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CDKN2A (cyclin dependent kinase 2a / p16)

Written2007-08Raphael Saffroy, Antoinette Lemoine, Brigitte Debuire
Laboratoire de Biochimie Biologie moléculaire, Hôpital Paul Brousse 94800 Villejuif, France
This article is an update of :
2004-08Raphael Saffroy, Antoinette Lemoine, Brigitte Debuire
Laboratoire de Biochimie Biologie moléculaire, Hôpital Paul Brousse 94800 Villejuif, France

(Note : for Links provided by Atlas : click)

Identity

Alias (NCBI)CDKN2a
p16
INK4
p16- INK4a
TP16
CDK4I
MTS1
HGNC (Hugo) CDKN2A
HGNC Alias symbCDK4I
p16
INK4a
MTS1
CMM2
ARF
p19
p14
INK4
p16INK4a
p19Arf
p14ARF
HGNC Previous nameCDKN2
 MLM
HGNC Previous namecyclin-dependent kinase inhibitor 2A (melanoma, p16, inhibits CDK4)
LocusID (NCBI) 1029
Atlas_Id 146
Location 9p21.3  [Link to chromosome band 9p21]
Location_base_pair Starts at 21967752 and ends at 21974827 bp from pter ( according to GRCh38/hg38-Dec_2013)  [Mapping CDKN2A.png]
 
  Probe(s) - Courtesy Mariano Rocchi, Resources for Molecular Cytogenetics
 
  CDKN2A (cyclin dependent kinase 2a / p16) Hybridization with Vysis CDKN2A/CEP 9 FISH Probe (Abbott Molecular, US) showing the CDKN2A gene on 9p21.3 (red signals) - Courtesy Adriana Zamecnikova.
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
ADAMTSL1 (9p22.2)::CDKN2A (9p21.3)CDKN2A (9p21.3)::CDKN2A (9p21.3)CDKN2A (9p21.3)::CDKN2B (9p21.3)
CDKN2A (9p21.3)::CDKN2B-AS1 (9p21.3)CDKN2A (9p21.3)::FAM230A (22q11.21)CDKN2A (9p21.3)::FOCAD (9p21.3)
CDKN2A (9p21.3)::IFNWP19 (9p22)CDKN2A (9p21.3)::MGA (15q15.1)CDKN2A (9p21.3)::MTAP (9p21.3)
CDKN2A (9p21.3)::SRGAP2 (1q32.1)FOCAD (9p21.3)::CDKN2A (9p21.3)GID4 (17p11.2)::CDKN2A (9p21.3)
MGA (15q15.1)::CDKN2A (9p21.3)MTAP (9p21.3)::CDKN2A (9p21.3)STPG1 (1p36.11)::CDKN2A (9p21.3)

DNA/RNA

Description The gene encompasses 6.6 kb of DNA; 3 exons.
Transcription 471 nucleotides mRNA. The CDKN2 gene generates several transcript variants from different promoters. Each transcript differs in its first exon (E1), and utilizes alternate polyadenylation sites. E1-alpha, which is spliced into the common exons E2 and E3, gives rise to the p16-INK4 transcript. A putative DNA replication origin has been identified in close proximity of INK4/Arf locus that appears to transcriptionally repress p16 in a manner dependent on CDC6.

Protein

Description 156 amino acids; 16.5 kDa protein.
Expression Moderately expressed in many organs as thymus, liver, pancreas, prostate, lung, or kidney.
Function P16-INK4a interacts strongly with cyclin-dependent kinase 4 and cyclin-dependent kinase 6 and inhibits their ability to interact with cyclins D. P16-INK4a induces cell cycle arrest at G1 and G2/M checkpoints, blocking them from phosphorylating RB1 and preventing exit from G1 phase of the cell cycle. P16-INK4a could act as a negative regulator of normal cells proliferation.
Homology Belongs to the cdkn2 cyclin-dependent kinase inhibitor family.

