CDKN2B

Summary

CDKN2B (cyclin dependent kinase inhibitor 2B, HGNC:1788) is a protein-coding gene on chromosome 9p21.3, encoding Cyclin-dependent kinase 4 inhibitor B (P42772). Interacts strongly with CDK4 and CDK6. In precision oncology, CDKN2B Loss confers sensitivity to Palbociclib in Renal Cell Carcinoma (CIViC Level D); 1 further curated variant–drug associations are listed below.

This gene lies adjacent to the tumor suppressor gene CDKN2A in a region that is frequently mutated and deleted in a wide variety of tumors. This gene encodes a cyclin-dependent kinase inhibitor, which forms a complex with CDK4 or CDK6, and prevents the activation of the CDK kinases, thus the encoded protein functions as a cell growth regulator that controls cell cycle G1 progression. The expression of this gene was found to be dramatically induced by TGF beta, which suggested its role in the TGF beta induced growth inhibition. Two alternatively spliced transcript variants of this gene, which encode distinct proteins, have been reported.

Source: NCBI Gene 1030 — RefSeq curated summary.

At a glance

• Gene–disease (curated): renal cell carcinoma (Moderate, GenCC) — +2 more curated relationships
• GWAS associations: 94
• Clinical variants (ClinVar): 51 total — 3 likely-pathogenic
• Phenotypes (HPO): 84
• Precision-oncology evidence (CIViC): 2 curated variant–drug associations
• MANE Select transcript: NM_004936

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1788
Approved symbol	CDKN2B
Name	cyclin dependent kinase inhibitor 2B
Location	9p21.3
Locus type	gene with protein product
Status	Approved
Aliases	P15, MTS2, INK4B, TP15, CDK4I, p15INK4b
Ensembl gene	ENSG00000147883
Ensembl biotype	protein_coding
OMIM	600431
Entrez	1030

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 3 protein_coding, 1 retained_intron

ENST00000276925, ENST00000380142, ENST00000579591, ENST00000851380

RefSeq mRNA: 2 — MANE Select: NM_004936 NM_004936, NM_078487

CCDS: CCDS6512, CCDS6513

Canonical transcript exons

ENST00000276925 — 2 exons

Exon	Start	End
ENSE00001377005	22008798	22009305
ENSE00001941512	22002903	22006247

Expression profiles

Bgee: expression breadth ubiquitous, 219 present calls, max score 94.36.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 12.9070 / max 405.7733, expressed in 1383 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
100269	12.3025	1374
100268	0.6045	300

Top tissues by expression

289 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
jejunal mucosa	UBERON:0000399	94.36	gold quality
colonic mucosa	UBERON:0000317	92.77	gold quality
lower esophagus mucosa	UBERON:0035834	92.68	gold quality
esophagus mucosa	UBERON:0002469	92.22	gold quality
mucosa of sigmoid colon	UBERON:0004993	91.58	gold quality
esophagus squamous epithelium	UBERON:0006920	91.44	gold quality
oral cavity	UBERON:0000167	90.90	gold quality
mucosa of transverse colon	UBERON:0004991	90.80	gold quality
rectum	UBERON:0001052	90.59	gold quality
buccal mucosa cell	CL:0002336	88.27	gold quality
duodenum	UBERON:0002114	88.13	gold quality
skin of hip	UBERON:0001554	88.02	gold quality
gingiva	UBERON:0001828	88.00	gold quality
upper leg skin	UBERON:0004262	87.99	gold quality
vagina	UBERON:0000996	87.65	gold quality
palpebral conjunctiva	UBERON:0001812	87.54	gold quality
gingival epithelium	UBERON:0001949	86.58	gold quality
adipose tissue	UBERON:0001013	86.24	gold quality
transverse colon	UBERON:0001157	85.79	gold quality
amniotic fluid	UBERON:0000173	85.09	gold quality
mammalian vulva	UBERON:0000997	85.07	gold quality
subcutaneous adipose tissue	UBERON:0002190	84.98	gold quality
connective tissue	UBERON:0002384	84.94	gold quality
epithelium of esophagus	UBERON:0001976	84.90	gold quality
small intestine Peyer’s patch	UBERON:0003454	84.57	gold quality
skin of leg	UBERON:0001511	84.15	gold quality
small intestine	UBERON:0002108	83.95	gold quality
skin of abdomen	UBERON:0001416	83.64	gold quality
esophagus	UBERON:0001043	83.10	gold quality
zone of skin	UBERON:0000014	83.06	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-MTAB-10596	yes	149.35
E-GEOD-125970	yes	23.44
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AHR, ARNT, ASXL1, BAP1, BCL6, CTNNBL1, DNMT1, DNMT3A, DNMT3B, EGR1, ELF4, EP300, ESR1, EZH2, FOXG1, FOXO1, FOXO3, FUBP1, GATA4, GFI1, HLTF, ID1, ID2, IRF6, JDP2, KDM2A, KLF4, KLF5, MAFK, MBD2, MEIS2, MYB, MYC, NCOR2, NR1H3, OLIG2, PAX6, PBX1, POU2F1, PPARG

miRNA regulators (miRDB)

99 targeting CDKN2B, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-4713-3P	100.00	65.92	505
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-433-3P	99.98	69.37	1203
HSA-MIR-8075	99.97	67.20	962
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-144-3P	99.94	73.98	2698
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-8063	99.91	69.76	3146
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-221-3P	99.86	71.56	1329
HSA-MIR-222-3P	99.86	71.35	1337
HSA-MIR-576-5P	99.84	70.46	2582
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-3680-3P	99.75	72.51	3095
HSA-MIR-3617-5P	99.75	69.41	1968
HSA-MIR-641	99.75	69.35	1975
HSA-MIR-6505-5P	99.73	69.25	1595
HSA-MIR-4755-5P	99.71	70.34	2716
HSA-MIR-5006-3P	99.71	70.26	2728
HSA-MIR-4699-3P	99.71	70.15	3142

