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RNASET2 (ribonuclease T2)

Written2014-06Francesco Acquati
Dept of Theoretical, Applied Sciences, University of Insubria - Varese, Italy
This article is an update of :
2007-02Francesco Acquati, Paola Campomenosi
Dept of Theoretical, Applied Sciences, University of Insubria - Varese, Italy

(Note : for Links provided by Atlas : click)


LocusID (NCBI) 8635
Atlas_Id 518
Location 6q27  [Link to chromosome band 6q27]
Location_base_pair Starts at 166922113 and ends at 166956550 bp from pter ( according to GRCh38/hg38-Dec_2013)  [Mapping RNASET2.png]
Local_order Telomeric to RPS6KA2, centromeric to FGFR1OP.
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
RNASET2 (6q27)::RPS6KA2 (6q27)SPRY4 (5q31.3)::RNASET2 (6q27)
Note This gene represents the first human member of the Rh/T2/S-glycoprotein family of extracellular ribonucleases. It belongs to the recently defined class of tumor-antagonizing genes, based on its ability to suppress tumor growth in vivo, but not in vitro. It is likely involved in the pathogenesis of several human neoplasias (both solid and haematological) such as ovarian cancer, melanoma and non-Hodgkin lymphoma.
Mutations in this gene have also been recently described in children affected by a rare congenital neurological defect. Moreover, GWAS studies have recently reported the association of gene variants mapping close to the RNASET2 gene with susceptibilty to a few autoimmune disorders.


  I-IX: RNASET2 exons; Red boxes: CAS I and CAS II catalytic sites; Dark green boxes: untranslated regions.
Description The RNASET2 gene has been mapped in the peritelomeric region of the long arm of human chromosome 6 (6q27), which has been consistently reported to be rearreanged in several human neoplasias. It's coding region is split in 9 exons, spanning approximatly 27 kb of genomic DNA. The translation initiation codon is located in exon 1 and the stop codon in exon 9. Exons III and VI encode the two CAS motifs (Catalytic Active Sites) responsible for the ribonuclease activity of the RNASET2 protein. However, the catalytic activity of the RNASET2 protein is apparently not required for some biological functions, as described for other members of the T2-Rh-S RNase gene family.
Transcription The RNASET2 gene is transcribed in the telomere-to-centromere orientation to produce an ubiquitously expressed mRNA approximately 1,4 kb in length. EST clones representing splice variants of the same gene have been described. Transcription of this gene is rather ubiquitous, with highest expression levels being reported in spleen, pancreas and leukocytes.
Pseudogene A processed pseudogene showing 85% identity with RNASET2 mRNA maps to chromosome 7p11.2. The expression pattern of this pseudogene is not known.