Implicated in

Note
  
Entity
Disease Malignant melanoma arises de novo or from a preexisting benign nevus, which occurs most often in the skin but also may involve other sites.
Oncogenesis Familial melanoma (comprising between 8 and 12% of all melanoma cases) is a genodermatosis transmitted as an autosomal dominant trait. CDKN2a has been identified as a major susceptibility gene for melanoma. However this gene accounts for a minority of familial melanoma. P16 is functionally inactivated by mutations or deletions, however, because many such mutations occur in exon 2, they can potentially also affect the alternative reading frame (ARF) protein.
  
  
Entity
Disease Patients with the FAMMM syndrome are genetically loaded with an increased risk of developing melanoma and other malignant neoplasms, for example, a pancreatic cancer.
Oncogenesis FAMMM syndrome is an autosomal dominant disorder with variable incomplete penetrance of the clinical phenotypes. Germline mutations in the p16-INK4a gene were found in approximately 40% of the FAMMM syndrome.
  
  
Entity Sporadic cancer
Disease Defects in CDKN2a are involved in tumor formation in a wide range of tissues.
Prognosis Aberrant p16 expression is associated with more aggressive behavior.
Oncogenesis LOH on 9p21 is one of the most frequent genetic alterations identified in human cancer. However, point mutations of p16 on the other chromosome are relatively rare. Promoter methylation appears as the commonest mechanism of p16 gene inactivation.
  
  
Entity Aging
Note Expression of p16 increases markedly with aging in many human tissues. This finding has led to the proposal that p16 expression could be used as a biomarker of physiologic, as opposed to chronologic, age. It was suggested that an age-induced increase in p16 expression contributes to the decline of replicative potential of certain self-renewing compartments with aging.
  

Bibliography

Frequent mutations of CDKN2 in primary pancreatic adenocarcinomas.
Bartsch D, Shevlin DW, Tung WS, Kisker O, Wells SA Jr, Goodfellow PJ
Genes, chromosomes & cancer. 1995 ; 14 (3) : 189-195.
PMID 8589035
 
Frequency of homozygous deletion at p16/CDKN2 in primary human tumours.
Cairns P, Polascik TJ, Eby Y, Tokino K, Califano J, Merlo A, Mao L, Herath J, Jenkins R, Westra W
Nature genetics. 1995 ; 11 (2) : 210-212.
PMID 7550353
 
Cytogenetic analysis of melanocytes from premalignant nevi and melanomas.
Cowan JM, Halaban R, Francke U
Journal of the National Cancer Institute. 1988 ; 80 (14) : 1159-1164.
PMID 3166071
 
FAMMM syndrome: pathogenesis and management.
Czajkowski R, Placek W, Drewa G, Czajkowska A, Uchańska G
Dermatologic surgery : official publication for American Society for Dermatologic Surgery [et al.]. 2004 ; 30 (2 Pt 2) : 291-296.
PMID 14871223
 
The CDKN2A (p16) gene and human cancer.
Foulkes WD, Flanders TY, Pollock PM, Hayward NK
Molecular medicine (Cambridge, Mass.). 1997 ; 3 (1) : 5-20.
PMID 9132280
 
Oncogenic activity of Cdc6 through repression of the INK4/ARF locus.
Gonzalez S, Klatt P, Delgado S, Conde E, Lopez-Rios F, Sanchez-Cespedes M, Mendez J, Antequera F, Serrano M
Nature. 2006 ; 440 (7084) : 702-706.
PMID 16572177
 
Germline p16 mutations in familial melanoma.
Hussussian CJ, Struewing JP, Goldstein AM, Higgins PA, Ally DS, Sheahan MD, Clark WH Jr, Tucker MA, Dracopoli NC
Nature genetics. 1994 ; 8 (1) : 15-21.
PMID 7987387
 
A cell cycle regulator potentially involved in genesis of many tumor types.
Kamb A, Gruis NA, Weaver-Feldhaus J, Liu Q, Harshman K, Tavtigian SV, Stockert E, Day RS 3rd, Johnson BE, Skolnick MH
Science (New York, N.Y.). 1994 ; 264 (5157) : 436-440.
PMID 8153634
 
