 5.0 × 10−8: an intergenic region on chromosome 2q32.3, close to nucleic acid binding protein 1 (most significant single nucleotide polymorphism: rs11903757; odds ratio [OR], 1.15 per risk allele; P = 3.7 × 10−8). We also found evidence for 3 additional loci with P values less than 5.0 × 10−7: a locus within the laminin gamma 1 gene on chromosome 1q25.3 (rs10911251; OR, 1.10 per risk allele; P = 9.5 × 10−8), a locus within the cyclin D2 gene on chromosome 12p13.32 (rs3217810 per risk allele; OR, 0.84; P = 5.9 × 10−8), and a locus in the T-box 3 gene on chromosome 12q24.21 (rs59336; OR, 0.91 per risk allele; P = 3.7 × 10−7).
In a large genome-wide association study, we associated polymorphisms close to nucleic acid binding protein 1 (which encodes a DNA-binding protein involved in DNA repair) with colorectal tumor risk. We also provided evidence for an association between colorectal tumor risk and polymorphisms in laminin gamma 1 (this is the second gene in the laminin family to be associated with colorectal cancers), cyclin D2 (which encodes for cyclin D2), and T-box 3 (which encodes a T-box transcription factor and is a target of Wnt signaling to β-catenin). The roles of these genes and their products in cancer pathogenesis warrant further investigation.
PMCID: PMC3636812  PMID: 23266556
Colon Cancer; Genetics; Risk Factors; SNP
15.  RAG-mediated recombination is the predominant driver of oncogenic rearrangement in ETV6-RUNX1 acute lymphoblastic leukemia 
Nature genetics  2014;46(2):116-125.
The ETV6-RUNX1 fusion gene, found in 25% of childhood acute lymphoblastic leukemia (ALL), is acquired in utero but requires additional somatic mutations for overt leukemia. We used exome and low-coverage whole-genome sequencing to characterize secondary events associated with leukemic transformation. RAG-mediated deletions emerge as the dominant mutational process, characterized by recombination signal sequence motifs near the breakpoints; incorporation of non-templated sequence at the junction; ~30-fold enrichment at promoters and enhancers of genes actively transcribed in B-cell development and an unexpectedly high ratio of recurrent to non-recurrent structural variants. Single cell tracking shows that this mechanism is active throughout leukemic evolution with evidence of localized clustering and re-iterated deletions. Integration of point mutation and rearrangement data identifies ATF7IP and MGA as two new tumor suppressor genes in ALL. Thus, a remarkably parsimonious mutational process transforms ETV6-RUNX1 lymphoblasts, targeting the promoters, enhancers and first exons of genes that normally regulate B-cell differentiation.
PMCID: PMC3960636  PMID: 24413735
16.  Signatures of mutational processes in human cancer 
Alexandrov, Ludmil B. | Nik-Zainal, Serena | Wedge, David C. | Aparicio, Samuel A.J.R. | Behjati, Sam | Biankin, Andrew V. | Bignell, Graham R. | Bolli, Niccolo | Borg, Ake | Børresen-Dale, Anne-Lise | Boyault, Sandrine | Burkhardt, Birgit | Butler, Adam P. | Caldas, Carlos | Davies, Helen R. | Desmedt, Christine | Eils, Roland | Eyfjörd, Jórunn Erla | Foekens, John A. | Greaves, Mel | Hosoda, Fumie | Hutter, Barbara | Ilicic, Tomislav | Imbeaud, Sandrine | Imielinsk, Marcin | Jäger, Natalie | Jones, David T.W. | Jones, David | Knappskog, Stian | Kool, Marcel | Lakhani, Sunil R. | López-Otín, Carlos | Martin, Sancha | Munshi, Nikhil C. | Nakamura, Hiromi | Northcott, Paul A. | Pajic, Marina | Papaemmanuil, Elli | Paradiso, Angelo | Pearson, John V. | Puente, Xose S. | Raine, Keiran | Ramakrishna, Manasa | Richardson, Andrea L. | Richter, Julia | Rosenstiel, Philip | Schlesner, Matthias | Schumacher, Ton N. | Span, Paul N. | Teague, Jon W. | Totoki, Yasushi | Tutt, Andrew N.J. | Valdés-Mas, Rafael | van Buuren, Marit M. | van ’t Veer, Laura | Vincent-Salomon, Anne | Waddell, Nicola | Yates, Lucy R. | Zucman-Rossi, Jessica | Futreal, P. Andrew | McDermott, Ultan | Lichter, Peter | Meyerson, Matthew | Grimmond, Sean M. | Siebert, Reiner | Campo, Elías | Shibata, Tatsuhiro | Pfister, Stefan M. | Campbell, Peter J. | Stratton, Michael R.
Nature  2013;500(7463):415-421.