  The RNASET2 protein contains 256 aminoacids. Gold box: signal peptide for secretion (residues 1-24); Gray box: catalytic fold; Red boxes: Conserved Active Sites (CAS I-II); Yellow boxes: putative N-glycosilation sites.
Description The aminoacid sequence of RNASET2 depicts a typical member of the highly conserved Rh7T2/S family of extracellular, acid ribonucleases. The X-ray structure of the protein was recently reported, showing the occurrence of the α+β core fold typically observed in other members of the Rh/T2/S protein family. The catalytic activity of the protein was shown to be significantly inhibited by zinc and copper ions.
Expression In normal human tissues, the RNASET2 protein has been detected in pancreas, stomach, small intestine, colon, salivary glands, liver, thyroid, adrenal glands, lymphoid organs, lungs, melanocytes, ovarian surface and Fallopian tube epithelium. Expression of the RNASET2 protein has also been detected in several human ovarian cancer cell lines and in some melanoma, prostate, pancreatic and breast carcinoma cell lines.
Localisation The full-length RNASET2 protein contains 256 aminoacids and displays an apparent MW of 36 kDa in its secreted form. Two 31 and 27 kDa C-terminal proteolytic products have also been observed intracellularly in several human cancer cell lines. The extracellular RNASET2 protein is detected in cell culture supernatants as the full lenght 36 kDa forms. The intracellular localization pattern of the RNASET2 protein suggests a localization in the secretory compartments (endoplasmic reticulum and Golgi apparatus) but also in lysosomes and processing bodies (P-bodies).
Function Biochemical function: RNASET2 is an acid ribonuclease with optimal activity at pH 5 and preferential cleavage of poly-A and poly-U homo-polyribonucleotides.
Biological function: RNASET2 behaves as a tumor antagonizing gene in ovarian cancer models, since experimental manipulation of this gene's expression levels in human ovarian cancer cell lines is associated with a significant change in their tumorigenic and metastasizing potential in vivo. The oncosuppressive role of this protein in ovarian cancer models is associated with a marked recruitment of cells form the monocyte/macrophage lineage within the tumor mass. In an experimental model of colorectal cancer, recombinant RNASET2 was also found to display a marked oncosuppressive activity. Strikingly, in both models the ribonuclease catalytic activity was apparently dispensable for RNASET2 to play such antioncogenic role. A role for in vivo tumor suppression for RNASET2 has also been established in a model of malignant melanoma.
Moreover, the human RNASET2 gene has been recently implicated in sperm motility and stress-induced apoptosis in melanocytes.
Recent investigations carried out on RNASET2 orthologs have suggested several additional biological roles for this gene family, such as in vivo priming of dendritic cells for Th2-helper response, inhibition of angiogenesis in vivo, ribosomal RNA decay in plants and CNS physiology.
Homology The primary sequenze of RNASET2 shows strong homology to the Rh/T2/S family of secreted ribonucleases.


Note Epigenetics: The RNASET2 gene has been reported to be frequently down-regulated in several human ovarian cancer cell lines and primary tumors. The underlying molecular mechanism is currently unknown.
Germinal A common exon-9 missense C708T germline mutation has been described but no evidence for an association of this allele with human cancer was found.
A missense mutation (550T>C ; C184R) and a 2,5 kb deletion spanning exon 2 were found to segregate in families affected with cystic leukoencephalopathy.
Somatic A few common polymorphisms in exons 1, 8 and 9 have been described. In general, coding mutations are rarely found in tumor samples.