Tumour-derived p16 alleles encoding proteins defective in cell-cycle inhibition.
Koh J, Enders GH, Dynlacht BD, Harlow E
Nature. 1995 ; 375 (6531) : 506-510.
PMID 7777061
 
Loss of p16Ink4a confers susceptibility to metastatic melanoma in mice.
Krimpenfort P, Quon KC, Mooi WJ, Loonstra A, Berns A
Nature. 2001 ; 413 (6851) : 83-86.
PMID 11544530
 
p16INK4a induces an age-dependent decline in islet regenerative potential.
Krishnamurthy J, Ramsey MR, Ligon KL, Torrice C, Koh A, Bonner-Weir S, Sharpless NE
Nature. 2006 ; 443 (7110) : 453-457.
PMID 16957737
 
Methylation and p16: suppressing the suppressor.
Little M, Wainwright B
Nature medicine. 1995 ; 1 (7) : 633-634.
PMID 7585141
 
5' CpG island methylation is associated with transcriptional silencing of the tumour suppressor p16/CDKN2/MTS1 in human cancers.
Merlo A, Herman JG, Mao L, Lee DJ, Gabrielson E, Burger PC, Baylin SB, Sidransky D
Nature medicine. 1995 ; 1 (7) : 686-692.
PMID 7585152
 
Cancer-associated mutations at the INK4a locus cancel cell cycle arrest by p16INK4a but not by the alternative reading frame protein p19ARF.
Quelle DE, Cheng M, Ashmun RA, Sherr CJ
Proceedings of the National Academy of Sciences of the United States of America. 1997 ; 94 (2) : 669-673.
PMID 9012842
 
Alternative reading frames of the INK4a tumor suppressor gene encode two unrelated proteins capable of inducing cell cycle arrest.
Quelle DE, Zindy F, Ashmun RA, Sherr CJ
Cell. 1995 ; 83 (6) : 993-1000.
PMID 8521522
 
A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4.
Serrano M, Hannon GJ, Beach D
Nature. 1993 ; 366 (6456) : 704-707.
PMID 8259215
 
Role of the INK4a locus in tumor suppression and cell mortality.
Serrano M, Lee H, Chin L, Cordon-Cardo C, Beach D, DePinho RA
Cell. 1996 ; 85 (1) : 27-37.
PMID 8620534
 
The INK4a/ARF locus and melanoma.
Sharpless E, Chin L
Oncogene. 2003 ; 22 (20) : 3092-3098.
PMID 12789286
 
Loss of p16Ink4a with retention of p19Arf predisposes mice to tumorigenesis.
Sharpless NE, Bardeesy N, Lee KH, Carrasco D, Castrillon DH, Aguirre AJ, Wu EA, Horner JW, DePinho RA
Nature. 2001 ; 413 (6851) : 86-91.
PMID 11544531
 
Complex structure and regulation of the P16 (MTS1) locus.
Stone S, Jiang P, Dayananth P, Tavtigian SV, Katcher H, Parry D, Peters G, Kamb A
Cancer research. 1995 ; 55 (14) : 2988-2994.
PMID 7606716
 

Citation

This paper should be referenced as such :
Saffroy, R ; Lemoine, A ; Debuire, B
CDKN2a (cyclin dependent kinase 2a / p16)
Atlas Genet Cytogenet Oncol Haematol. 2008;12(2):89-90.
Free journal version : [ pdf ]   [ DOI ]
History of this paper:
Saffroy, R ; Lemoine, A ; Debuire, B. CDKN2a (cyclin dependent kinase 2a / p16). Atlas Genet Cytogenet Oncol Haematol. 2004;8(4):280-281.
http://documents.irevues.inist.fr/bitstream/handle/2042/38121/08-2004-CDKN2aID146.pdf