Literature-anchored findings (GeneRIF, showing 40)

• A method of detecting deletions in the INK4B gene is described in detail. (PMID:11692873)
• CDKIs mediate growth arrest in human osteosarcoma cell lines and provides further evidence of the existence of molecular links between cellular mortality and immortality. (PMID:11695244)
• Losses of INK4a/INK4b gene products play a big role in meningioma formation & malignant progression. Inactivation of p16/p15 and pl4ARF pendent pathways possibly along with telomerase activation might be critical for meningioma immortalization. (PMID:11859969)
• Frequent abnormalities of the p15 gene in mycosis fungoides and sezary syndrome.polymorphisms promoter methylation (PMID:11874489)
• Inactivation of p16/CDKN2 and p15/MTS2 is associated with prognosis and response to chemotherapy in ovarian cancer. (PMID:11992549)
• Deletion analysis of p16(INKa) and p15(INKb) in relapsed childhood acute lymphoblastic leukemia. (PMID:12036898)
• Inactivation of tumor suppressor genes p15(INK4b) and p16(INK4a) in primary cutaneous B cell lymphoma. (PMID:12060387)
• Activation of ERK together with its downstream transcriptional machinery mediated p15(INK4b) expression that led to HepG2 growth inhibition triggered by TPA and Saikosaponin a. (PMID:12592382)
• Methylation inactivation of P15 is associated with oral cancer (PMID:12684640)
• Methylation of p15INK4B is associated with myelodysplasia and acute myeloid leukemia. (PMID:12970781)
• Tumor suppressor genes p15(INK4b), p14(ARF) and p16(INK4a) are located at the 9p21 locus in 26 cryopreserved neurofibromatosis type 1-related malignant peripheral nerve sheath tumors. (PMID:14519636)
• Up-regulation of p15(INK4b) by trichostatin A is associated with cell growth inhibition of HCT116 p21 (-/-) cells. (PMID:14623092)
• Compared with normal colonic mucosa, in which virtually no p16 expression was observed, p16 was overexpressed in hyperplastic polyps (33%:2/6) adenomas (46%:27/59), carcinoma in adenoma (88%:7/8) and in adenocarcinomas (98%:82/84). (PMID:14696398)
• Cyclin-dependent kinase inhibitor p15INK4B plays an important role in activin-induced cell cycle arrest in liver cells. (PMID:15093610)
• Results describe the significance of p16INK4A and p15INK5B transcription suppression with hypermethylation of their genes’ 5’CpG islands during human hepatocellular carcinogenesis. (PMID:15112341)
• Similar to T-ALL, p15INK4B mRNA was absent in 13 of 14 T-cell lymphoblastic lymphoma/leukemia biopsies and its promoter methylated in 6 of 10 (64%) cases (PMID:15475071)
• Transcriptional repression of the p15 gene by dna methylation is associated with adult acute leukemia (PMID:15755508)
• Inacativaton of this cell cycle regulatory genes by DNA methylation could be associated with tumorigenesis in NK cell disorders. (PMID:15813917)
• TP53, CDKN1A, CDKN2A, and CDKN2B have roles in tumorigenesis in skin melanomas, but none of them is a main mutation target for melanoma tumorigenesis (PMID:15819981)
• Expression and methylation of CpG islands in the promoter of p15INK4B gene in children with acute myeloid leukemia. (PMID:15833197)
• PKCalpha is specifically required for TPA-induced ERK(MAPK) signaling to trigger gene expressions of p15(INK4b) and p16(INK4a) leading to HepG2 growth inhibition (PMID:15917995)
• Comprehensive analysis of the 9p21 locus including the CDKN2A, ARF, and CDKN2B genes in 53 individuals from melanoma index cases considered to be at heightened risk of melanoma (PMID:15937071)
• The P15 was methylated in 3 (15%) pediatric patients , compared to 16 (30%)respectively in adult patients. (PMID:15978938)
• Results suggest that epigenetic alterations in p15INK4b have an important role in ovarian carcinogenesis and that mechanisms other than methylation may exist to reduce gene expression of p15INK4b in ovarian cancer. (PMID:16000597)
• Homozygous deletion of CDKN2B and CDKN2A detected in head and neck squamous cell carcinoma cell lines. (PMID:16618910)
• all RARS patients had a methylated p15(INK4b) promoter correlating with non-detectable expression of this gene in bone marrow cells from those patients. (PMID:16682076)
• P15(INK4b) was found positive in 81 and 33% normal, 46 and 10% nodular hyperplasia, 74 and 36% PIN tissues, 87 and 89% low-grade carcinomas, and 100 and 93% high-grade carcinomas. (PMID:16799475)
• Our results suggest that methylation of the p15(INK4b) gene contributes to the process of carcinogenesis in colorectal cancer as well as p16(INK4a) and is useful as a prognostic factor in the early stage (PMID:16872319)
• The CDKN2B was methylated in 50%(6/12)of the analyzed samples in pediatric myelodysplastic syndrome(MDS). (PMID:16890288)
• Homozygous CDKN2A/p14(ARF)/CDKN2B deletion plays an important role in pleomorphic xanthoastrocytoma. (PMID:16909113)
• TGF-beta1 and/or TGF-beta2 inhibit proliferation of primary cultured human limbal epithelial cells, and p57 and p15 play roles in this process. (PMID:16943770)
• The variable expression levels of cell-cycle inhibitor genes CDKN2A, CDKN2B, and CDKN1B due to regulatory polymorphisms could indeed influence the risk of childhood pre-B ALL and contribute to carcinogenesis. (PMID:17008550)
• Perturbed modifications of histone H3 around the p15 CpG island region is associated with acute myeloblastic leukemia (PMID:17074388)
• Oct-1 is an important transcriptional repressor for p15(INK4b) gene and the transcriptional repression of the p15(INK4b) gene by Oct-1 may be one of the regulatory mechanisms of cellular senescence. (PMID:17316622)
• induction of p15(INK4b) by inhibition of the MAPK/ERK pathway is associated with the antiproliferative effects of ZD1839 (PMID:17513607)
• Hypermethylation of the p15INK4b gene promoter in B-chronic lymphocytic leukemia was studied. (PMID:17546638)
• p15(INK4b), rather than p27(KIP1), is the cyclin-dependent kinase inhibitor responsible for G0/G1 arrest of human melanoma cells grown on fibrillar collagen (PMID:17553787)
• Thus, high glucose-induced growth arrest is dependent on p15(INK4b) and oxidative stress in endothelial cells. (PMID:17597576)
• Aberrant methylation of multiple genes (E-cadherin, estrogen receptor, RB1 , p16, p15, p14, and MGMT) is involved in gastric carcinogenesis. (PMID:17652530)
• Promoter hypermethylation of CDKN2B was a consistent epigenetic event in sinonasal papillomas. (PMID:17673925)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Cdkn2b	ENSMUSG00000073802
rattus_norvegicus	Cdkn2b	ENSRNOG00000006735

