|Haploinsufficiency of Tumor Suppressor Genes is Driven by the Cumulative Effect of microRNAs, microRNA Binding Site Polymorphisms and microRNA Polymorphisms: An In silico Approach.|
|Jump to Full Text|
|PMID: 23032637 Owner: NLM Status: PubMed-not-MEDLINE|
|Haploinsufficiency of tumor suppressor genes, wherein the reduced production and activity of proteins results in the inability of the cell to maintain normal cellular function, is one among the various causes of cancer. However the precise molecular mechanisms underlying this condition remain unclear. Here we hypothesize that single nucleotide polymorphisms (SNPs) in the 3'untranslated region (UTR) of mRNAs and microRNA seed sequence (miR-SNPs) may cause haploinsufficiency at the level of proteins through altered binding specificity of microRNAs (miRNAs). Bioinformatics analysis of haploinsufficient genes for variations in their 3'UTR showed that the occurrence of SNPs result in the creation of new binding sites for miRNAs, thereby bringing the respective mRNA variant under the control of more miRNAs. In addition, 19 miR-SNPs were found to result in non-specific binding of microRNAs to tumor suppressors. Networking analysis suggests that the haploinsufficient tumor suppressor genes strongly interact with one another, and any subtle alterations in this network will contribute to tumorigenesis.|
|Mayakannan Manikandan; Ganesh Raksha; Arasambattu Kannan Munirajan|
Related Documents :
|24788517 - Coordination of trna transcription with export at nuclear pore complexes in budding yeast.
21070277 - Targets of selection in the thoroughbred genome contain exercise-relevant gene snps ass...
900887 - Genetic polymorphisms in afghanistan.
20937887 - Ecosystem-specific selection pressures revealed through comparative population genomics.
15791247 - Full-genome rnai profiling of early embryogenesis in caenorhabditis elegans.
7553627 - The retinoblastoma gene product in acute myeloid leukemia: a possible involvement in pr...
|Type: Journal Article Date: 2012-08-29|
|Title: Cancer informatics Volume: 11 ISSN: 1176-9351 ISO Abbreviation: Cancer Inform Publication Date: 2012|
|Created Date: 2012-10-03 Completed Date: 2012-10-04 Revised Date: 2013-05-30|
Medline Journal Info:
|Nlm Unique ID: 101258149 Medline TA: Cancer Inform Country: New Zealand|
|Languages: eng Pagination: 157-71 Citation Subset: -|
|Department of Genetics, Dr. ALM PG Institute of Basic Medical Sciences, University of Madras, Taramani Campus, Chennai - 600113, Tamil Nadu, India.|
|APA/MLA Format Download EndNote Download BibTex|
Journal ID (nlm-ta): Cancer Inform
Journal ID (iso-abbrev): Cancer Inform
Journal ID (publisher-id): 101258149
Publisher: Libertas Academica
© the author(s), publisher and licensee Libertas Academica Ltd.
collection publication date: Year: 2012
Electronic publication date: Day: 29 Month: 8 Year: 2012
Volume: 11First Page: 157 Last Page: 171
PubMed Id: 23032637
Publisher Id: cin-11-2012-157
|Haploinsufficiency of Tumor Suppressor Genes is Driven by the Cumulative Effect of microRNAs, microRNA Binding Site Polymorphisms and microRNA Polymorphisms: An In silico Approach|
|Arasambattu Kannan Munirajan|
|Department of Genetics, Dr. ALM PG Institute of Basic Medical Sciences, University of Madras, Taramani Campus, Chennai – 600113, Tamil Nadu, India.
|Correspondence: Corresponding author email: firstname.lastname@example.org
Cancer is a complex genetic disease involving structural and expression abnormalities of both coding and non-coding genes. The search for cancer causing genes has identified two major classes namely the oncogenes and tumor suppressor genes (TSGs). Activation or over expression of a proto-oncogene, such as cMyc,1 or inactivation of a tumor suppressor, such as TP53,2,3 causes tumorigenicity. Oncogene activation in tumors is straightforward, while the inactivation of TSGs is a complex process attained by different means including mutations, deletions, down regulation by microRNAs, epigenetic silencing etc. Although complete loss of TSG is common in tumors, recent studies indicate that a partial compromise in TSG function termed ‘haploinsufficiency’ contributes to the development and progression of many cancers.4 The condition where one functional allele of a gene is lost by mutation or deletion, and the remaining normal allele is insufficient to execute its original physiological function, is called haploinsufficiency. This phenomenon is extensively applicable to TSGs5 as they offer a benefit for cancer cells in regards to proliferation,6 survival,7 and metastasis.8
In principle, haploinsufficient TSGs are impaired by a 50% reduction in expression or activity. However, in vivo studies demonstrate that even a subtle 20% reduction of PTEN protein level—termed as ‘quasi-insufficiency’— could contribute to the development of cancer.9 Another example is that TP53, when targeted by short hairpin RNAs (shRNAs), is shown to elicit distinct phenotypes ranging from hyperplasia to malignancy in mouse models depending on the reduction in its protein level.10 This proves that some TSGs, like PTEN, are exquisitely sensitive to dose, while some, like TP53, are intermediately sensitive. Based on such observations, Berger et al has proposed a continuum model that accounts for subtle dosage effects of tumor suppressors including their regulation by microRNAs.11 The dosage and function of haploinsufficient genes are critical, and understanding the impact of haploinsufficiency is important for assessment of interindividual genetic variation, as well as the molecular basis of haploinsufficiency disorders.