Other Leukemias implicated (Data extracted from papers in the Atlas) [ 28 ]
  9p Rearrangements in ALL
Acute Lymphoblastic Leukemia with Hypereosinophilia
Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN)
Burkitt's lymphoma (BL)
Chronic myelogenous leukaemia (CML)
del(5)(q32q33) EBF1::PDGFRB
del(9p) in Acute Lymphoblastic Leukemia
dic(9;12)(p13;p13) PAX5::ETV6
Primary cutaneous DLBCL, leg type
Follicular Dendritic Cell Sarcoma
Follicular lymphoma (FL)
Nasal T cell lymphoma (published in 2008)
Pediatric T-Cell Acute Lymphoblastic Leukemia
Primary Cutaneous B-Cell Lymphomas
t(3;5)(q25;q34) NPM1::MLF1
t(5;9)(q35;q34) SQSTM1::NUP214
t(6;14)(p22;q32) IGH::ID4
t(7;12)(q34;p13) TRB::CCND2::t(12;14)(p13;q11) TRA or TRD::CCND2
t(9;14)(q34;q32) EML1::ABL1
TAL1 (1p32) deletion in lymphoid malignancies
T-lineage acute lymphoblastic leukemia (T-ALL)
Classification of T-Cell disorders
Therapy-Related Hematopoietic Neoplasia
t(2;9)(p11;p21) CDKN2A::IGK
t(9;9)(p21;p21) CDKN2A::IFNWP19
t(9;9)(p21;p21) CDKN2A::MTAP
t(9;14)(p21;q11) CDKN2A::TRA
t(9;14)(p21;q11) TRA::CDKN2A


Other Cancer prone implicated (Data extracted from papers in the Atlas) [ 6 ]
  Dysplastic nevus syndrome (DNS) Familial glioma Familial melanoma Hereditary pancreatic cancer Li-Fraumeni syndrome Melanoma-Astrocytoma syndrome


External links

 