Paralogs (1): CDKN2A (ENSG00000147889)

Protein

Protein identifiers

Cyclin-dependent kinase 4 inhibitor B — P42772 (reviewed: P42772)

Alternative names: Multiple tumor suppressor 2, p14-INK4b, p15-INK4b

All UniProt accessions (2): P42772, K7PPU3

UniProt curated annotations — full annotation on UniProt →

Function. Interacts strongly with CDK4 and CDK6. Potent inhibitor. Potential effector of TGF-beta induced cell cycle arrest.

Subunit / interactions. Heterodimer of CDKN2B with CDK4 or CDK6. Isoform 2 does not interact with CDK4 nor CDK6.

Subcellular location. Cytoplasm.

Tissue specificity. Isoform 2 is expressed in normal (keratinocytes, fibroblasts) and tumor cell lines.

Similarity. Belongs to the CDKN2 cyclin-dependent kinase inhibitor family.

Isoforms (2)

UniProt ID	Names	Canonical?
P42772-1	1, p15	yes
P42772-2	2, p10

RefSeq proteins (2): NP_004927, NP_511042 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002110	Ankyrin_rpt	Repeat
IPR036770	Ankyrin_rpt-contain_sf	Homologous_superfamily
IPR050776	Ank_Repeat/CDKN_Inhibitor	Family

Pfam: PF12796

UniProt features (10 total): repeat 4, sequence variant 2, sequence conflict 2, chain 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P42772-F1	90.12	0.82

Function

Pathways and Gene Ontology

Reactome pathways

19 pathways

ID	Pathway
R-HSA-2173796	SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription
R-HSA-2559580	Oxidative Stress Induced Senescence
R-HSA-2559582	Senescence-Associated Secretory Phenotype (SASP)
R-HSA-2559585	Oncogene Induced Senescence
R-HSA-69231	Cyclin D associated events in G1
R-HSA-162582	Signal Transduction
R-HSA-1640170	Cell Cycle
R-HSA-170834	Signaling by TGF-beta Receptor Complex
R-HSA-212436	Generic Transcription Pathway
R-HSA-2173793	Transcriptional activity of SMAD2/SMAD3:SMAD4 heterotrimer
R-HSA-2262752	Cellular responses to stress
R-HSA-2559583	Cellular Senescence
R-HSA-453279	Mitotic G1 phase and G1/S transition
R-HSA-69236	G1 Phase
R-HSA-69278	Cell Cycle, Mitotic
R-HSA-73857	RNA Polymerase II Transcription
R-HSA-74160	Gene expression (Transcription)
R-HSA-8953897	Cellular responses to stimuli
R-HSA-9006936	Signaling by TGFB family members

MSigDB gene sets: 461 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, GOBP_NEGATIVE_REGULATION_OF_EPITHELIAL_CELL_PROLIFERATION, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, REACTOME_SIGNALING_BY_TGF_BETA_RECEPTOR_COMPLEX, TSENG_IRS1_TARGETS_UP, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, GOZGIT_ESR1_TARGETS_DN, GOBP_CELL_CYCLE_PHASE_TRANSITION, CAIRO_PML_TARGETS_BOUND_BY_MYC_DN, DACOSTA_UV_RESPONSE_VIA_ERCC3_UP, MCBRYAN_PUBERTAL_TGFB1_TARGETS_UP, WEIGEL_OXIDATIVE_STRESS_BY_TBH_AND_H2O2, GOBP_CELLULAR_SENESCENCE, GOBP_POSITIVE_REGULATION_OF_CELLULAR_RESPONSE_TO_TRANSFORMING_GROWTH_FACTOR_BETA_STIMULUS, OHM_METHYLATED_IN_ADULT_CANCERS