Implicated in

Entity Ovarian cancer
Note Loss of expression or downregulation of RNASET2 occurs in a significant fraction of human ovarian cancer cell lines and primary ovarian tumours. Moreover, the genomic region (chromosome 6q27) where the RNASET2 genes maps has been reported to be frequently deleted or otherwise rearranged in a high fraction of ovarian cancer samples. However, no mutation in the RNASET2 gene have been described so far in human ovarian cancer samples. Therefore, this gene seems to be involved in tumor suppression mainly by means of its downregulation at the transcript/protein level in this cancer type. When overexpressed by gene transfer experiments in human ovarian cancer cell lines displaying a low level of endogenous mRNA, RNASET2 strongly suppresses the tumorigenic and metastatic potential of these cell lines in a murine xenogratf model in vivo. The same observation was reported following a complementary experiment, i.e. by knocking-down RNASET2 expression in a poorly aggressive ovarian cancer cell line expressing high levels of endogenous RNASET2.
In both in vivo models, RNASET2-mediated tumor suppression was associated with a marked recruitment of cells from the monocyte/macrophage lineage in the tumor mass. Further experiments have demonstrated a direct chemotactic role for cells from the monocyte/macrophage carried out by the RNASET2 protein. Very recently, downregulation of RNASET2 expression has been associated with resistance to cis-platin and carboplatin in ovarian cancer cells and tissues.
Entity Malignant melanoma
Note Besides ovarian carcinoma, the chromosome region 6q27 (where the RNASET2 genes maps) has been reported to be frequently deleted or rearranged in malignant melanoma. Downregulation of RNASET2 has also been reported in cell lines representing this cancer type. Overexpression of RNASET2 in the human melanoma-derived SK-MEL28 cell line was associated with a significant suppression of tumor growth in vivo (in a xenograft model with immunocompromised mice), but not in vitro, supporting the notion of RNASET2 as a tumor-antagonizing gene whose oncosuppressive action is carried out asimmetrically, i.e. only in the context of a complex tissue architecture where a significant cross-talk between cancer cells and the stromal compartment take place. Moreover, the T2 RNase protein encoded from the Aspergillus niger ortholog gene has been shown to inhibit human melanoma cell growth and metastasis in a xenograft model. The underlying oncosuppressive mechanism in this model was the inhibition of tumor angiogenesis by means of competitive inhibition with angiogenin.
Entity Colorectal cancer
Note In an HT29 human colon cancer-derived xenograft experimental model, human recombinant RNASET2 was shown to greatly suppress tumor growth in vivo independent from its catalytic activity. Tumor angiogenesis was mainly affected by recombinant RNASET2 injection in this cancer model.
Entity Anaplastic large cell lymphoma
Note More recently, screening of a protein microarray with sera from anaplastic large cell lymphoma (ALCL) patients identified RNASET2 as an ALK-negative ALCL-associated antigen.
Entity Cystic leukoencephalopathy
Disease Several loss-of function mutations have been reported in probands affected by cystic leukoencephalopathy, an autosomal recessive disorder whose clinical and radiological phenotype is indistinguishable with respect to the pattern of brain abnormalities observed in people suffering from congenital cytomegalovirus infection. Affected people develop several neurologic abnormalities in the early post-natal period, including psychomotor defects, seizures and sensorineural hearing impairment, characterized by a diagnostic MRI pattern.
Cytogenetics Six independent mutations in the RNASET2 gene have been reported in both familial and sporadic cases affected by cystic leukoencephalopathy. All mutations are predicted to result in a loss of function phenotype.
Abnormal Protein The C184R mutant RNASET2 protein expressed from the 550T>C allele showed defective intracellular trafficking, likely due to impaired protein folding or stability.
Entity Autoimmune disorders
Disease Genome-wide association studies have recently implicated the RNASET2 locus in the susceptibility for a few autoimmune disorder, such as vitiligo, Crohns' disease and Graves' disease.