Haploinsufficiency of multiple genes cooperate to promote tumorigenesis, a phenomenon called ‘compound haploinsufficiency’. The 5q deletion syndrome (5q-) is a paradigm of compound haploinsufficiency and demonstrates the importance of combinatorial interactions to elicit specific phenotypes.12 Experimental evidence has shown that co-suppression of linked 8p TSGs promotes tumor formation more potently than any individual gene.13 All the available evidence indicates that the functioning of a cell depends on the appropriate expression levels of proteins and, more importantly, that cell signalling pathways involve complex interactions between many proteins. Not only genes, but also microRNAs (miRNAs), a class of small noncoding RNAs, are shown to be haploinsufficient and to cause developmental abnormalities in humans.14 In addition, genes involved in miRNA biosynthesis pathway, such as DICER1, TARBP2 and XPO5, are identified as haploinsufficient tumor suppressors.15–17
miRNAs act at the post-transcriptional level of gene regulation through RNA-induced silencing complex (RISC) mediated translational inhibition or mRNA cleavage. The miRNA target recognition is mediated through the sequence complementarity between the 2–8 nt at the 5′ end of miRNA (seed sequence) and the 3′-UTR of target mRNA.18 Based on the degree of complementarity, the mRNA is either guided for inhibition of translation or degradation resulting in the decrease of protein encoded by the target messenger.19 This has extended the dimensions of haploinsufficiency as miRNAs can lead to the production of insufficient amount of proteins. Bioinformatics prediction and experimental analysis suggested that miRNAs can regulate approximately half of the mammalian genes, with a significant number of important oncogenes and tumor suppressor genes involved.20,21 A recent genome-wide association study has suggested that a gene with more than two miRNA target sites will have higher variability of expression than a gene which is not regulated by a miRNA. The variability is further increased by SNPs in the miRNA target sites.22 Polymorphisms in the miRNA regulatory pathway are a novel class of functional polymorphisms present in the human genome. The initial demonstration that miRNA binding site variations can result in a phenotype was provided by Abelson et al who identified a mutation in the miR-189 binding site of SLITRK1 and its association with Tourette’s syndrome.23 A pioneering study conducted by Carlo Croce’s group showed that a germline mutation in pri-miR-16-1 resulted in low levels of miR-16-1 expression in familial chronic lymphocytic leukemia,24,25 providing evidence that sequence variation in miRNA genes may affect function and result in cancer susceptibility. Pre- and pri-miRNA SNPs in miR-124-1, miR-146a, miR-196-a2, miR-218, miR-219-1, miR-26a-1, miR-27a, miR-423, miR-492, and miR-499 have already been shown to increase/decrease cancer risk in various populations.26
Single nucleotide polymorphisms (SNPs) are single base pair changes in DNA that occur with a frequency of about 1 in 12,500 bp in the genome.27 Several studies have shown that SNPs in microRNA networks moderately increase the risk of cancer incidence.28 In general, sequence variations in pri-miRNAs, premiRNAs, mature miRNAs, and microRNA binding sites potentially affects the processing and/or target selection of miRNAs. As a consequence, aberrant expression of hundreds of genes and pathways greatly affecting miRNA function may occur.29 SNPs in mature miRNAs and miRNA binding sites function analogously to modulate the miRNA-mRNA interaction and create or destroy miRNA binding sites. Supporting this idea, SNPs within the miRNA binding sites of genes have been implicated in susceptibility to various types of cancer.30–33 Additionally, functional support for individual miR-SNPs implicated in cancer do exist.
In this study we analyzed the role of SNPs that occur at miRNA binding sites and miR-SNPs and their contribution towards haploinsufficiency of tumor suppressor genes.
A total of 110 haploinsufficient genes known to have a role in tumor initiation and progression were considered for the study. Among the total list, 63 tumorigenic haploinsufficient genes were obtained from Dang et al, 200834 while the remaining 47 genes were compiled using keyword search in PubMed and Online Mendelian Inheritance in Man (OMIM) database. For a comprehensive list of the haploinsufficient tumorigenic genes included in this study with their corresponding reference, see Supplement 1.
The haploinsufficient genes were analyzed for polymorphisms in their 3′UTR by submitting the respective gene ID in ‘Polymorphism in microRNA Target Site’ (PolymiRTS) database,35http://compbio.uthsc.edu/miRSNP/, designed to identify SNPs that disrupt the regulation of gene expression by miRNAs in human and mouse (last accessed on June 7th, 2012). The database is organized to provide links between SNPs in miRNA target sites, cis-acting expression quantitative trait loci (eQTLs), and the results of genome-wide association studies (GWAS) of human diseases. We applied filters to identify only the SNPs in the 3′UTR that were known to create binding sites for miRNAs and SNPs occurring in the seed region of miRNA themselves.
The SNPs predicted by the polymiRTS database were classified based on their effect into the following categories: (i) SNPs that lead to the creation of miRNA binding sites in the mRNA, (ii) SNPs that disrupted the originally existing miRNA binding sites and also resulted in creation of new miRNA binding sites in the mRNA, and (iii) miR-SNPs that altered the binding specificity of miRNAs. After classification, the SNPs were verified by submitting their rs ID in the NCBI’s dbSNP Short genetic variation database http://www.ncbi.nlm.nih.gov/projects/SNP/using the batch query option. The output was downloaded in BED format and analyzed. Among the total 158 SNPs submitted, 156 SNPs were validated by dbSNP while 2 miR-SNPs (rs116596918 and rs116838571) were found to be new entries and validated by microRNA-related Single Nucleotide Polymorphism database (http://www.bioguo.org/miRNASNP/miRNA_details.php).36
To identify the functional significance, GeneMANIA Cytoscape plug-in which employs the GeneMANIA algorithm37,38 was utilized with default settings to plot the interactions among the haploinsufficient TSGs. The complete list of tumorigenic haploinsufficient genes were uploaded to Cytoscape39 using GeneMANIA plug-in (http://www.genemania.org/plugin/). Further, only the genes that were found to have SNPs in their miRNA binding sites and those that are non-specifically targeted by miRNAs harboring miR-SNPs were uploaded individually to study the interactions among this subgroup. The GeneMANIA Cytoscape plug-in integrates association networks from multiple sources into a single composite network using a conjugate gradient optimization algorithm. This algorithm produces networks from the data either directly (as in the case of protein or genetic interactions) or by using an in-house analysis pipeline to convert profiles to functional association networks.