GO Biological Process (12): transforming growth factor beta receptor signaling pathway (GO:0007179), negative regulation of cell population proliferation (GO:0008285), megakaryocyte differentiation (GO:0030219), positive regulation of transforming growth factor beta receptor signaling pathway (GO:0030511), cellular response to nutrient (GO:0031670), spleen development (GO:0048536), negative regulation of epithelial cell proliferation (GO:0050680), regulation of G0 to G1 transition (GO:0070316), cellular response to cell-matrix adhesion (GO:0071460), cellular senescence (GO:0090398), regulation of G1/S transition of mitotic cell cycle (GO:2000045), negative regulation of G1/S transition of mitotic cell cycle (GO:2000134)

GO Molecular Function (3): cyclin-dependent protein serine/threonine kinase inhibitor activity (GO:0004861), protein kinase binding (GO:0019901), protein binding (GO:0005515)

GO Cellular Component (3): nucleus (GO:0005634), cytoplasm (GO:0005737), cytosol (GO:0005829)

Reactome top-level categories

Rollup of top-14 pathways:

Category	Pathways
Cellular Senescence	3
Transcriptional activity of SMAD2/SMAD3:SMAD4 heterotrimer	1
G1 Phase	1
Signaling by TGFB family members	1
RNA Polymerase II Transcription	1
Signaling by TGF-beta Receptor Complex	1
Generic Transcription Pathway	1
Cellular responses to stimuli	1
Cellular responses to stress	1
Cell Cycle, Mitotic	1
Mitotic G1 phase and G1/S transition	1
Cell Cycle	1
Gene expression (Transcription)	1
Signal Transduction	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
G1/S transition of mitotic cell cycle	2
cellular anatomical structure	2
cellular response to transforming growth factor beta stimulus	1
transforming growth factor beta receptor superfamily signaling pathway	1
cell population proliferation	1
regulation of cell population proliferation	1
negative regulation of cellular process	1
myeloid cell differentiation	1
transforming growth factor beta receptor signaling pathway	1
regulation of transforming growth factor beta receptor signaling pathway	1
positive regulation of transmembrane receptor protein serine/threonine kinase signaling pathway	1
positive regulation of cellular response to transforming growth factor beta stimulus	1
response to nutrient	1
cellular response to nutrient levels	1
cellular response to chemical stimulus	1
hematopoietic or lymphoid organ development	1
negative regulation of cell population proliferation	1
epithelial cell proliferation	1
regulation of epithelial cell proliferation	1
regulation of cell cycle process	1
G0 to G1 transition	1
cellular response to stimulus	1
cellular process	1
cellular response to stress	1
regulation of mitotic cell cycle phase transition	1
regulation of cell cycle G1/S phase transition	1
negative regulation of mitotic cell cycle phase transition	1
negative regulation of cell cycle G1/S phase transition	1
regulation of G1/S transition of mitotic cell cycle	1
cyclin-dependent protein serine/threonine kinase activity	1
cyclin-dependent protein serine/threonine kinase regulator activity	1
protein serine/threonine kinase inhibitor activity	1
kinase binding	1
binding	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
cytoplasm	1

Protein interactions and networks

STRING

3208 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CDKN2B	CDK4	P11802	998
CDKN2B	CDK6	Q00534	998
CDKN2B	CCNL2	Q96S94	846
CDKN2B	TP53	P04637	838
CDKN2B	MTAP	Q13126	807
CDKN2B	CDK2	P24941	787
CDKN2B	CDKN1A	P38936	779
CDKN2B	IGF2BP2	Q9Y6M1	773
CDKN2B	CCND1	P24385	759
CDKN2B	CBX7	O95931	737
CDKN2B	CDKN1B	P46527	728
CDKN2B	CDKN3	Q16667	714
CDKN2B	CDKAL1	Q5VV42	712
CDKN2B	CDKN1C	P49918	678
CDKN2B	SLC30A8	Q8IWU4	652

IntAct

114 interactions, top by confidence:

A	B	Type	Score
CDK4	CCND3	psi-mi:“MI:0914”(association)	0.980
CDK4	CDKN2B	psi-mi:“MI:0915”(physical association)	0.970
CDKN2B	CDK4	psi-mi:“MI:0915”(physical association)	0.970
CDK4	CDKN2A	psi-mi:“MI:0914”(association)	0.960
CDKN2B	CDK6	psi-mi:“MI:0915”(physical association)	0.920
CDKN2B	TRAF1	psi-mi:“MI:0915”(physical association)	0.740
TRAF1	CDKN2B	psi-mi:“MI:0915”(physical association)	0.740
CDKN2B	MAGEA11	psi-mi:“MI:0915”(physical association)	0.670
CDK4	HSP90AA1	psi-mi:“MI:0914”(association)	0.640

BioGRID (109): CDKN2B (Two-hybrid), TRAF1 (Two-hybrid), NIF3L1 (Two-hybrid), CCDC33 (Two-hybrid), CDKN2B (Affinity Capture-MS), CDKN2B (Affinity Capture-MS), MAGEA11 (Two-hybrid), CDKN2B (Two-hybrid), CDK6 (FRET), CDKN2B (Affinity Capture-MS), CDKN2B (Co-localization), CDKN2B (Two-hybrid), CDKN2B (Affinity Capture-MS), CDKN2B (Affinity Capture-MS), CDK6 (Affinity Capture-Western)