Microenvironmental control of malignancy exerted by RNASET2, a widely conserved extracellular RNase.
Acquati F, Bertilaccio S, Grimaldi A, Monti L, Cinquetti R, Bonetti P, Lualdi M, Vidalino L, Fabbri M, Sacco MG, van Rooijen N, Campomenosi P, Vigetti D, Passi A, Riva C, Capella C, Sanvito F, Doglioni C, Gribaldo L, Macchi P, Sica A, Noonan DM, Ghia P, Taramelli R.
Proc Natl Acad Sci U S A. 2011 Jan 18;108(3):1104-9. doi: 10.1073/pnas.1013746108. Epub 2010 Dec 28.
PMID 21189302
Loss of function of Ribonuclease T2, an ancient and phylogenetically conserved RNase, plays a crucial role in ovarian tumorigenesis.
Acquati F, Lualdi M, Bertilaccio S, Monti L, Turconi G, Fabbri M, Grimaldi A, Anselmo A, Inforzato A, Collotta A, Cimetti L, Riva C, Gribaldo L, Ghia P, Taramelli R.
Proc Natl Acad Sci U S A. 2013 May 14;110(20):8140-5. doi: 10.1073/pnas.1222079110. Epub 2013 Apr 29.
PMID 23630276
Cloning and characterization of a senescence inducing and class II tumor suppressor gene in ovarian carcinoma at chromosome region 6q27.
Acquati F, Morelli C, Cinquetti R, Bianchi MG, Porrini D, Varesco L, Gismondi V, Rocchetti R, Talevi S, Possati L, Magnanini C, Tibiletti MG, Bernasconi B, Daidone MG, Shridhar V, Smith DI, Negrini M, Barbanti-Brodano G, Taramelli R.
Oncogene. 2001a Feb 22;20(8):980-8.
PMID 11314033
Molecular cloning, tissue distribution, and chromosomal localization of the human homolog of the R2/Th/Stylar ribonuclease gene family.
Acquati F, Nucci C, Bianchi MG, Gorletta T, Taramelli R.
Methods Mol Biol. 2001b;160:87-101.
PMID 11265308
Tumor and metastasis suppression by the human RNASET2 gene.
Acquati F, Possati L, Ferrante L, Campomenosi P, Talevi S, Bardelli S, Margiotta C, Russo A, Bortoletto E, Rocchetti R, Calza R, Cinquetti R, Monti L, Salis S, Barbanti-Brodano G, Taramelli R.
Int J Oncol. 2005 May;26(5):1159-68.
PMID 15809705
Characterization of RNASET2, the first human member of the Rh/T2/S family of glycoproteins.
Campomenosi P, Salis S, Lindqvist C, Mariani D, Nordstrom T, Acquati F, Taramelli R.
Arch Biochem Biophys. 2006 May 15;449(1-2):17-26. Epub 2006 Mar 13.
PMID 16620762
A genome-wide association study identifies two new risk loci for Graves' disease.
Chu X, Pan CM, Zhao SX, Liang J, Gao GQ, Zhang XM, Yuan GY, Li CG, Xue LQ, Shen M, Liu W, Xie F, Yang SY, Wang HF, Shi JY, Sun WW, Du WH, Zuo CL, Shi JX, Liu BL, Guo CC, Zhan M, Gu ZH, Zhang XN, Sun F, Wang ZQ, Song ZY, Zou CY, Sun WH, Guo T, Cao HM, Ma JH, Han B, Li P, Jiang H, Huang QH, Liang L, Liu LB, Chen G, Su Q, Peng YD, Zhao JJ, Ning G, Chen Z, Chen JL, Chen SJ, Huang W, Song HD; China Consortium for Genetics of Autoimmune Thyroid Disease.
Nat Genet. 2011 Aug 14;43(9):897-901. doi: 10.1038/ng.898.
PMID 21841780
rnaset2 mutant zebrafish model familial cystic leukoencephalopathy and reveal a role for RNase T2 in degrading ribosomal RNA.