All cancers are caused by somatic mutations. However, understanding of the biological processes generating these mutations is limited. The catalogue of somatic mutations from a cancer genome bears the signatures of the mutational processes that have been operative. Here, we analysed 4,938,362 mutations from 7,042 cancers and extracted more than 20 distinct mutational signatures. Some are present in many cancer types, notably a signature attributed to the APOBEC family of cytidine deaminases, whereas others are confined to a single class. Certain signatures are associated with age of the patient at cancer diagnosis, known mutagenic exposures or defects in DNA maintenance, but many are of cryptic origin. In addition to these genome-wide mutational signatures, hypermutation localized to small genomic regions, kataegis, is found in many cancer types. The results reveal the diversity of mutational processes underlying the development of cancer with potential implications for understanding of cancer etiology, prevention and therapy.
PMCID: PMC3776390  PMID: 23945592
17.  Subclonal variant calling with multiple samples and prior knowledge 
Bioinformatics  2014;30(9):1198-1204.
Motivation: Targeted resequencing of cancer genes in large cohorts of patients is important to understand the biological and clinical consequences of mutations. Cancers are often clonally heterogeneous, and the detection of subclonal mutations is important from a diagnostic point of view, but presents strong statistical challenges.
Results: Here we present a novel statistical approach for calling mutations from large cohorts of deeply resequenced cancer genes. These data allow for precisely estimating local error profiles and enable detecting mutations with high sensitivity and specificity. Our probabilistic method incorporates knowledge about the distribution of variants in terms of a prior probability. We show that our algorithm has a high accuracy of calling cancer mutations and demonstrate that the detected clonal and subclonal variants have important prognostic consequences.
Availability: Code is available as part of the Bioconductor package deepSNV.
PMCID: PMC3998123  PMID: 24443148
19.  IκBKβ and NFκB1, NSAID use and risk of colorectal cancer in the Colon Cancer Family Registry 
Carcinogenesis  2012;34(1):79-85.
The NFκB-signaling pathway regulates cell proliferation and inflammation. Activation of the pathway is implicated in the etiology of colorectal cancer (CRC). NSAIDs may reduce CRC risk partially through a nuclear factor-kappa B (NFκB)-dependent pathway. In this study, we investigated associations between 34 NFκB1 and 8 IκBKβ tagSNPs and CRC risk and examined interactions with non-steroidal anti-inflammatory drug (NSAID) use. Using conditional logistic regression, we investigated these associations among 1584 incident CRC cases and 2516 sibling controls from the Colon Cancer Family Registry. Three IκBKβ SNPs were associated with a statistically significant lower colorectal or colon cancer risk: rs9694958 (A>G intron 5) (colorectal: ORhzv = 0.26(0.07–0.99), Ptrend = 0.048, Padj = 0.25), rs10958713 (A>C intron 19) (colon: ORhzv = 0.62(0.42–0.92), Ptrend = 0.005, Padj = 0.03) and rs5029748 (C>A intron 2) (colon: ORhet = 0.72(0.56–0.91), Ptrend = 0.01, Padj = 0.08). We replicated trends associated with NFκB1 and IκBKβ variants identified in a previous study (rs4648110 (T>A intron 22), rs13117745 (G>A intron 5) and rs3747811 (T>A intron 1)). IκBKβ’s rs6474387 (C>T intron 20) and rs11986055 (A>C intron 2) showed substantially lower colon cancer risk among current NSAID users (Pinteraction = 0.01 and Pinteraction = 0.045, respectively), whereas NFκB1’s rs230490 (G>A 5ʹ (outside UTR)) and rs997476 (C>A 3ʹ (outside UTR)) showed higher CRC risk among current NSAID users (Pinteraction = 0.01 and Pinteraction = 0.03, respectively). These findings suggest that variants in NFκB1 and IκBKβ are associated with CRC risk and NSAIDs may function partially through an NFκB-dependent pathway. The SNPs identified here should be considered for future functional studies and may be useful in designing a pharmacogenetic approach to preventive NSAID use.
PMCID: PMC3534188  PMID: 23002237
20.  A Yearlong Exercise Intervention Decreases CRP among Obese Postmenopausal Women 
Medicine and science in sports and exercise  2009;41(8):10.1249/MSS.0b013e31819c7feb.
To investigate the effect of a yearlong moderate-intensity aerobic exercise intervention on C-reactive protein (CRP), serum amyloid A (SAA), and interleukin 6 (IL-6) among overweight or obese postmenopausal women.
In a randomized controlled trial, 115 postmenopausal, overweight or obese, sedentary women, aged 50-75 years were randomized to an aerobic exercise intervention of moderate-intensity (60-75% observed maximal heart rate), for ≥45 min/day, 5 days/week (n=53), or to a 1 day/week stretching control (n=62), on an intent-to-treat basis. CRP, SAA, and IL-6 were measured at baseline, 3-months, and 12-months.