ESM2 similar proteins: A0QSY0, A0QVI7, A1TH50, A4FM88, A4T7D6, A4X982, B1MB15, B1WVN5, C1B2W9, E3VWI6, E3VWK2, E5KIC0, G0FUS0, G7CBF5, I6YBX3, K7QRJ5, O06733, O53518, P05530, P0DW63, P16559, P20187, P25256, P39896, P42772, P52659, P63392, P9WQJ8, P9WQJ9, P9WQL2, P9WQL3, Q06528, Q0BV59, Q0RH38, Q0S0X2, Q0S258, Q0SFY5, Q2KJD8, Q2PT27, Q3S8P6

Diamond homologs: F1M5M3, O77617, P42771, P42772, P42773, P51480, P55271, P55272, P55273, Q29RV0, Q2KJD8, Q38998, Q60772, Q60773, Q91ZU1, Q9R0Z3, Q18297, Q28FJ2, Q6ZVH7, Q5R4M7, Q69ZR2, Q9NWX5, Q9ULT8, Q9VL06, A0A084B9Z8, Q25338, Q5ZLC8, Q8BTI7, Q8NB46, Q9J5I7, P53356, Q14161, Q3SX00, Q5R8C8, Q66H91, Q68FF6, Q76K24, Q86W74, Q8BTZ5, Q9JLQ2

SIGNOR signaling

17 interactions.

A	Effect	B	Mechanism
MYC	“down-regulates quantity by repression”	CDKN2B	“transcriptional regulation”
FOXO1	“up-regulates quantity by expression”	CDKN2B	“transcriptional regulation”
SMAD3	“up-regulates quantity by expression”	CDKN2B	“transcriptional regulation”
FOXO	“up-regulates quantity by expression”	CDKN2B	“transcriptional regulation”
SMAD3/SMAD4	“up-regulates quantity by expression”	CDKN2B	“transcriptional regulation”
SMAD2/SMAD4	“up-regulates quantity by expression”	CDKN2B	“transcriptional regulation”
SP1	“up-regulates quantity by expression”	CDKN2B	“transcriptional regulation”
“SWI/SNF complex”	“up-regulates quantity by expression”	CDKN2B	“transcriptional regulation”
FUBP1	“down-regulates quantity by repression”	CDKN2B	“transcriptional regulation”
DNMT3A	“down-regulates quantity by repression”	CDKN2B	“transcriptional regulation”
ZNF304	“down-regulates quantity by repression”	CDKN2B	“transcriptional regulation”
CDKL1	“up-regulates activity”	CDKN2B	phosphorylation
TGFB1	“up-regulates quantity by expression”	CDKN2B	“transcriptional regulation”
CDKN2B	down-regulates	CDK4	binding
BAP1	“up-regulates quantity by expression”	CDKN2B	“transcriptional regulation”
ASXL1	“up-regulates quantity by expression”	CDKN2B	“transcriptional regulation”
CDKN2B	down-regulates	Proliferation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 36 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Oncogene Induced Senescence	5	67.2×	6e-07
Cellular Senescence	5	27.5×	3e-05
Oxidative Stress Induced Senescence	5	18.1×	1e-04
Diseases of signal transduction by growth factor receptors and second messengers	5	11.4×	9e-04
Cell Cycle, Mitotic	5	9.6×	2e-03
Cell Cycle	6	8.7×	8e-04
Cellular responses to stress	5	7.4×	4e-03
Cellular responses to stimuli	5	6.3×	7e-03

GO biological processes:

GO term	Partners	Fold	FDR
epidermal growth factor receptor signaling pathway	5	36.4×	1e-04

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

51 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	3
Uncertain significance	29
Likely benign	10
Benign	6

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
2664472	NM_004936.4(CDKN2B):c.*845_*846insCACA	Likely pathogenic
2664473	NM_004936.4(CDKN2B):c.*845_*846insCA	Likely pathogenic
2664475	NM_004936.4(CDKN2B):c.*2763G>T	Likely pathogenic

SpliceAI

532 predictions. Top by Δscore:

Variant	Effect	Δscore
9:22006244:TGAC:T	acceptor_gain	0.9900
9:22006248:C:CC	acceptor_gain	0.9900
9:22006249:T:A	acceptor_loss	0.9900
9:22008812:T:TA	donor_gain	0.9900
9:22008813:C:A	donor_gain	0.9900
9:22006243:ATGAC:A	acceptor_gain	0.9800
9:22006245:GAC:G	acceptor_gain	0.9800
9:22006246:AC:A	acceptor_gain	0.9800
9:22006247:CC:C	acceptor_gain	0.9800
9:22006252:C:CT	acceptor_gain	0.9800
9:22008793:GCTAC:G	donor_loss	0.9800
9:22008794:CTAC:C	donor_loss	0.9800
9:22008795:TAC:T	donor_loss	0.9800
9:22008796:A:G	donor_loss	0.9800
9:22008797:CCT:C	donor_loss	0.9800
9:22009010:A:C	donor_gain	0.9800
9:22008829:C:CA	donor_gain	0.9700
9:22009021:C:A	donor_gain	0.9700
9:22006252:C:T	acceptor_gain	0.9600
9:22006253:A:T	acceptor_gain	0.9600
9:22008798:C:G	donor_loss	0.9600
9:22008461:T:C	donor_gain	0.9400
9:22008809:G:A	donor_gain	0.9400
9:22008850:T:TA	donor_gain	0.9400
9:22008500:C:A	donor_gain	0.9100
9:22009020:T:TA	donor_gain	0.9100
9:22006128:G:GT	donor_gain	0.9000
9:22008676:T:TA	donor_gain	0.9000
9:22009083:A:AC	donor_gain	0.8900
9:22008457:CTTAT:C	donor_gain	0.8700