Nomenclature
HGNC (Hugo)CDKN2A   1787
LRG (Locus Reference Genomic)LRG_11
Cards
AtlasCDKN2aID146
Entrez_Gene (NCBI)CDKN2A    cyclin dependent kinase inhibitor 2A
AliasesARF; CDK4I; CDKN2; CMM2; 
INK4; INK4A; MLM; MTS-1; MTS1; P14; P14ARF; P16; P16-INK4A; P16INK4; P16INK4A; P19; P19ARF; TP16
GeneCards (Weizmann)CDKN2A
Ensembl hg19 (Hinxton)ENSG00000147889 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000147889 [Gene_View]  ENSG00000147889 [Sequence]  chr9:21967752-21974827 [Contig_View]  CDKN2A [Vega]
ICGC DataPortalENSG00000147889
TCGA cBioPortalCDKN2A
AceView (NCBI)CDKN2A
Genatlas (Paris)CDKN2A
SOURCE (Princeton)CDKN2A
Genetics Home Reference (NIH)CDKN2A
Genomic and cartography
GoldenPath hg38 (UCSC)CDKN2A  -     chr9:21967752-21974827 -  9p21.3   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)CDKN2A  -     9p21.3   [Description]    (hg19-Feb_2009)
GoldenPathCDKN2A - 9p21.3 [CytoView hg19]  CDKN2A - 9p21.3 [CytoView hg38]
ImmunoBaseENSG00000147889
Genome Data Viewer NCBICDKN2A [Mapview hg19]  
OMIM155601   155755   600160   606719   
Gene and transcription
Genbank (Entrez)AF115544 AI859822 AJ844636 AL582909 BC015960
RefSeq transcript (Entrez)NM_000077 NM_001195132 NM_001363763 NM_058195 NM_058196 NM_058197
Consensus coding sequences : CCDS (NCBI)CDKN2A
Gene ExpressionCDKN2A [ NCBI-GEO ]   CDKN2A [ EBI - ARRAY_EXPRESS ]   CDKN2A [ SEEK ]   CDKN2A [ MEM ]
Gene Expression Viewer (FireBrowse)CDKN2A [ Firebrowse - Broad ]
GenevisibleExpression of CDKN2A in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)1029
GTEX Portal (Tissue expression)CDKN2A
Human Protein AtlasENSG00000147889-CDKN2A [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ8N726   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ8N726  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ8N726
PhosPhoSitePlusQ8N726
Domains : Interpro (EBI)Tumor_suppres_ARF   
Domain families : Pfam (Sanger)P19Arf_N (PF07392)   
Domain families : Pfam (NCBI)pfam07392   
Conserved Domain (NCBI)CDKN2A
SuperfamilyQ8N726
AlphaFold pdb e-kbQ8N726   
Human Protein Atlas [tissue]ENSG00000147889-CDKN2A [tissue]
HPRD02542
Protein Interaction databases
DIP (DOE-UCLA)Q8N726
IntAct (EBI)Q8N726
BioGRIDCDKN2A
STRING (EMBL)CDKN2A
ZODIACCDKN2A
Ontologies - Pathways
QuickGOQ8N726
Ontology : AmiGOG1/S transition of mitotic cell cycle  negative regulation of cell-matrix adhesion  RNA binding  cyclin-dependent protein serine/threonine kinase inhibitor activity  protein binding  nucleus  cytoplasm  cytosol  Ras protein signal transduction  negative regulation of cell population proliferation  negative regulation of cell population proliferation  protein kinase binding  negative regulation of cell growth  negative regulation of NF-kappaB transcription factor activity  positive regulation of smooth muscle cell apoptotic process  senescence-associated heterochromatin focus  senescence-associated heterochromatin focus assembly  negative regulation of phosphorylation  negative regulation of cyclin-dependent protein serine/threonine kinase activity  negative regulation of cyclin-dependent protein serine/threonine kinase activity  negative regulation of transcription, DNA-templated  NF-kappaB binding  regulation of cell cycle  regulation of cell cycle  regulation of transcription initiation from RNA polymerase II promoter  cellular senescence  replicative senescence  positive regulation of macrophage apoptotic process  negative regulation of G1/S transition of mitotic cell cycle  positive regulation of cellular senescence  