Our analysis of tumorigenic haploinsufficient genes for genetic variations in the 3′UTR showed that 26% (29 out of 110) of them had at least one 3′UTR SNP resulting in creation of new binding sites for miRNAs thereby bringing the respective mRNA variant under the control of more new miRNAs. In total, 129 SNPs were found to create binding sites for 234 miRNAs in 29 genes (Table 1). Altogether, these SNPs contribute to haploinsufficiency by bringing the polymorphic mRNA under the control of more new microRNAs thereby leading to translational repression or mRNA degradation. PPARA, a nuclear transcription factor and KIF1B, a kinesin implicated in neuronal and non-neuronal tumors was found to harbor 17 SNPs creating putative binding sites for many miRNAs. On the contrary, the SNP rs121912664 in TP53 creates putative miRNA binding site for miRNA-302 family, miR-520 family, miR-372, and miR-373-3p. The cell adhesion molecule CDH1, an important gene in tumor invasion with frequent allelic loss in metastatic tumors, was found to have 5 different SNPs that create putative binding sites for new miRNAs thereby altering the repertoire of miRNAs controlling this gene. Even RB1, the classical TSG, was predicted to have 3 SNPs that may down regulate its expression. If one allele is already lost in tumors, the remaining allele having at least one of these SNPs may be targeted by miRNAs and thereby lead to complete loss of cellular function, as postulated by Knudson’s “two-hit hypothesis.”
Another 10 SNPs were found to bring 8 different genes under the control of additional new miRNAs due to the presence of the respective SNP (Fig. 1). A single SNP can create miR binding site for several miRNAs as well as delete a miR binding site. For example, the SNP rs186304832 in the 3′UTR of KIF1B results in the loss of binding of 2 different microRNAs to the variant mRNA while 7 new microRNAs will be targeting this particular variant. This alters the miRNA mediated gene expression control resulting in aberrant regulation of expression. A gene that was previously under the control of one miRNA comes under the control of 3 different new miRNAs which leads to extensive translational repression resulting in protein haploinsufficiency as represented by the polymorphism rs1138533 in CDH1. This mechanism is totally new, since one allele is not lost due to mutation or deletion, as in the case of classical haploinsufficiency. Rather there is a decrease in the overall protein product. In homozygous state, this SNP may result in complete or partial reduction in the expression based on the ability of the repressing miRNA. However, in heterozygous state, the same SNP can lead to 50% or even subtler reduction in expression, which can explain ‘quasi-insufficiency’.
Ours is the first study to identify the SNP and miRNA mediated control of tumor suppressor dose as well as highlighting the importance of genetic variations in cancer. This mechanism is in agreement with the continuum model for tumor suppression that is related to the level of expression or activity of the TSG rather than to the discrete step-by-step changes in gene copy number.11
In addition, SNPs that occur in the seed sequence of miRNAs can alter the binding specificity of these miRNAs resulting in the binding to new non-target mRNAs. We analyzed 19 such miR-SNPs that cause miRNAs to bind new haploinsufficient tumor suppressor genes (Table 2). The SNP rs4636784 occurring in the seed of hsa-miR-4305 alters the binding specificity, thereby enabling it to target 6 new haploinsufficient genes (CDH1, KIF1B, SMAD4, DFFB, FOXP1, and PTEN). This can contribute to compound haploinsufficiency, wherein multiple genes cooperate to cause a particular phenotype.7,13 Alteration in one miRNA can alter the entire set of genes under its control thereby providing an advantage for cancer initiation and progression. In addition, the acquisition of miR-SNPs in tumors is simple enough to deregulate many genes than the need for individual mutations in all of them. This mechanism of miR-SNP mediated down regulation can also be extended to the unexplained allelic loss of KIF1B in neuroblastomas, where the tumor suppressor was shown to have no mutations or promoter methylation.40 Tumors not showing genetic alterations in the TSG, but with aberrant TSG levels due to miRNA misregulation, could behave like tumors with deletion or mutation of the gene. Importantly, mapping the interactions between miRNAs and TSGs could be useful for defining and predicting cancer susceptibility and therapeutic response.
Although reports on haploinsufficient genes associated with cancer is limited, analysis of the existing data shows that at least one third of total haploinsufficient genes to be tumorigenic. Tumor suppressors often act as components of complex networks, the overall function of which can be impaired by genetic and epigenetic alterations.41,42 For this reason we analyzed whether the haploinsufficient tumor suppressor genes share a common pathway or fall in a common interacting or functional network. The GeneMANIA algorithm was utilized for this purpose, and results indicate that almost 99% of haploinsufficient genes have a strong interaction, either directly or indirectly. SMAD5 was excluded from the list as it was not recognized by the algorithm. Co-expression, co-localization, physical and genetic interactions, pathway interactions, and other interactions that arise through shared structural domains were shown to exist between the queried genes (Fig. 2). SPRED1 was the only gene to fall out of this network however co-expression links it to the group. Apart from the queried list of genes, the algorithm identified several other genes to be a part of this network including DROSHA, DFFA, MRE11A, TRAPPC2L, TERF2, CDK6, BUB1, WRN, CCNA2, and RAD51. Interestingly, the haploinsufficient status of some of these genes has already been described in developmental abnormalities and other diseases,43–45 while some others are shown to have a role in tumor formation and their haploinsufficient status is yet to be established.46
Next we tested whether the 39 genes with SNPs in miRNA binding sites or targeted by miRNAs with altered specificity due to miR-SNPs fall in to a particular network or pathway. Results of GeneMANIA networking analysis suggested strong interactions between these genes (Fig. 3). DNA repair genes and cell cycle checkpoint genes were enriched in this network and any aberrations in their expression offers selective advantage for the tumors to acquire additional genomic changes or mutations. DFFB was linked by co-expression, while DIRC2 was shown to be completely out of the group. The following genes were found to be a part of this network and to mediate interactions between the queried genes: MRE11A, DFFA, CCNB1, POLQ, AP1B1, RAD51, CCNG1, NPM1, DDB1, and WRN. The identification of the mRNA targets that mediate the actions of miRNAs in disease pathways can reveal previously unrecognized components that may serve as targets for more traditional drug development.