AlphaMissense

877 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
9:22006141:G:T	A88D	0.992
9:22006076:C:G	D110H	0.988
9:22006075:T:A	D110V	0.983
9:22006057:G:T	P116H	0.982
9:22006144:G:T	A87D	0.981
9:22006142:C:G	A88P	0.977
9:22006075:T:G	D110A	0.976
9:22006045:G:T	A120D	0.974
9:22006074:A:C	D110E	0.973
9:22006074:A:T	D110E	0.973
9:22006076:C:A	D110Y	0.973
9:22006128:G:C	F92L	0.972
9:22006128:G:T	F92L	0.972
9:22006130:A:G	F92L	0.972
9:22006132:C:A	G91V	0.971
9:22008810:C:A	R48S	0.968
9:22008810:C:G	R48S	0.968
9:22006057:G:C	P116R	0.962
9:22008822:G:C	N44K	0.962
9:22008822:G:T	N44K	0.962
9:22006210:A:G	L65P	0.961
9:22006138:C:G	R89P	0.959
9:22006210:A:T	L65Q	0.957
9:22006133:C:G	G91R	0.956
9:22006145:C:G	A87P	0.956
9:22006156:G:C	P83R	0.956
9:22006207:A:G	L66P	0.954
9:22008811:C:G	R48T	0.951
9:22008889:G:T	A22E	0.949
9:22006013:A:C	Y131D	0.948

dbSNP variants (sampled 300 via entrez): RS1000342321 (9:22006658 C>T), RS1000479752 (9:22006429 AC>A,ACCC), RS1000932694 (9:22008258 T>A), RS1002162923 (9:22006185 G>A), RS1002368976 (9:22007454 G>A), RS1003034887 (9:22004631 G>A), RS1003403329 (9:22006250 G>A,C), RS1004483606 (9:22007372 T>C), RS1004854839 (9:22007127 T>C,G), RS1005237374 (9:22011240 T>C), RS1005926371 (9:22006955 A>C), RS1007220596 (9:22011169 T>C), RS1007263689 (9:22006315 G>A,C), RS1007968474 (9:22003814 T>A), RS1008037072 (9:22010341 G>A,T)

Disease associations

OMIM: gene MIM:600431 | disease phenotypes: MIM:131100

GenCC curated gene-disease

Disease	Classification	Inheritance
renal cell carcinoma	Moderate	Autosomal dominant
glaucoma 1, open angle, E	Limited	Autosomal dominant
multiple endocrine neoplasia	Limited	Autosomal dominant

Mondo (4): breast cancer (MONDO:0007254), multiple endocrine neoplasia (MONDO:0017169), (MONDO:0007665), renal cell carcinoma (MONDO:0005086)

Orphanet (1): Multiple endocrine neoplasia (Orphanet:276161)

HPO phenotypes

84 total (30 of 84 shown, HPO-id order):

HPO	Term
HP:0000141	Amenorrhea
HP:0000169	Gingival fibromatosis
HP:0000488	Retinopathy
HP:0000716	Depression
HP:0000736	Short attention span
HP:0000787	Nephrolithiasis
HP:0000802	Impotence
HP:0000822	Hypertension
HP:0000845	Elevated circulating growth hormone concentration
HP:0000849	Adrenocortical abnormality
HP:0000853	Goiter
HP:0000958	Dry skin
HP:0001012	Multiple lipomas
HP:0001254	Lethargy
HP:0001259	Coma
HP:0001289	Confusion
HP:0001293	Cranial nerve compression
HP:0001480	Freckling
HP:0001579	Primary hypercortisolism
HP:0001595	Abnormal hair morphology
HP:0001824	Weight loss
HP:0001944	Dehydration
HP:0002013	Vomiting
HP:0002014	Diarrhea
HP:0002018	Nausea
HP:0002019	Constipation
HP:0002020	Gastroesophageal reflux
HP:0002027	Abdominal pain
HP:0002039	Anorexia
HP:0002044	Zollinger-Ellison syndrome

GWAS associations

94 associations (top):

Study	Trait	p-value
GCST000024_7	Type 2 diabetes	8.000000e-15
GCST000025_5	Type 2 diabetes	1.000000e-06
GCST000025_8	Type 2 diabetes	5.000000e-06
GCST000028_2	Type 2 diabetes	8.000000e-15
GCST000030_1	Myocardial infarction	1.000000e-20
GCST000045_1	Coronary heart disease	1.000000e-13
GCST000167_5	Type 2 diabetes	2.000000e-07
GCST000262_3	Intracranial aneurysm	1.000000e-10
GCST000277_2	Type 2 diabetes	7.000000e-07
GCST000340_1	Myocardial infarction (early onset)	3.000000e-44
GCST000383_2	Type 2 diabetes	2.000000e-29
GCST000439_7	Glioma	7.000000e-15
GCST000646_5	Intracranial aneurysm	2.000000e-22
GCST000678_8	Breast cancer	3.000000e-08
GCST000687_4	Nasopharyngeal carcinoma	5.000000e-07
GCST000700_5	Vertical cup-disc ratio	4.000000e-15
GCST000712_25	Type 2 diabetes	1.000000e-10
GCST000945_3	Coronary artery disease	5.000000e-14
GCST000998_24	Coronary heart disease	1.000000e-22
GCST001058_3	Glioma	5.000000e-16
GCST001070_2	Type 2 diabetes	6.000000e-10
GCST001084_4	Coronary heart disease (SNP X SNP interaction)	7.000000e-14
GCST001260_2	Coronary heart disease	6.000000e-16
GCST001347_1	Coronary artery calcification	3.000000e-24
GCST001361_1	Ankle-brachial index	9.000000e-09
GCST001397_1	Type 2 diabetes	3.000000e-08
GCST001451_2	Glaucoma (primary open-angle)	5.000000e-11
GCST001527_33	Fasting blood glucose (BMI interaction)	7.000000e-06
GCST001596_1	Glaucoma	5.000000e-11
GCST001666_4	Type 2 diabetes	3.000000e-17

