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ATG2B (Autophagy-related 2B)

Written2016-10Christine Bellanné-Chantelot, Isabelle Plo
Département de Génétique, Hôpitaux Universitaires Pitié-Salpétrière-Charles Foix, Paris (CBC); INSERM UMR1170, Institut Gustave Roussy, Villejuif, (CBC, IP), France. christine.bellanne-chantelot@aphp.fr; isabelle.plo@gustaveroussy.fr

Abstract Autophagy is a cellular process involved in the sequestration of cytosolic components and their degradation by lysosomes. Autophagy has been involved in physiological responses to stress or aging and in the development of many human diseases including solid and haematological cancers. In humans, 16 autophagy-related genes are known. The ATG2B protein is involved in the late steps of the autophagy process i.e. the formation of autophagosomes that fuse with lysosomes before degradation. Loss-of -function (frameshift) acquired mutations of ATG2B have been identified in gastric and colorectal carcinomas with high microsatellite instability. Both pharmacologic and genetic evidence indicate that autophagy plays pleiotropic functions in hematopoietic cell homeostasis and leukemogeneis. Autophagy could exert two opposite roles (cell death and survival) depending on the nature of the hematopoietic malignancy.
The germline duplication of ATG2B and GSKIP, both located in 14q32.2, predisposes to the development of familial myeloproliferative neoplasms with autosomal dominant inheritance, in particular essential thrombocythemia progressing to leukemia. Overexpression of ATG2B and GSKIP enhances megakaryocyte progenitor differentiation by increasing progenitor sensitivity to thrombopoietin. Both genes cooperate with somatic JAK2, MPL and CALR mutations and their overexpression provides a growth advantage to hematopoietic cells carrying these driver mutations that may explain the familial aggregation and the progression of essential thrombocythemia to myelofibrosis and leukemia.

Keywords ATG2B; Myeloproliferative neoplasms (MPN); essential thrombocythemia; myelofibrosis; leukemia; predisposition; ATG2B/GSKIP; chromosome 14; CNV; autophagy; Wnt/beta-catenin pathway

(Note : for Links provided by Atlas : click)

Identity

Alias_namesC14orf103
chromosome 14 open reading frame 103
ATG2 autophagy related 2 homolog B (S. cerevisiae)
Alias_symbol (synonym)FLJ10242
Other alias
HGNC (Hugo) ATG2B
LocusID (NCBI) 55102
Atlas_Id 55326
Location 14q32.2  [Link to chromosome band 14q32]
Location_base_pair Starts at 96279202 and ends at 96363401 bp from pter ( according to hg19-Feb_2009)  [Mapping ATG2B.png]
Local_order telomere to centromere.
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
ATG2B (14q32.2) / SLC22A17 (14q11.2)
Note cooperates with GSKIP, also located in 14q32.2 and included in the 700 kb duplication NC_000014.9:g.96.163.103_96.857.129dup (on Assembly GRCh37)

DNA/RNA

Description The ATG2B gene consists of 42 exons spanning a region of 82.08 kb.
Transcription A single mRNA transcript (NM_018036.6) of the ATG2B gene, with a total length of 6234 nucleotides, has been annotated.
Pseudogene Not yet identified.

Protein

Description The protein encoded by the ATG2B gene is the autophagy-related protein 2 homolog B of 2078 amino acids, with a calculated molecular mass of 232.8 kDa
Expression Expression of ATG2B has been detected in various normal human tissues (bone marrow, whole blood, thymus, brain, heart, muscle, colon, kidney, liver, lung, pancreas, thyroid, salivary and adrenal glands, skin, ovary, uterus, placenta, prostate and testis).
In hematopoietic cells, ATG2B is expressed in CD34+ purified hematopoietic progenitors and CD36+ erythroblasts or CD41+ megakaryocytes derived from CD34+ progenitors cultured in vitro (Saliba et al, 2016)
Localisation ATG2B is mainly localized in the nucleus.
Function Autophagy is an intracellular degradation system by which cytoplasmic materials are enclosed by the autophagosomes and transferred to lysosomes before degradation. The autophagy process has been extensively studied in yeast; 35 autophagy-related genes (ATG) have been identified, of which 16 are currently known in humans . This cellular process is a highly conserved among species. In humans, two ATG2 proteins, ATG2A and ATG2B, have redundant functions and are required for autophagosome formation (Velikkakath AK et al , 2012).
Homology 44.5% of human ATG2B residues are identical to those of human ATG2A.

Mutations

Germinal A germline 14q32.2 head-to-tail duplication of 700 kb has been associated with familial myeloid malignancies (Saliba et al , 2015). The germline duplication includes the genes TCL1A, GSKIP, ATG2B, BDKRB1, BDKRB2 and the first exon of AK7. The overexpression of ATG2B and GSKIP that are expressed in myeloid cells, enhances hematopoietic progenitor differentiation, particularly of megacaryocytes. The development of myeloid malignancies required the cooperation of both genes with the myeloproliferative neoplasms (MPN) driver JAK2 Val617Phe mutation, MPL or CALR mutations. The mechanism of cooperation between ATG2B and GSKIP with MPN driver mutations remains unknown.
The germline duplication with the same distal and proximal breakpoints has only been identified in MPN families originated from West Indies (Martinique) suggesting a founder effect.
Somatic A loss-of-function somatic mutation (c.3120delA, p.Lys1040fs) in gastric carcinomas (15.6%) and in colorectal carcinomas (11.6%) (Klionsky DJ, 2009).