Haud N, Kara F, Diekmann S, Henneke M, Willer JR, Hillwig MS, Gregg RG, Macintosh GC, Gartner J, Alia A, Hurlstone AF.
Proc Natl Acad Sci U S A. 2011 Jan 18;108(3):1099-103. doi: 10.1073/pnas.1009811107. Epub 2011 Jan 3.
PMID 21199949
RNASET2-deficient cystic leukoencephalopathy resembles congenital cytomegalovirus brain infection.
Henneke M, Diekmann S, Ohlenbusch A, Kaiser J, Engelbrecht V, Kohlschütter A, Kratzner R, Madruga-Garrido M, Mayer M, Opitz L, Rodriguez D, Ruschendorf F, Schumacher J, Thiele H, Thoms S, Steinfeld R, Nurnberg P, Gartner J.
Nat Genet. 2009 Jul;41(7):773-5. doi: 10.1038/ng.398. Epub 2009 Jun 14.
PMID 19525954
RNASET2 as a tumor antagonizing gene in a melanoma cancer model.
Monti L, Rodolfo M, Lo Russo G, Noonan D, Acquati F, Taramelli R.
Oncol Res. 2008;17(2):69-74.
PMID 18543608
RNASET2--an autoantigen in anaplastic large cell lymphoma identified by protein array analysis.
Patel S, Chen H, Monti L, Gould E, Haralambieva E, Schmid J, Toomey D, Woessmann W, Roncador G, Hatton CS, Liggins AP, Taramelli R, Banham AH, Acquati F, Murphy D, Pulford K.
J Proteomics. 2012 Sep 18;75(17):5279-92. doi: 10.1016/j.jprot.2012.06.009. Epub 2012 Jun 23.
PMID 22732457
Genome-wide association study for vitiligo identifies susceptibility loci at 6q27 and the MHC.
Quan C, Ren YQ, Xiang LH, Sun LD, Xu AE, Gao XH, Chen HD, Pu XM, Wu RN, Liang CZ, Li JB, Gao TW, Zhang JZ, Wang XL, Wang J, Yang RY, Liang L, Yu JB, Zuo XB, Zhang SQ, Zhang SM, Chen G, Zheng XD, Li P, Zhu J, Li YW, Wei XD, Hong WS, Ye Y, Zhang Y, Wu WS, Cheng H, Dong PL, Hu DY, Li Y, Li M, Zhang X, Tang HY, Tang XF, Xu SX, He SM, Lv YM, Shen M, Jiang HQ, Wang Y, Li K, Kang XJ, Liu YQ, Sun L, Liu ZF, Xie SQ, Zhu CY, Xu Q, Gao JP, Hu WL, Ni C, Pan TM, Li Y, Yao S, He CF, Liu YS, Yu ZY, Yin XY, Zhang FY, Yang S, Zhou Y, Zhang XJ.
Nat Genet. 2010 Jul;42(7):614-8. doi: 10.1038/ng.603. Epub 2010 Jun 6.
PMID 20526339
Mammalian Rh/T2/S-glycoprotein ribonuclease family genes: cloning of a human member located in a region of chromosome 6 (6q27) frequently deleted in human malignancies.
Trubia M, Sessa L, Taramelli R.
Genomics. 1997 Jun 1;42(2):342-4.
PMID 9192857
Stress-induced RNASET2 overexpression mediates melanocyte apoptosis via the TRAF2 pathway in vitro.
Wang Q, Jiang M, Wu J, Ma Y, Li T, Chen Q, Zhang X, Xiang L.
Cell Death Dis. 2014 Jan 23;5:e1022. doi: 10.1038/cddis.2013.539.
PMID 24457966
Genome-wide association study of Crohn's disease in Koreans revealed three new susceptibility loci and common attributes of genetic susceptibility across ethnic populations.
Yang SK, Hong M, Zhao W, Jung Y, Baek J, Tayebi N, Kim KM, Ye BD, Kim KJ, Park SH, Lee I, Lee EJ, Kim WH, Cheon JH, Kim YH, Jang BI, Kim HS, Choi JH, Koo JS, Lee JH, Jung SA, Lee YJ, Jang JY, Shin HD, Kang D, Youn HS, Liu J, Song K.
Gut. 2014 Jan;63(1):80-7. doi: 10.1136/gutjnl-2013-305193. Epub 2013 Jul 14.
PMID 23850713