EFO canonical traits (13, from GWAS)

EFO ID	Trait name
EFO:0004723	coronary artery calcification
EFO:0003912	ankle brachial index
EFO:0004340	body mass index
EFO:1001515	ovarian endometrioid carcinoma
EFO:1001516	ovarian serous carcinoma
EFO:0006501	carotid plaque build
EFO:0008337	psychosis predisposition measurement
EFO:0009260	non-melanoma skin carcinoma
EFO:0004847	age at onset
EFO:0007796	parental longevity
EFO:0005763	pulse pressure measurement
EFO:0010413	triacylglycerol 52:1 measurement
EFO:0000195	metabolic syndrome

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D002292	Carcinoma, Renal Cell	C04.557.470.200.025.390; C04.588.945.947.535.160; C12.050.351.937.820.535.160; C12.050.351.968.419.473.160; C12.200.758.820.750.160; C12.200.777.419.473.160; C12.900.820.535.160; C12.950.419.473.160; C12.950.983.535.160
D009377	Multiple Endocrine Neoplasia	C04.588.322.400; C04.651.600; C04.700.630; C16.320.700.630; C19.344.400

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

Clinical evidence (CIViC)

Drug × variant × indication: 2 predictive associations from 2 curated evidence items; also 1 prognostic.

Variant	Therapy	Indication	Effect	Level	CIViC
CDKN2B Loss	Palbociclib	Renal Cell Carcinoma	Sensitivity/Response	CIViC D	EID1374
CDKN2B Loss	Palbociclib + Linsitinib	Ewing Sarcoma	Sensitivity/Response	CIViC D	EID1880

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1063192	CDKN2B, CDKN2B-AS1		0.00	0

CTD chemical–gene interactions

113 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Decitabine	affects expression, affects methylation, increases expression, increases reaction, decreases methylation	8
Arsenic Trioxide	decreases methylation, increases expression, affects cotreatment	7
Estradiol	affects cotreatment, decreases expression, increases expression	5
sodium arsenite	affects expression, decreases expression, increases abundance	4
Valproic Acid	affects cotreatment, increases expression	4
Azacitidine	decreases methylation, affects response to substance, affects cotreatment, increases expression	3
Benzo(a)pyrene	increases expression	3
Doxorubicin	increases expression, decreases expression	3
Tobacco Smoke Pollution	decreases expression, increases expression, increases methylation	3
Tretinoin	increases expression	3
Aflatoxin B1	affects expression, increases expression	3
Cadmium Chloride	increases expression	3
ochratoxin A	decreases acetylation, decreases expression	2
palbociclib	decreases response to substance, decreases reaction, increases expression	2
(+)-JQ1 compound	increases expression, decreases expression	2
Resveratrol	affects cotreatment, decreases expression, increases expression	2
Acetaminophen	affects expression, increases expression	2
Arsenic	decreases expression, increases abundance	2
Mustard Gas	increases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Quercetin	affects cotreatment, increases expression	2
Smoke	decreases expression	2
Tetrachlorodibenzodioxin	decreases expression, affects expression	2
Cyclosporine	increases expression	2
Asbestos, Crocidolite	affects expression, decreases expression	2
aristolochic acid I	increases expression	1
triphenyl phosphate	affects expression	1
pirinixic acid	affects binding, decreases expression, increases activity	1
lead acetate	increases expression	1
sodium arsenate	decreases expression, increases abundance	1

Cellosaurus cell lines

430 cell lines: 265 cancer cell line, 151 spontaneously immortalized cell line, 14 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_0039	SK-MEL-30	Cancer cell line	Male
CVCL_0040	WM115	Cancer cell line	Female
CVCL_0062	MDA-MB-231	Cancer cell line	Female
CVCL_0411	MCF10A-Myc	Spontaneously immortalized cell line	Female
CVCL_0445	MeWo	Cancer cell line	Male
CVCL_0598	MCF-10A	Spontaneously immortalized cell line	Female
CVCL_0600	SK-MEL-31	Cancer cell line	Female
CVCL_0B67	WM1985	Cancer cell line	Sex unspecified
CVCL_0B68	WM2032	Cancer cell line	Sex unspecified
CVCL_0B71	WM3282	Cancer cell line	Female

Clinical trials (associated diseases)