Implicated in

  
Entity Familial myeloproliferative neoplasms (MPN)
Disease Familial MPN, in particular, essential thrombocythemia progressing to myelofibrosis and/or acute myeloid leukemia and primary myelofibrosis, with autosomal dominant inheritance and originated from West-indies (Martinique) may be linked to ATG2B/GSKIP germline duplication. The predisposition is highly penetrant (80%) and is characterized by an earlier age of MPN onset in comparison to sporadic cases (41 years versus > 60 years). The spectrum of acquired driver mutations (JAK2 Val617Phe, MPL and CALR mutations) is similar to the spectrum of mutations in sporadic MPN cases.
Prognosis The percentage of transformation is close to 50% in these familial MPN cases and is related to the detection of mutations affecting epigenetic regulator genes such as TET2 IDH1 or IDH2.
  
  
Entity Acute myeloid leukemia (AML)
Disease AML originated from West-indies (Martinique) may be linked to ATG2B/GSKIP germline duplication.
Prognosis The prognosis of the disease is also linked to the detection of acquired mutations in TET2, IDH1 or in IDH2. No TP53 mutation was found, contrary to what was observed in AML evolving from MPN, suggesting a different pathway for leukemic transformation.
  
  
Entity Gastric carcinoma
Note Loss-of-functions somatic mutations in ATG genes (ATG2B, ATG5, ATG9B and ATG12) are identified in 28% of gastric carcinomas with high microsatellite instability. These mutations may contribute to cancer development by deregulating the autophagy process (Kang et al, 2009).
  
  
Entity Colorectal cancer
Note Loss-of-functions somatic mutations in ATG genes (ATG2B, ATG5, ATG9B and ATG12) are identified in 28% of colorectal carcinomas with high microsatellite instability. These mutations may contribute to cancer development by deregulating the autophagy process (Kang et al, 2009).
  

Bibliography

Frameshift mutations of autophagy-related genes ATG2B, ATG5, ATG9B and ATG12 in gastric and colorectal cancers with microsatellite instability.
Kang MR, Kim MS, Oh JE, Kim YR, Song SY, Kim SS, Ahn CH, Yoo NJ, Lee SH
J Pathol; 2009;217:702-6
PMID 19197948
 
Autophagy: from phenomenology to molecular understanding in less than a decade.
Klionsky DJ.
Nat Rev Mol Cell Biol 2007;8:931-937.
PMID 17712358
 
Germline duplication of ATG2B and GSKIP predisposes to familial myeloid malignancies
Saliba J, Saint-Martin C, Di Stefano A, Lenglet G, Marty C, Keren B, Pasquier F, Valle VD, Secardin L, Leroy G, Mahfoudhi E, Grosjean S, Droin N, Diop M, Dessen P, Charrier S, Palazzo A, Merlevede J, Meniane JC, Delaunay-Darivon C, Fuseau P, Isnard F, Casadevall N, Solary E, Debili N, Bernard OA, Raslova H, Najman A, Vainchenker W, Bellanné-Chantelot C, Plo I
Nat Genet. 2015;47:1131-40
PMID 26280900
 
Autophagy: from phenomenology to molecular understanding in less than a decade.
Velikkakath AK, Nishimura T, Oita E, Ishihara N, Mizushima N.
Mol Biol Cell. 201;23:896-909.
PMID 22219374
 

Citation

This paper should be referenced as such :
Bellanné-Chantelot C, Plo I
ATG2B (Autophagy-related 2B);
Atlas Genet Cytogenet Oncol Haematol. in press
On line version : http://AtlasGeneticsOncology.org/Genes/ATG2BID55326ch14q32.html


Other Cancer prone implicated (Data extracted from papers in the Atlas) [ 1 ]
  Familial Myeloproliferative Disorders