From baseline to 12-months, CRP decreased 10% in exercisers and increased 12% in controls (p=0.01); no effects were observed for SAA and IL-6. Among participants at baseline who were obese (BMI≥30kg/m2) or had abdominal obesity (waist circumference (WC)≥88cm), exercise resulted in a more pronounced reduction in CRP (BMI≥30kg/m2: p=0.002; WC≥88cm: p<0.0001), borderline for SAA (BMI≥30kg/m2: p=0.08; WC≥88cm: p=0.04); no intervention effects were observed among women who did not have these characteristics. Overall, weight loss was minimal in the exercise intervention (~1.8kg). Linear trends were observed between CRP and 12-month changes in: aerobic fitness (ptrend = 0.006), exercise adherence (ptrend = 0.004), percentage body fat (ptrend = 0.002), body weight (ptrend = 0.002), waist circumference (ptrend = 0.02), and intra-abdominal fat (ptrend = 0.03).
A moderate-intensity exercise intervention reduced CRP over 12-months among women who were obese at baseline. These findings support the role of exercise in modulating inflammatory processes that are related to increased risk of chronic disease among obese women.
PMCID: PMC3850754  PMID: 19568208
overweight; inflammation; C-reactive protein; physical activity; randomized controlled trial; serum amyloid A
21.  Distinct H3F3A and H3F3B driver variants define chondroblastoma and giant cell tumour of bone 
Nature genetics  2013;45(12):10.1038/ng.2814.
It is recognised that some mutated cancer genes contribute to the development of many cancer types whilst others are cancer-type specific. Amongst genes that affect multiple cancer classes, mutations are usually similar in the different cancer types. Here, however, we observed exquisite tumour-type specificity of different histone 3.3 driver mutations. In 73/77 (95%) cases of chondroblastoma we found K36M mutations predominantly in H3F3B, which is one of two genes encoding histone 3.3. By contrast, 92% (49/53) of giant cell tumours of bone harboured histone 3.3 variants exclusively in H3F3A, which were G34W or, in one case, G34L. The mutations were restricted to the stromal cell population and not detected in osteoclasts or their precursors. In the context of previously reported H3F3A K27M and G34R/V mutations of childhood brain tumours, a remarkable picture of tumour-type specificity of histone 3.3 mutations emerges, indicating distinct functions of histone 3.3 residues, mutations and genes.
PMCID: PMC3839851  PMID: 24162739
22.  A pooled analysis of smoking and colorectal cancer: timing of exposure and interactions with environmental factors 
Considerable evidence suggests that cigarette smoking is associated with a higher risk of colorectal cancer. What is unclear, however, is the impact of quitting smoking on risk attenuation and whether other risk factors for colorectal cancer modify this association.
We performed a pooled analysis of 8 studies, including 6,796 colorectal cancer cases and 7,770 controls to evaluate the association between cigarette smoking history and colorectal cancer risk, and to investigate potential effect modification by other risk factors.
Current smokers (OR=1.26, 95% CI=1.11–1.43) and former smokers (OR=1.18, 95% CI=1.09–1.27), relative to never smokers, showed higher risks of colorectal cancer. Former smokers remained at higher colorectal cancer risk, relative to never smokers, for up to about 25 years after quitting. The impact of time since quitting varied by cancer subsite: the excess risk due to smoking decreased immediately after quitting for proximal colon and rectal cancer, but not until about 20 years post-quitting for distal colon cancer. Further, we observed borderline statistically significant additive interactions between smoking status and BMI (relative excess risk due to interaction [RERI]=0.15, 95% CI:−0.01–0.31, P=0.06) and significant additive interaction between smoking status and fruit consumption (RERI=0.16, 95% CI: 0.01–0.30, P=0.04).
Colorectal cancer risk remained increased for about 25 years after quitting smoking, and the pattern of decline in risk varied by cancer subsite. BMI and fruit intake modified the risk associated with smoking.
These results contribute to a better understanding of the mechanisms through which smoking impacts colorectal cancer etiology.
PMCID: PMC3493822  PMID: 23001243
smoking; colorectal cancer; smoking status; time since quitting smoking; multiplicative and additive interaction; body mass index; vegetable and fruit intake
23.  A Four-Year Field Program Investigating Long-Term Effects of Repeated Exposure of Honey Bee Colonies to Flowering Crops Treated with Thiamethoxam 
PLoS ONE  2013;8(10):e77193.