600 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00204373	PHASE4	COMPLETED	Treatment of Zollinger-Ellison Syndrome With Prevacid
NCT00414765	PHASE4	COMPLETED	Aldesleukin in Participants With Metastatic Renal Cell Carcinoma or Metastatic Melanoma
NCT00777504	PHASE4	UNKNOWN	Study to the Optimal Duration of Therapy With Oral Angiogenesis Inhibitors
NCT00930345	PHASE4	TERMINATED	Biological, Pathological and Imagery Markers in the First-line Treatment of Metastatic Clear-cell Renal Cell Carcinoma
NCT01206764	PHASE4	COMPLETED	A Trial of Everolimis in Patients With Advanced Renal Cell Carcinoma.
NCT01266837	PHASE4	COMPLETED	Open Label, Single Arm Trial to Characterize Patients With Metastatic RCC Treated With Everolimus After Failure of the First VEGF-targeted Therapy (MARC-2)
NCT02056587	PHASE4	COMPLETED	Everolimus in Patients With Metastatic Renal Cell Carcinoma Following Progression on Prior Bevacizumab Treatment
NCT02338570	PHASE4	TERMINATED	Outcome-related Factors in Patients With Metastatic Renal Cell Carcinoma Treated With Everolimus (ORCHIDEE)
NCT02596035	PHASE4	COMPLETED	An Investigational Immuno-therapy Safety Trial of Nivolumab in Patients With Advanced or Metastatic Renal Cell Carcinoma
NCT02982954	PHASE4	COMPLETED	A Study to Evaluate the Safety of Nivolumab and Ipilimumab in Subjects With Previously Untreated Advanced or Metastatic Renal Cell Cancer
NCT05949424	PHASE4	UNKNOWN	OPTI - DOSE: Optimal Dosing of Oral Anticancer Drugs in Older Adults
NCT07028125	PHASE4	RECRUITING	Digital Monitoring of Self-reported Symptoms by Patients Treated With Cabozantinib Plus Nivolumab for Advanced Clear-cell Renal Carcinoma
NCT07405086	PHASE4	RECRUITING	Morning Versus Afternoon Administration of Immunotherapy for the Treatment of Advanced or Metastatic Solid Tumors, The Knight SHIFT Study
NCT00014638	PHASE4	COMPLETED	Letrozole in Treating Postmenopausal Women With Metastatic Breast Cancer
NCT00022386	PHASE4	COMPLETED	Epoetin Alfa in Treating Chemotherapy-Related Anemia in Women With Stage I, Stage II, or Stage III Breast Cancer
NCT00029224	PHASE4	COMPLETED	Treatment With Zoledronic Acid in Patients With Breast Cancer, Multiple Myeloma, and Prostate Cancer With Cancer Related Bone Lesions
NCT00030758	PHASE4	UNKNOWN	Filgrastim or Pegfilgrastim in Preventing Neutropenia in Women Receiving Chemotherapy Following Surgery for Breast Cancer
NCT00082277	PHASE4	COMPLETED	Anastrozole Biphosphonate Study in Postmenopausal Women With Hormone-Receptor-Positive Early Breast Cancer
NCT00087620	PHASE4	TERMINATED	A Study of Capecitabine In Combination With Docetaxel vs Capecitabine Followed by Docetaxel As First-Line Treatment For Metastatic Breast Cancer
NCT00121836	PHASE4	COMPLETED	A Study of Xeloda (Capecitabine) in Women With HER2-Negative Metastatic Breast Cancer
NCT00126360	PHASE4	UNKNOWN	STARS Breast Trial (Study of Anastrozole and Radiotherapy Sequencing Pilot)
NCT00127933	PHASE4	COMPLETED	XeNA Study - A Study of Xeloda (Capecitabine) in Patients With Invasive Breast Cancer
NCT00128297	PHASE4	COMPLETED	Pamidronate Administration in Breast Cancer Patients With Bone Metastases
NCT00129597	PHASE4	UNKNOWN	Effect of Ketalar to Prevent Postoperative Chronic Pain After Mastectomy
NCT00131170	PHASE4	COMPLETED	Paravertebral Block for Breast Surgery
NCT00156039	PHASE4	COMPLETED	Randomized Trial of Follow-up Strategies in Breast Cancer
NCT00160901	PHASE4	COMPLETED	Complementary Therapies for the Reduction of Side Effects During Chemotherapy for Breast Cancer
NCT00171847	PHASE4	TERMINATED	Study of the Efficacy and Safety of Letrozole Combined With Trastuzumab in Patients With Metastatic Breast Cancer
NCT00176046	PHASE4	COMPLETED	Mistletoe Extract in Early or Advanced Breast Cancer, A Feasibility Study
NCT00190697	PHASE4	COMPLETED	A Study of LY353381 (Arzoxifene) for Patients Who Benefitted From This Drug in Other Oncology Trials and Wished to Continue Treatment
NCT00234195	PHASE4	COMPLETED	Wellbutrin XL, Major Depressive Disorder and Breast Cancer
NCT00237133	PHASE4	COMPLETED	Treatment of Locally Advanced Breast Cancer With Letrozole in Postmenopausal Women
NCT00237224	PHASE4	COMPLETED	Open Label Study of Postmenopausal Women With ER and /or PgR Positive Breast Cancer Treated With Letrozole
NCT00241046	PHASE4	TERMINATED	Letrozole in the Treatment of 1st and 2nd Line Hormone Receptor Positive Breast Cancer: Pre-therapeutic Risk Assessment
NCT00277160	PHASE4	COMPLETED	A Study of Primary Prophylaxis With Neulasta (Pegfilgrastim) Versus Secondary Prophylaxis After Chemotherapy in Elderly Subjects (>/= 65 Years Old) With Cancer
NCT00323479	PHASE4	COMPLETED	Arthralgia During Anastrozole Therapy for Breast Cancer
NCT00334139	PHASE4	COMPLETED	Effect of Zoledronic Acid on Bone Metabolism in Patients With Bone Metastasis and Prostate or Breast Cancer
NCT00356148	PHASE4	COMPLETED	The Efficacy of Prophylactic Antibiotic Administration During Breast Cancer Surgery in Overweight Patients.
NCT00372476	PHASE4	COMPLETED	Efficacy and Safety of Imatinib and Vinorelbine in Patients With Advanced Breast Cancer
NCT00413491	PHASE4	UNKNOWN	National Screening in Denmark With MR Versus Mammography and Ultrasound of Women With BRCA1 or BRCA2 Mutations