With the expanding understanding of the roles of miRNAs in various cellular processes and diseases, this is the first report to discuss the role of miRNAs and its contribution towards tumor suppressor gene haploinsufficiency at the protein level via 3′UTR SNPs and miR-SNPs. Further, this could be an alternate means for attaining compound heterozygosity observed in several tumors and the mechanism is in complete agreement with the continuum model of tumor suppression.11 Our data suggests that 26% of the tumorigenic haploinsufficient genes were brought under the control of new miRNAs due to 3′UTR SNPs. The identification of 10 SNPs that drive haploinsufficiency by bringing the polymorphic mRNA under the control of miRNAs, other than the miRNAs which are deleted, needs experimental validation in tumors. This alteration in the miRNA mediated gene regulation may cause predisposition to cancer initiation and progression.
Evidence for co-operative contribution of oncogenic mutations with tumor suppressor haploinsufficiency also exist.47 The realization that miR-SNPs play central roles in the aberrant regulation of tumor suppressor genes has provided a new perspective on our understanding of pathophysiologic mechanisms. In addition, networking analysis reveals strong interactions between the haploinsufficient tumor suppressor genes. Any subtle alteration in this network of genes due to SNPs at the 3′UTR and miR-SNPs may contribute to pathogenesis. We suggest that at least a few among these SNPs and their effect on miRNA binding will aid in the diagnosis and/or prognosis of such type of cancers, if experimentally validated. While challenges remain in this regard, the pace of development in this field suggests that new discoveries are forthcoming.
Our approach has currently focused only on analyzing 3′UTRs, although a small subset of miRNAs can target 5′UTRs, coding regions, and gene promoters. miR-SNPs leading to non-specific binding of miRNAs to tumor suppressors may also result in the loss of binding to their original targets. If the target is an oncogene, it will be over expressed and will result in tumorigenesis. This has not been focused on in this study. Since the rules for miRNA binding to its target changes constantly,48 the databases need constant updating. The 110 tumor suppressor genes chosen for our study were already proven to be haploinsufficient in several cancers through experimental evidence. This list may likely grow due to continuous identification of haploinsufficient tumor suppressors.
|1.||Amsterdam A,Sadler KC,et al. Many ribosomal protein genes are cancer genes in zebrafishPLoS BiolYear: 200425E13915138505|
|2.||Bahubeshi A,Bal N,et al. Germline DICER1 mutations and familial cystic nephromaJ Med GenetYear: 20104712863621036787|
|3.||Barlow JL,Drynan LF,et al. A p53-dependent mechanism underlies macrocytic anemia in a mouse model of human 5q- syndromeNat MedYear: 2010161596619966810|
|4.||Berger AH,Niki M,et al. Identification of DOK genes as lung tumor suppressorsNat GenetYear: 20104232162320139980|
|5.||Blough RI,Petrij F,et al. Variation in microdeletions of the cyclic AMP-responsive element-binding protein gene at chromosome band 16p13.3 in the Rubinstein-Taybi syndromeAm J Med GenetYear: 2000901293410602114|
|6.||Bouffler SD,Hofland N,et al. Evidence for Msh2 haploinsufficiency in mice revealed by MNU-induced sister-chromatid exchange analysisBr J CancerYear: 200083101291411044352|
|7.||Braggio E,Keats JJ,et al. Identification of copy number abnormalities and inactivating mutations in two negative regulators of nuclear factor-kappaB signaling pathways in Waldenstrom’s macroglobulinemiaCancer ResYear: 200969835798819351844|
|8.||Bric A,Miething C,et al. Functional identification of tumor-suppressor genes through an in vivo RNA interference screen in a mouse lymphoma modelCancer CellYear: 20091643243519800577|
|9.||Chayka O,Corvetta D,et al. Clusterin, a haploinsufficient tumor suppressor gene in neuroblastomasJ Natl Cancer InstYear: 200910196637719401549|
|10.||Chen C,Bhalala HV,et al. A possible tumor suppressor role of the KLF5 transcription factor in human breast cancerOncogeneYear: 2002214365677212242654|
|11.||Dang VT,Kassahn KS,et al. Identification of human haploinsufficient genes and their genomic proximity to segmental duplicationsEur J Hum GenetYear: 200816111350718523451|
|12.||de Wind N,Dekker M,et al. Mouse models for hereditary nonpolyposis colorectal cancerCancer ResYear: 1998582248559443401|
|13.||DeWeese TL,Shipman JM,et al. Mouse embryonic stem cells carrying one or two defective Msh2 alleles respond abnormally to oxidative stress inflicted by low-level radiationProc Natl Acad Sci U S AYear: 1998952011915209751765|
|14.||Duan S,Cermak L,et al. FBXO11 targets BCL6 for degradation and is inactivated in diffuse large B-cell lymphomasNatureYear: 2012481737990322113614|
|15.||Dumon-Jones V,Frappart PO,et al. Nbn heterozygosity renders mice susceptible to tumor formation and ionizing radiation-induced tumorigenesisCancer ResYear: 200363217263914612522|
|16.||Ebert BL,Pretz J,et al. Identification of RPS14 as a 5q- syndrome gene by RNA interference screenNatureYear: 20084517176335918202658|
|17.||Egle A,Harris AW,et al. Bim is a suppressor of Myc-induced mouse B cell leukemiaProc Natl Acad Sci U S AYear: 2004101166164915079075|