This paper should be referenced as such :
F Acquati
RNASET2 (ribonuclease T2)
Atlas Genet Cytogenet Oncol Haematol. 2015;19(4):240-244.
Free journal version : [ pdf ]   [ DOI ]
History of this paper:
Campomenosi, P ; Acquati, F. RNASET2 (ribonuclease T2). Atlas Genet Cytogenet Oncol Haematol. 2007;11(3):219-221.

External links


HGNC (Hugo)RNASET2   21686
Entrez_Gene (NCBI)RNASET2    ribonuclease T2
AliasesRNASE6PL; bA514O12.3
GeneCards (Weizmann)RNASET2
Ensembl hg19 (Hinxton)ENSG00000026297 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000026297 [Gene_View]  ENSG00000026297 [Sequence]  chr6:166922113-166956550 [Contig_View]  RNASET2 [Vega]
ICGC DataPortalENSG00000026297
Genatlas (Paris)RNASET2
Genetics Home Reference (NIH)RNASET2
Genomic and cartography
GoldenPath hg38 (UCSC)RNASET2  -     chr6:166922113-166956550 -  6q27   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)RNASET2  -     6q27   [Description]    (hg19-Feb_2009)
GoldenPathRNASET2 - 6q27 [CytoView hg19]  RNASET2 - 6q27 [CytoView hg38]
Genome Data Viewer NCBIRNASET2 [Mapview hg19]  
OMIM612944   612951   
Gene and transcription
Genbank (Entrez)AJ419865 AJ419866 AJ419867 AK001769 AK124363
RefSeq transcript (Entrez)NM_003730
Consensus coding sequences : CCDS (NCBI)RNASET2
Gene Expression Viewer (FireBrowse)RNASET2 [ Firebrowse - Broad ]
GenevisibleExpression of RNASET2 in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)8635
GTEX Portal (Tissue expression)RNASET2
Human Protein AtlasENSG00000026297-RNASET2 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtO00584   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtO00584  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProO00584
Domaine pattern : Prosite (Expaxy)RNASE_T2_1 (PS00530)    RNASE_T2_2 (PS00531)   
Domains : Interpro (EBI)Ribonuclease_T2_eukaryotic    RNase_T2-like    RNase_T2-like_sf    RNase_T2_His_AS_1    RNase_T2_His_AS_2   
Domain families : Pfam (Sanger)Ribonuclease_T2 (PF00445)   
Domain families : Pfam (NCBI)pfam00445   
Conserved Domain (NCBI)RNASET2
PDB Europe3T0O   
PDB (PDBSum)3T0O   
PDB (IMB)3T0O   
Structural Biology KnowledgeBase3T0O   
SCOP (Structural Classification of Proteins)3T0O   
CATH (Classification of proteins structures)3T0O   
AlphaFold pdb e-kbO00584   
Human Protein Atlas [tissue]ENSG00000026297-RNASET2 [tissue]
Protein Interaction databases
IntAct (EBI)O00584
Ontologies - Pathways
Ontology : AmiGORNA binding  endoribonuclease activity  ribonuclease activity  extracellular region  extracellular region  extracellular space  extracellular space  mitochondrial intermembrane space  lysosome  endoplasmic reticulum lumen  RNA catabolic process  RNA catabolic process  lyase activity  ribonuclease T2 activity  azurophil granule lumen  lysosomal lumen  neutrophil degranulation  innate immune response  extracellular exosome  RNA phosphodiester bond hydrolysis, endonucleolytic  
Ontology : EGO-EBIRNA binding  endoribonuclease activity  ribonuclease activity  extracellular region  extracellular region  extracellular space  extracellular space  mitochondrial intermembrane space  lysosome  endoplasmic reticulum lumen  RNA catabolic process  RNA catabolic process  lyase activity  ribonuclease T2 activity  azurophil granule lumen  lysosomal lumen  neutrophil degranulation  innate immune response  extracellular exosome  RNA phosphodiester bond hydrolysis, endonucleolytic  
REACTOMEO00584 [protein]
REACTOME PathwaysR-HSA-6798695 [pathway]   
Atlas of Cancer Signalling NetworkRNASET2
Wikipedia pathwaysRNASET2
Orthology - Evolution
GeneTree (enSembl)ENSG00000026297
Phylogenetic Trees/Animal Genes : TreeFamRNASET2
Homologs : HomoloGeneRNASET2
Homology/Alignments : Family Browser (UCSC)RNASET2
Gene fusions - Rearrangements
Fusion : QuiverRNASET2
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerRNASET2 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)RNASET2
Exome Variant ServerRNASET2
GNOMAD BrowserENSG00000026297
Varsome BrowserRNASET2
ACMGRNASET2 variants
Genomic Variants (DGV)RNASET2 [DGVbeta]
DECIPHERRNASET2 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisRNASET2 
ICGC Data PortalRNASET2 
TCGA Data PortalRNASET2 
Broad Tumor PortalRNASET2
OASIS PortalRNASET2 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICRNASET2  [overview]  [genome browser]  [tissue]  [distribution]  
Somatic Mutations in Cancer : COSMIC3DRNASET2
Mutations and Diseases : HGMDRNASET2
LOVD (Leiden Open Variation Database)[gene] [transcripts] [variants]
DgiDB (Drug Gene Interaction Database)RNASET2
DoCM (Curated mutations)RNASET2
CIViC (Clinical Interpretations of Variants in Cancer)RNASET2
Impact of mutations[PolyPhen2] [Provean] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
OMIM612944    612951   
Genetic Testing Registry RNASET2
NextProtO00584 [Medical]
Target ValidationRNASET2
Huge Navigator RNASET2 [HugePedia]
Clinical trials, drugs, therapy
Protein Interactions : CTDRNASET2
Pharm GKB GenePA128394541
Clinical trialRNASET2
DataMed IndexRNASET2
PubMed60 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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