External links

Nomenclature
HGNC (Hugo)ATG2B   20187
Cards
AtlasATG2BID55326ch14q32
Entrez_Gene (NCBI)ATG2B  55102  autophagy related 2B
AliasesC14orf103
GeneCards (Weizmann)ATG2B
Ensembl hg19 (Hinxton)ENSG00000066739 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000066739 [Gene_View]  chr14:96279202-96363401 [Contig_View]  ATG2B [Vega]
ICGC DataPortalENSG00000066739
TCGA cBioPortalATG2B
AceView (NCBI)ATG2B
Genatlas (Paris)ATG2B
WikiGenes55102
SOURCE (Princeton)ATG2B
Genetics Home Reference (NIH)ATG2B
Genomic and cartography
GoldenPath hg38 (UCSC)ATG2B  -     chr14:96279202-96363401 -  14q32.2   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)ATG2B  -     14q32.2   [Description]    (hg19-Feb_2009)
EnsemblATG2B - 14q32.2 [CytoView hg19]  ATG2B - 14q32.2 [CytoView hg38]
Mapping of homologs : NCBIATG2B [Mapview hg19]  ATG2B [Mapview hg38]
OMIM616226   
Gene and transcription
Genbank (Entrez)AK001104 AK055200 AK123451 AK128275 AK302641
RefSeq transcript (Entrez)NM_018036
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)ATG2B
Cluster EST : UnigeneHs.609306 [ NCBI ]
CGAP (NCI)Hs.609306
Alternative Splicing GalleryENSG00000066739
Gene ExpressionATG2B [ NCBI-GEO ]   ATG2B [ EBI - ARRAY_EXPRESS ]   ATG2B [ SEEK ]   ATG2B [ MEM ]
Gene Expression Viewer (FireBrowse)ATG2B [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevestigatorExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)55102
GTEX Portal (Tissue expression)ATG2B
Human Protein AtlasENSG00000066739-ATG2B [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ96BY7   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ96BY7  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ96BY7
Splice isoforms : SwissVarQ96BY7
PhosPhoSitePlusQ96BY7
Domains : Interpro (EBI)ATG2    ATG2_CAD_motif    Autophagy-rel_C    VPS13_N   
Domain families : Pfam (Sanger)ATG2_CAD (PF13329)    ATG_C (PF09333)    Chorein_N (PF12624)   
Domain families : Pfam (NCBI)pfam13329    pfam09333    pfam12624   
Conserved Domain (NCBI)ATG2B
DMDM Disease mutations55102
Blocks (Seattle)ATG2B
SuperfamilyQ96BY7
Human Protein Atlas [tissue]ENSG00000066739-ATG2B [tissue]
Peptide AtlasQ96BY7
HPRD12626
IPIIPI00872410   
Protein Interaction databases
DIP (DOE-UCLA)Q96BY7
IntAct (EBI)Q96BY7
FunCoupENSG00000066739
BioGRIDATG2B
STRING (EMBL)ATG2B
ZODIACATG2B
Ontologies - Pathways
QuickGOQ96BY7
Ontology : AmiGOautophagosome assembly  pre-autophagosomal structure  mitophagy  lipid particle  extrinsic component of membrane  pre-autophagosomal structure membrane  nucleophagy  
Ontology : EGO-EBIautophagosome assembly  pre-autophagosomal structure  mitophagy  lipid particle  extrinsic component of membrane  pre-autophagosomal structure membrane  nucleophagy  
NDEx NetworkATG2B
Atlas of Cancer Signalling NetworkATG2B
Wikipedia pathwaysATG2B
Orthology - Evolution
OrthoDB55102
GeneTree (enSembl)ENSG00000066739
Phylogenetic Trees/Animal Genes : TreeFamATG2B
HOVERGENQ96BY7
HOGENOMQ96BY7
Homologs : HomoloGeneATG2B
Homology/Alignments : Family Browser (UCSC)ATG2B
Gene fusions - Rearrangements
Fusion : MitelmanATG2B/SLC22A17 [14q32.2/14q11.2]  
Fusion: TCGA_MDACCATG2B 14q32.2 SLC22A17 14q11.2 BLCA
Tumor Fusion PortalATG2B
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerATG2B [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)ATG2B
dbVarATG2B
ClinVarATG2B
1000_GenomesATG2B 
Exome Variant ServerATG2B
ExAC (Exome Aggregation Consortium)ENSG00000066739
GNOMAD BrowserENSG00000066739
Genetic variants : HAPMAP55102
Genomic Variants (DGV)ATG2B [DGVbeta]
DECIPHERATG2B [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisATG2B 
Mutations
ICGC Data PortalATG2B 
TCGA Data PortalATG2B 
Broad Tumor PortalATG2B
OASIS PortalATG2B [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICATG2B  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDATG2B
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch ATG2B
DgiDB (Drug Gene Interaction Database)ATG2B
DoCM (Curated mutations)ATG2B (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)ATG2B (select a term)
intoGenATG2B
NCG5 (London)ATG2B
Cancer3DATG2B(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM616226   
Orphanet
DisGeNETATG2B
MedgenATG2B
Genetic Testing Registry ATG2B
NextProtQ96BY7 [Medical]
TSGene55102
GENETestsATG2B
Target ValidationATG2B
Huge Navigator ATG2B [HugePedia]
snp3D : Map Gene to Disease55102
BioCentury BCIQATG2B
ClinGenATG2B
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD55102
Chemical/Pharm GKB GenePA162377102
Clinical trialATG2B
Miscellaneous
canSAR (ICR)ATG2B (select the gene name)
Probes
Litterature
PubMed18 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineATG2B
EVEXATG2B
GoPubMedATG2B
iHOPATG2B
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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indexed on : Tue Nov 21 14:44:30 CET 2017

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