|18.||Fang Y,Tsao CC,et al. ATR functions as a gene dosage-dependent tumor suppressor on a mismatch repair-deficient backgroundEMBO JYear: 2004231531647415282542|
|19.||Gale NW,Dominguez MG,et al. Haploinsufficiency of delta-like 4 ligand results in embryonic lethality due to major defects in arterial and vascular developmentProc Natl Acad Sci U S AYear: 200410145159495415520367|
|20.||Gorrini C,Squatrito M,et al. Tip60 is a haplo-insufficient tumour suppressor required for an oncogene-induced DNA damage responseNatureYear: 200744871571063717728759|
|21.||Goss KH,Risinger MA,et al. Enhanced tumor formation in mice heterozygous for Blm mutationScienceYear: 200229755892051312242442|
|22.||Grosshans H,Bussing I. MicroRNA biogenesis takes another single hit from microsatellite instabilityCancer CellYear: 2010184295720951937|
|23.||Hellstrom M,Phng LK,et al. Dll4 signalling through Notch1 regulates formation of tip cells during angiogenesisNatureYear: 200744571297768017259973|
|24.||Huang J,Powell WC,et al. Prostatic intraepithelial neoplasia in mice with conditional disruption of the retinoid X receptor alpha allele in the prostate epitheliumCancer ResYear: 200262164812912183441|
|25.||Inoue K,Zindy F,et al. Dmp1 is haplo-insufficient for tumor suppression and modifies the frequencies of Arf and p53 mutations in Myc-induced lymphomasGenes DevYear: 200115222934911711428|
|26.||Itoh T,Iwashita S,et al. Ddb2 is a haploinsufficient tumor suppressor and controls spontaneous germ cell apoptosisHum Mol GenetYear: 2007161315788617468495|
|27.||Jacks T,Shih TS,et al. Tumour predisposition in mice heterozygous for a targeted mutation in Nf1Nat GenetYear: 199473353617920653|
|28.||Jackson RJ,Engelman RW,et al. p21Cip1 nullizygosity increases tumor metastasis in irradiated miceCancer ResYear: 200363123021512810620|
|29.||Jager R,Gisslinger H,et al. Deletions of the transcription factor Ikaros in myeloproliferative neoplasmsLeukemiaYear: 20102471290820508609|
|30.||Kalitsis P,Fowler KJ,et al. Increased chromosome instability but not cancer predisposition in haploinsufficient Bub3 miceGenes Chromosomes CancerYear: 2005441293615898111|
|31.||Kucherlapati M,Yang K,et al. Haploinsufficiency of Flap endonuclease (Fen1) leads to rapid tumor progressionProc Natl Acad Sci U S AYear: 200299159924912119409|
|32.||Kumar MS,Pester RE,et al. Dicer1 functions as a haploinsufficient tumor suppressorGenes DevYear: 200923232700419903759|
|33.||Lam MH,Liu Q,et al. Chk1 is haploinsufficient for multiple functions critical to tumor suppressionCancer CellYear: 200461455915261141|
|34.||Mallakin A,Sugiyama T,et al. Mutually exclusive inactivation of DMP1 and ARF/p53 in lung cancerCancer CellYear: 20071243819417936562|
|35.||McClatchey AI,Saotome I,et al. The Nf2 tumor suppressor gene product is essential for extraembryonic development immediately prior to gastrulationGenes DevYear: 199711101253659171370|
|36.||McPherson JP,Lemmers B,et al. Involvement of mammalian Mus81 in genome integrity and tumor suppressionScienceYear: 200430456781822615205536|
|37.||Melo SA,Ropero S,et al. A TARBP2 mutation in human cancer impairs microRNA processing and DICER1 functionNat GenetYear: 20094133657019219043|
|38.||Michel LS,Liberal V,et al. MAD2 haplo-insufficiency causes premature anaphase and chromosome instability in mammalian cellsNatureYear: 20014096818355911201745|
|39.||Mullighan CG,Miller CB,et al. BCR-ABL1 lymphoblastic leukaemia is characterized by the deletion of IkarosNatureYear: 20084537191110418408710|
|40.||Munirajan AK,Ando K,et al. KIF1Bbeta functions as a haploinsufficient tumor suppressor gene mapped to chromosome 1p36.2 by inducing apoptotic cell deathJ Biol ChemYear: 200828336244263418614535|
|41.||Rio Frio T,Bahubeshi A,et al. DICER1 mutations in familial multinodular goiter with and without ovarian Sertoli-Leydig cell tumorsJAMAYear: 20113051687721205968|
|42.||Schofield CM,Hsu R,et al. Monoallelic deletion of the microRNA biogenesis gene Dgcr8 produces deficits in the development of excitatory synaptic transmission in the prefrontal cortexNeural DevYear: 201161121466685|
|43.||Shao LJ,Shi HY,et al. Haploinsufficiency of the maspin tumor suppressor gene leads to hyperplastic lesions in prostateCancer ResYear: 2008681351435118593913|
|44.||Smits R,Ruiz P,et al. E-cadherin and adenomatous polyposis coli mutations are synergistic in intestinal tumor initiation in miceGastroenterologyYear: 2000119410455311040191|
|45.||Song WJ,Sullivan MG,et al. Haploinsufficiency of CBFA2 causes familial thrombocytopenia with propensity to develop acute myelogenous leukaemiaNat GenetYear: 19992321667510508512|
|46.||Su X,Chakravarti D,et al. TAp63 suppresses metastasis through coordinate regulation of Dicer and miRNAsNatureYear: 201046773189869020962848|
|47.||Taine L,Goizet C,et al. Submicroscopic deletion of chromosome 16p13.3 in patients with Rubinstein-Taybi syndromeAm J Med GenetYear: 1998783267709677064|
|48.||Takagi Y,Takahashi M,et al. Roles of MGMT and MLH1 proteins in alkylation-induced apoptosis and mutagenesisDNA Repair (Amst)Year: 200321011354613679151|
|49.||Tanaka Y,Naruse I,et al. Abnormal skeletal patterning in embryos lacking a single Cbp allele: a partial similarity with Rubinstein-Taybi syndromeProc Natl Acad Sci U S AYear: 1997941910215209294190|
|50.||Terzian T,Wang Y,et al. Haploinsufficiency of Mdm2 and Mdm4 in tumorigenesis and developmentMol Cell BiolYear: 2007271554798517526734|