Neonicotinoid residues in nectar and pollen from crop plants have been implicated as one of the potential factors causing the declines of honey bee populations. Median residues of thiamethoxam in pollen collected from honey bees after foraging on flowering seed treated maize were found to be between 1 and 7 µg/kg, median residues of the metabolite CGA322704 (clothianidin) in the pollen were between 1 and 4 µg/kg. In oilseed rape, median residues of thiamethoxam found in pollen collected from bees were between <1 and 3.5 µg/kg and in nectar from foraging bees were between 0.65 and 2.4 µg/kg. Median residues of CGA322704 in pollen and nectar in the oilseed rape trials were all below the limit of quantification (1 µg/kg). Residues in the hive were even lower in both the maize and oilseed rape trials, being at or below the level of detection of 1 µg/kg for bee bread in the hive and at or below the level of detection of 0.5 µg/kg for hive nectar, honey and royal jelly samples. The long-term risk to honey bee colonies in the field was also investigated, including the sensitive overwintering stage, from four years consecutive single treatment crop exposures to flowering maize and oilseed rape grown from thiamethoxam treated seeds at rates recommended for insect control. Throughout the study, mortality, foraging behavior, colony strength, colony weight, brood development and food storage levels were similar between treatment and control colonies. Detailed examination of brood development throughout the year demonstrated that colonies exposed to the treated crop were able to successfully overwinter and had a similar health status to the control colonies in the following spring. We conclude that these data demonstrate there is a low risk to honey bees from systemic residues in nectar and pollen following the use of thiamethoxam as a seed treatment on oilseed rape and maize.
PMCID: PMC3806756  PMID: 24194871
24.  The genetic heterogeneity and mutational burden of engineered melanomas in zebrafish models 
Genome Biology  2013;14(10):R113.
Melanoma is the most deadly form of skin cancer. Expression of oncogenic BRAF or NRAS, which are frequently mutated in human melanomas, promote the formation of nevi but are not sufficient for tumorigenesis. Even with germline mutated p53, these engineered melanomas present with variable onset and pathology, implicating additional somatic mutations in a multi-hit tumorigenic process.
To decipher the genetics of these melanomas, we sequence the protein coding exons of 53 primary melanomas generated from several BRAFV600E or NRASQ61K driven transgenic zebrafish lines. We find that engineered zebrafish melanomas show an overall low mutation burden, which has a strong, inverse association with the number of initiating germline drivers. Although tumors reveal distinct mutation spectrums, they show mostly C > T transitions without UV light exposure, and enrichment of mutations in melanogenesis, p53 and MAPK signaling. Importantly, a recurrent amplification occurring with pre-configured drivers BRAFV600E and p53-/- suggests a novel path of BRAF cooperativity through the protein kinase A pathway.
This is the first analysis of a melanoma mutational landscape in the absence of UV light, where tumors manifest with remarkably low mutation burden and high heterogeneity. Genotype specific amplification of protein kinase A in cooperation with BRAF and p53 mutation suggests the involvement of melanogenesis in these tumors. This work is important for defining the spectrum of events in BRAF or NRAS driven melanoma in the absence of UV light, and for informed exploitation of models such as transgenic zebrafish to better understand mechanisms leading to human melanoma formation.
PMCID: PMC3983654  PMID: 24148783
25.  The transporter ABCB7 is a mediator of the phenotype of acquired refractory anemia with ring sideroblasts 
Leukemia  2012;27(4):889-896.
Refractory anemia with ring sideroblasts (RARS) is characterized by mitochondrial ferritin (FTMT) accumulation and markedly suppressed expression of the iron transporter ABCB7. To test the hypothesis that ABCB7 is a key mediator of ineffective erythropoiesis of RARS, we modulated its expression in hematopoietic cells. ABCB7 up and down-regulation did not influence growth and survival of K562 cells. In normal bone marrow, ABCB7 down-regulation reduced erythroid differentiation, growth, and colony formation, and resulted in a gene expression pattern similar to that observed in intermediate RARS erythroblasts, and in the accumulation of FTMT. Importantly, forced ABCB7 expression restored erythroid colony growth and decreased FTMT expression level in RARS CD34+ marrow cells. Mutations in the SF3B1 gene, a core component of the RNA splicing machinery, were recently identified in a high proportion of patients with RARS and eleven of the thirteen RARS patients in this study carried this mutation. Interestingly, ABCB7 exon usage differed between NBM and RARS, as well as within the RARS cohort. In addition, SF3B1 silencing resulted in down-regulation of ABCB7 in K562 cells undergoing erythroid differentiation. Our findings support that ABCB7 is implicated in the phenotype of acquired RARS and suggest a relation between SF3B1 mutations and ABCB7 down-regulation.
PMCID: PMC3794445  PMID: 23070040
Acquired sideroblastic anemia; RARS; ABCB7; SF3B1; iron sulfur cluster biogenesis; mitochondrial ferritin (FTMT)

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