Ontology : EGO-EBIG1/S transition of mitotic cell cycle  negative regulation of cell-matrix adhesion  RNA binding  cyclin-dependent protein serine/threonine kinase inhibitor activity  protein binding  nucleus  cytoplasm  cytosol  Ras protein signal transduction  negative regulation of cell population proliferation  negative regulation of cell population proliferation  protein kinase binding  negative regulation of cell growth  negative regulation of NF-kappaB transcription factor activity  positive regulation of smooth muscle cell apoptotic process  senescence-associated heterochromatin focus  senescence-associated heterochromatin focus assembly  negative regulation of phosphorylation  negative regulation of cyclin-dependent protein serine/threonine kinase activity  negative regulation of cyclin-dependent protein serine/threonine kinase activity  negative regulation of transcription, DNA-templated  NF-kappaB binding  regulation of cell cycle  regulation of cell cycle  regulation of transcription initiation from RNA polymerase II promoter  cellular senescence  replicative senescence  positive regulation of macrophage apoptotic process  negative regulation of G1/S transition of mitotic cell cycle  positive regulation of cellular senescence  
Pathways : BIOCARTATumor Suppressor Arf Inhibits Ribosomal Biogenesis [Genes]    Cyclins and Cell Cycle Regulation [Genes]    CTCF: First Multivalent Nuclear Factor [Genes]    Cell Cycle: G1/S Check Point [Genes]   
Pathways : KEGGCell cycle    p53 signaling pathway    HTLV-I infection    Pathways in cancer    Viral carcinogenesis    MicroRNAs in cancer    Pancreatic cancer    Glioma    Melanoma    Bladder cancer    Chronic myeloid leukemia    Non-small cell lung cancer   
REACTOMEQ8N726 [protein]
REACTOME PathwaysR-HSA-69231 [pathway]   
NDEx NetworkCDKN2A
Atlas of Cancer Signalling NetworkCDKN2A
Wikipedia pathwaysCDKN2A
Orthology - Evolution
OrthoDB1029
GeneTree (enSembl)ENSG00000147889
Phylogenetic Trees/Animal Genes : TreeFamCDKN2A
Homologs : HomoloGeneCDKN2A
Homology/Alignments : Family Browser (UCSC)CDKN2A
Gene fusions - Rearrangements
Fusion : MitelmanCDKN2A::FOCAD [9p21.3/9p21.3]  
Fusion : MitelmanCDKN2A::IFNWP19 [9p21.3/-]  
Fusion : MitelmanCDKN2A::MGA [9p21.3/15q15.1]  
Fusion : MitelmanCDKN2A::MTAP [9p21.3/9p21.3]  
Fusion : MitelmanCDKN2A::SRGAP2 [9p21.3/1q32.1]  
Fusion : MitelmanFOCAD::CDKN2A [9p21.3/9p21.3]  
Fusion : MitelmanMGA::CDKN2A [15q15.1/9p21.3]  
Fusion : MitelmanMTAP::CDKN2A [9p21.3/9p21.3]  
Fusion : MitelmanTRA::CDKN2A [-/9p21.3]  
Fusion Cancer (Beijing)CDKN2A [9p21.3]  -  CDKN2B-AS1 [9p21.3]  [FUSC001041]  [FUSC001041]
Fusion : QuiverCDKN2A
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerCDKN2A [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)CDKN2A
dbVarCDKN2A
ClinVarCDKN2A
MonarchCDKN2A
1000_GenomesCDKN2A 
Exome Variant ServerCDKN2A
GNOMAD BrowserENSG00000147889
Varsome BrowserCDKN2A
ACMGCDKN2A variants
VarityQ8N726
Genomic Variants (DGV)CDKN2A [DGVbeta]
DECIPHERCDKN2A [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisCDKN2A 
Mutations
ICGC Data PortalCDKN2A 
TCGA Data PortalCDKN2A 
Broad Tumor PortalCDKN2A
OASIS PortalCDKN2A [ Somatic mutations - Copy number]
Cancer Gene: CensusCDKN2A 
Somatic Mutations in Cancer : COSMICCDKN2A  [overview]  [genome browser]  [tissue]  [distribution]  
Somatic Mutations in Cancer : COSMIC3DCDKN2A
Mutations and Diseases : HGMDCDKN2A
intOGen PortalCDKN2A
LOVD (Leiden Open Variation Database)[gene] [transcripts] [variants]
BioMutaCDKN2A
DgiDB (Drug Gene Interaction Database)CDKN2A
DoCM (Curated mutations)CDKN2A
CIViC (Clinical Interpretations of Variants in Cancer)CDKN2A
OncoKBCDKN2A
NCG (London)CDKN2A
Cancer3DCDKN2A
Impact of mutations[PolyPhen2] [Provean] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM155601    155755    600160    606719   
Orphanet19732    3560    3708    22939    14433    14434   
DisGeNETCDKN2A
MedgenCDKN2A
Genetic Testing Registry CDKN2A
NextProtQ8N726 [Medical]
GENETestsCDKN2A
Target ValidationCDKN2A
Huge Navigator CDKN2A [HugePedia]
ClinGenCDKN2A
Clinical trials, drugs, therapy
MyCancerGenomeCDKN2A
Protein Interactions : CTDCDKN2A
Pharm GKB GenePA106
PharosQ8N726
Drug Sensitivity CDKN2A
Clinical trialCDKN2A
Miscellaneous
canSAR (ICR)CDKN2A
HarmonizomeCDKN2A
DataMed IndexCDKN2A
Other databasehttp://cancergenome.broadinstitute.org/index.php?tgene=CDKN2A
Probes
Litterature
PubMed499 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
EVEXCDKN2A
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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indexed on : Fri Oct 8 21:14:45 CEST 2021

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