|51.||Umesako S,Fujisawa K,et al. Atm heterozygous deficiency enhances development of mammary carcinomas in p53 heterozygous knockout miceBreast Cancer ResYear: 200571R1647015642165|
|52.||Virely C,Moulin S,et al. Haploinsufficiency of the IKZF1 (IKAROS) tumor suppressor gene cooperates with BCR-ABL in a transgenic model of acute lymphoblastic leukemiaLeukemiaYear: 20102461200420393504|
|53.||Vooijs M,Berns A. Developmental defects and tumor predisposition in Rb mutant miceOncogeneYear: 19991838529330310498881|
|54.||Ward IM,Difilippantonio S,et al. 53BP1 cooperates with p53 and functions as a haploinsufficient tumor suppressor in miceMol Cell BiolYear: 20052522100798616260621|
|55.||Wolfrum S,Teupser D,et al. The protective effect of A20 on atherosclerosis in apolipoprotein E-deficient mice is associated with reduced expression of NF-kappaB target genesProc Natl Acad Sci U S AYear: 20071044718601618006655|
|56.||Xu X,Brodie SG,et al. Haploid loss of the tumor suppressor Smad4/Dpc4 initiates gastric polyposis and cancer in miceOncogeneYear: 2000191518687410773876|
|57.||Zheng L,Flesken-Nikitin A,et al. Deficiency of Retinoblastoma gene in mouse embryonic stem cells leads to genetic instabilityCancer ResYear: 2002629249850211980640|
|58.||Zhou XZ,Huang P,et al. The telomerase inhibitor PinX1 is a major haploin-sufficient tumor suppressor essential for chromosome stability in miceJ Clin InvestYear: 2011121412668221436583|
|59.||Zhu Y,Ghosh P,et al. Neurofibromas in NF1: Schwann cell origin and role of tumor environmentScienceYear: 20022965569920211988578|
AKM conceived and designed the study. MM and GR performed the experiments. AKM, MM, and GR analyzed the data. MM and AKM prepared the manuscript. All authors read and approved the final manuscript.
Author(s) disclose no potential conflicts of interest.
fn3-cin-11-2012-157Disclosures and Ethics
As a requirement of publication author(s) have provided to the publisher signed confirmation of compliance with legal and ethical obligations including but not limited to the following: authorship and contributorship, conflicts of interest, privacy and confidentiality and (where applicable) protection of human and animal research subjects. The authors have read and confirmed their agreement with the ICMJE authorship and conflict of interest criteria. The authors have also confirmed that this article is unique and not under consideration or published in any other publication, and that they have permission from rights holders to reproduce any copyrighted material. Any disclosures are made in this section. The external blind peer reviewers report no conflicts of interest.
This research was supported in part by a grant from the Department of Biotechnology (DBT), New Delhi (Grant Number BT/PR10023/AGR/36/27/2007) to AKM. MM is a recipient of research fellowship from Council of Scientific and Industrial Research (CSIR), New Delhi. We also thank DST-FIST and UGC-SAP for the infrastructure provided by grants to the department.
|1.||Nesbit CE,Tersak JM,Prochownik EV. MYC oncogenes and human neoplastic diseaseOncogeneYear: 1999181930041610378696|
|2.||Caron de Fromentel C,Soussi T. TP53 tumor suppressor gene: a model for investigating human mutagenesisGenes Chromosomes CancerYear: 1992411151377002|
|3.||Hainaut P,Hernandez T,Robinson A,et al. IARCDatabase of p53 gene mutations in human tumors and cell lines: updated compilation, revised formats and new visualisation toolsNucleic Acids ResYear: 199826120513|
|4.||Santarosa M,Ashworth A. Haploinsufficiency for tumor suppressor genes: when you don’t need to go all the wayBiochim Biophys ActaYear: 2004165421052215172699|
|5.||Payne SR,Kemp CJ. Tumor suppressor geneticsCarcinogenesisYear: 2005261220314516150895|
|6.||Solimini NL,Xu Q,Mermel CH,et al. Recurrent hemizygous feletions in cancers may optimize proliferative potentialScienceYear: 20123376090104922628553|
|7.||Smilenov LB,Lieberman HB,Mitchell SA,Baker RA,Hopkins KM,Hall EJ. Combined haploinsufficiency for ATM and RAD9 as a factor in cell transformation, apoptosis, and DNA lesion repair dynamicsCancer ResYear: 2005653933815705893|
|8.||Iwakuma T,Tochigi Y,Van Pelt CS,et al. Mtbp haploinsufficiency in mice increases tumor metastasisOncogeneYear: 2008271318132017906694|
|9.||Alimonti A,Carracedo A,Clohessy JG,et al. Subtle variations in Pten dose determine cancer susceptibilityNat GenetYear: 2010425454820400965|
|10.||Hemann MT,Fridman JS,Zilfou JT,et al. An epi-allelic series of p53 hypomorphs created by stable RNAi produces distinct tumor phenotypes in vivoNat GenetYear: 200333339640012567186|
|11.||Berger AH,Knudson AG,Pandolfi PP. A continuum model for tumor suppressionNatureYear: 20114767359163921833082|
|12.||Ebert BL. Deletion 5q in myelodysplastic syndrome: a paradigm for the study of hemizygous deletions in cancerLeukemiaYear: 20092371252619322210|
|13.||Xue W,Kitzing T,Roessler S,et al. A cluster of cooperating tumor-suppressor gene candidates in chromosomal deletionsProc Natl Acad Sci U S AYear: 2012109218212722566646|
|14.||de Pontual L,Yao E,Callier P,et al. Germline deletion of the miR-17 ~92 cluster causes skeletal and growth defects in humansNat GenetYear: 2011431010263021892160|
|15.||Kumar MS,Pester RE,Chen CY,et al. Dicer1 functions as a haploinsufficient tumor suppressorGenes DevYear: 200923232700419903759|
|16.||Melo SA,Ropero S,Moutinho C,et al. A TARBP2 mutation in human cancer impairs microRNA processing and DICER1 functionNat GenetYear: 20094133657019219043|
|17.||Grosshans H,Bussing I. MicroRNA biogenesis takes another single hit from microsatellite instabilityCancer CellYear: 2010184295720951937|
|18.||Lewis BP,Burge CB,Bartel DP. Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targetsCellYear: 20051201152015652477|
|19.||Bartel DP. MicroRNAs: target recognition and regulatory functionsCellYear: 200913622153319167326|
|20.||Krol J,Loedige I,Filipowicz W. The widespread regulation of microRNA biogenesis, function and decayNat Rev GenetYear: 201011959761020661255|
|21.||Fabbri M,Croce CM,Calin GA. MicroRNAsCancer JYear: 20081411618303474|
|22.||Liu J,Rivas FV,Wohlschlegel J,Yates JR 3rd,Parker R,Hannon GJ. A role for the P-body component GW182 in microRNA functionNat Cell BiolYear: 20057121261616284623|
|23.||Abelson JF,Kwan KY,O’Roak BJ,et al. Sequence variants in SLITRK1 are associated with Tourette’s syndromeScienceYear: 200531057463172016224024|
|24.||Calin GA,Ferracin M,Cimmino A,et al. A MicroRNA signature associated with prognosis and progression in chronic lymphocytic leukemiaN Engl J MedYear: 200535317179380116251535|
|25.||Wojcik SE,Rossi S,Shimizu M,et al. Non-codingRNA sequence variations in human chronic lymphocytic leukemia and colorectal cancerCarcinogenesisYear: 20103122081519926640|
|26.||Slaby O,Bienertova-Vasku J,Svoboda M,Vyzula R. Genetic polymorphisms and microRNAs: new direction in molecular epidemiology of solid cancerJ Cell Mol MedYear: 201216182121692980|
|27.||Kruglyak L,Nickerson DA. Variation is the spice of lifeNat GenetYear: 2001273234611242096|
|28.||Ryan BM,Robles AI,Harris CC. Genetic variation in microRNA networks: the implications for cancer researchNat Rev CancerYear: 201010638940220495573|
|29.||Georges M,Coppieters W,Charlier C. Polymorphic miRNA-mediated gene regulation: contribution to phenotypic variation and diseaseCurr Opin Genet DevYear: 20071731667617467975|
|30.||Nicoloso MS,Sun H,Spizzo R,et al. Single-nucleotide polymorphisms inside microRNA target sites influence tumor susceptibilityCancer ResYear: 201070727899820332227|
|31.||Brendle A,Lei H,Brandt A,et al. Polymorphisms in predicted microRNA-binding sites in integrin genes and breast cancer: ITGB4 as prognostic markerCarcinogenesisYear: 20082971394918550570|
|32.||Chin LJ,Ratner E,Leng S,et al. A SNP in a let-7 microRNA complementary site in the KRAS 3′untranslated region increases non-small cell lung cancer riskCancer ResYear: 2008682085354018922928|
|33.||Saetrom P,Biesinger J,Li SM,et al. A risk variant in an miR-125b binding site in BMPR1B is associated with breast cancer pathogenesisCancer ResMonth: 9 Day: 15 Year: 2009691874596519738052|
|34.||Dang VT,Kassahn KS,Marcos AE,Ragan MA. Identification of human haploinsufficient genes and their genomic proximity to segmental duplicationsEur J Hum GenetYear: 200816111350718523451|
|35.||Ziebarth JD,Bhattacharya A,Chen A,Cui Y. PolymiRTS Database 2.0: linking polymorphisms in microRNA target sites with human diseases and complex traitsNucleic Acids ResYear: 201240Database issueD2162122080514|
|36.||Gong J,Tong Y,Zhang HM,et al. Genome-wide identification of SNPs in microRNA genes and the SNP effects on microRNA target binding and biogenesisHum MutatYear: 20123312546322045659|
|37.||Warde-Farley D,Donaldson SL,Comes O,et al. The GeneMANIA prediction server: biological network integration for gene prioritization and predicting gene functionNucleic Acids ResYear: 201038Web Server issueW2142020576703|
|38.||Montojo J,Zuberi K,Rodriguez H,et al. GeneMANIA Cytoscape plug-in: fast gene function predictions on the desktopBioinformaticsYear: 201026222927820926419|
|39.||Smoot ME,Ono K,Ruscheinski J,Wang PL,Ideker T. Cytoscape 2.8: new features for data integration and network visualizationBioinformaticsYear: 2011273431221149340|
|40.||Munirajan AK,Ando K,Mukai A,et al. KIF1Bbeta functions as a haploinsufficient tumor suppressor gene mapped to chromosome 1p36.2 by inducing apoptotic cell deathJ Biol ChemYear: 200828336244263418614535|
|41.||Jones RG,Thompson CB. Tumor suppressors and cell metabolism: a recipe for cancer growthGenes DevYear: 20092355374819270154|
|42.||Scuoppo C,Miething C,Lindqvist L,et al. A tumor suppressor network relying on the polyamine-hypusine axisNatureYear: 20124877406244822722845|
|43.||Chong MM,Rasmussen JP,Rudensky AY,Littman DR. The RNAseIII enzyme Drosha is critical in T cells for preventing lethal inflammatory diseaseJ Exp MedYear: 2008205920051718725527|
|44.||Moser MJ,Kamath-Loeb AS,Jacob JE,Bennett SE,Oshima J,Monnat RJ Jr. WRN helicase expression in Werner syndrome cell linesNucleic Acids ResYear: 20002826485410606667|
|45.||Depienne C,Bouteiller D,Meneret A,et al. RAD51 haploinsufficiency causes congenital mirror movements in humansAm J Hum GenetYear: 2012902301722305526|
|46.||Kim DH,Park SE,Kim M,et al. A functional single nucleotide polymorphism at the promoter region of cyclin A2 is associated with increased risk of colon, liver, and lung cancersCancerYear: 20111171740809121858804|
|47.||Izeradjene K,Combs C,Best M,et al. Kras(G12D) and Smad4/Dpc4 haplo-insufficiency cooperate to induce mucinous cystic neoplasms and invasive adenocarcinoma of the pancreasCancer CellYear: 20071132294317349581|
|48.||Stefani G,Slack FJ. A ‘pivotal’ new rule for microRNA-mRNA interactionsNat Struct Mol BiolYear: 2012193265622388780|
List of Haploinsufficient genes known to be involved in tumorigenesis.
|ANX7, APC, ARF, ATM, BAG1, BECN1, BRCA1, BRCA2, BUBR1, CAMTA1, CAV1, CDKN1B, CDKN1C, CDKN2B, CSN5, CTCF, DFFB, DIRC2, EEF1E1, ETV6, FBXW7, FOXP1, H2 AX, INI1, INK4C, KLF6, LIG4, LIS1, LKB1, MEL-18, MYH, NHERF1, NKX3–1, NPM1, P53, PAX5, PLK4, PPARA, PPARG, PRKAR1 A, PTCH1, PTEN, RAD50, RASSF1 A, ROR2, RPRM, SAM68, SERCA2, SMAD5, SOCS1, SOX9, SPRED1, ST7, TGFB1, TP53BP2, TP73, TRAPPC2, TSC1, TSC2, VHL, WT1, WWOX, YWHAE||11|
|BIM (BCL2 L11)||17|
|CREBBP (CBP)||49, 47, 5|
|DICER1||32, 2, 41|
|DMP1||25, 51, 34|
|IKZF1 (IKAROS)||39, 29, 52|
|MDM2 and MDM4||50|
|MSH2||12, 13, 6|
|Ribosomal proteins (RPL35, RPL37 A, RPS19 and RPS8)||1|
Supporting information for Table 1.
|Gene||Location||SNP ID||Allele change||miR ID|
|ATM||108237837||rs227091||C to T||hsa-miR-3664-3p, hsa-miR-4433-3p, hsa-miR-4768-3p, hsa-miR-512-5p|
|CDH1||68867609||rs35942505||C to T||hsa-miR-548ae, hsa-miR-548ah-3p, hsa-miR-548aj-3p, hsa-miR-548am-3p, hsa-miR-548aq-3p, hsa-miR-548x-3p|
|DFFB||3800570||rs140704651||C to T||hsa-miR-3664-3p, hsa-miR-4433-3p, hsa-miR-4768-3p, hsa-miR-512-5p|
|KIF1B||10367348||rs142468272||C to A||hsa-miR-4435, hsa-miR-4701-5p, hsa-miR-548s, hsa-miR-588|
|10367422||rs2004034||G to A||hsa-miR-25-3p, hsa-miR-32-5p, hsa-miR-363-3p, hsa-miR-367-3p, hsa-miR-92a-3p, hsa-miR-92b-3p|
|10437247||rs2155760||C to T||hsa-miR-125a-5p, hsa-miR-125b-5p, hsa-miR-4319, hsa-miR-4446-5p, hsa-miR-4732-3p, hsa-miR-4755-5p, hsa-miR-5006-3p, hsa-miR-670|
|MDM2||69236548||rs1690917||G to T||hsa-miR-548ac, hsa-miR-548d-3p, hsa-miR-548h-3p, hsa-miR-548z|
|69238940||rs184278637||G to A||hsa-miR-3609, hsa-miR-4796-3p, hsa-miR-519a-3p, hsa-miR-519b-3p, hsa-miR-519c-3p, hsa-miR-548ah-5p|
|RAD50||131980270||rs75939007||A to G||hsa-miR-199a-3p, hsa-miR-199b-3p, hsa-miR-3129-5p, hsa-miR-936|
|RXRA||137330802||rs10119893||G to A||hsa-miR-1254, hsa-miR-1271-3p, hsa-miR-3116, hsa-miR-550a-3-5p, hsa-miR-550a-5p|
|SMAD4||48610254||rs146551171||T to C||hsa-miR-142-5p, hsa-miR-548a-5p, hsa-miR-548ab, hsa-miR-548ak, hsa-miR-548am-5p, hsa-miR-548ap-5p, hsa-miR-548aq-5p, hsamiR-548ar-5p, hsa-miR-548as-5p, hsa-miR-548au-5p, hsa-miR-548av-5p, hsa-miR-548b-5p, hsa-miR-548c-5p, hsa-miR-548d-5p, hsa-miR-548h-5p, hsa-miR-548i, hsa-miR-548j, hsa-miR-548k, hsamiR-548o-5p, hsa-miR-548w, hsa-miR-548y, hsa-miR-559, hsa-miR- 5590-3p|
|TP53||7574015||rs121912664||G to A||hsa-miR-302a-3p, hsa-miR-302b-3p, hsa-miR-302c-3p, hsa-miR-302d-3p, hsa-miR-302e, hsa-miR-372, hsa-miR-373-3p, hsa-miR-520a-3p, hsa-miR-520b, hsa-miR-520c-3p, hsa-miR- 520d-3p, hsa-miR-520e|
Keywords: haploinsufficiency, microRNA, single nucleotide polymorphism, miR-SNPs, tumor suppressor genes, cancer.
Previous Document: Renal perforation due to the migration of metal cerclage in hip arthroplasty.
Next Document: CT to cone-beam CT deformable registration with simultaneous intensity correction.