CDKN2A

Overview

CDKN2A encodes the p16^INK4a and p14^ARF tumor suppressors that restrain CDK4/6-RB and MDM2-p53 axes; deep deletions are recurrent drivers across lymphoid and solid tumors and carry prognostic weight.

Alterations observed in the corpus

  • Homozygous/heterozygous CDKN2A deletions in 7% (9/132) of nodal peripheral T-cell lymphomas on MSK-IMPACT; strong independent predictor of inferior OS (HR 12.1; 95% CI 2.8–52.0; P<.001) with median OS 17.6 vs 56.7 months; 3/4 MEITL cases carried CDKN2A aberrancies PMID:37078708.
  • CDKN2A inactivation correlated with site-specific shorter time to metastasis in the 2,532-specimen LUAD organotropism cohort, with inactivation more frequent in CNS and liver metastases than in matched primary tumors PMID:37084736.
  • CDKN2A was among the recurrent events in extremity alveolar RMS (8%–17% frequency); CDKN2A deletions were mutually exclusive with CDK4 amplification, enriched in acral and high-risk lesions, and correlated with poor OS (P=.02) PMID:37315267.
  • CDKN2A/CDKN2B alterations were enriched in NSCLC brain metastases compared with primary tumors (34% BM vs 13% PT; p=0.003, q=0.04), with cell-cycle pathway alterations 56% BM vs 32% PT (p=0.004, q=0.041) driven by CDKN2A/B; in the LUAD subset the enrichment persisted (31% BM vs 18% PT; p=0.004) PMID:37591896.
  • Frequently co-altered with FGFR3 in urothelial carcinoma (alongside CDKN2B and KDM6A) in the MSK bladder_msk_2023 cohort PMID:37682528.
  • Homozygous CDKN2A/B deletion (“molecular grade-high”) drove ~2x faster tumor-volume growth (19.17% per 6 months vs 9.54%) in IDH-mutant WHO Grade 2 low-grade glioma on active surveillance, supporting WHO 2021 Grade 4 upgrade PMID:37910594.
  • High small bowel GIST risk class in an elastic-net Cox genomic risk model was defined in part by CDKN2A alterations (along with RB1 and MAX/MGA/MYC) PMID:37477937.
  • Alterations (loss/mutation) enriched in average-onset esophagogastric cancer vs. early-onset (22% vs. 11%, P<0.001, Q=0.011); associated with worse survival (HR=1.55, P<0.001) PMID:37406106 PMID:37699004.
  • Loss-of-function mutations rare in normal skin keratinocytes but recurrent in actinic keratoses; 9p allelic imbalance affecting CDKN2A observed in cSCC evolutionary trajectories PMID:39091884.
  • Homozygous deletion is a diagnostic molecular marker for CNS WHO grade 4 IDH-mutant astrocytoma; associated with radiotherapy-related acquisition at tumor recurrence PMID:38117484.
  • Genomic driver in gastric-type adenocarcinoma of the cervix, resembling pancreatobiliary tumors PMID:37643132.
  • Detected at 8% frequency by cfDNA profiling in advanced HCC; adjusted HR = 1.84 (95% CI: 1.29–2.63) for VTE prediction in pan-cancer liquid biopsy analysis PMID:37769223 PMID:39147831.
  • Deletions more common in ULMS (10%) than STLMS (2.6%) in leiomyosarcoma genomic risk models PMID:38488807.
  • CDKN2A/CDKN2B classical DPM drivers not enriched in the genomic near-haploidization (GNH) subset of diffuse pleural mesothelioma PMID:38630790.
  • Discussed in context of familial melanoma predisposition (germline hit); CDK4 amplification and CDKN2A deletion co-occur in tanning-bed melanoma risk analysis PMID:38895302.
  • Deletions co-occurring with BRAF fusions in 14% of BRAF fusion-positive tumors across histologies PMID:38922339.
  • Adjusted HR = 1.84 (95% CI: 1.29–2.63) for cancer-associated VTE by ctDNA-based liquid biopsy; not independently associated with VTE after multivariate adjustment for ctDNA detection status PMID:39147831.
  • Loss acquired in a recurrent, metastatic pituitary neuroendocrine tumor (patient TR-9) together with CCND3 amplification PMID:38758238.
  • Deleted in 42% of anaplastic thyroid carcinomas (ATCs), recurrent in co-occurring differentiated thyroid cancer (co-DTCs), rare in PTCs (~5%) PMID:38412093.
  • CDKN2A loss characterized “biliary-class” intrahepatic cholangiocarcinoma (along with KRAS and SMAD4) in the MSK hidden-genome classifier cohort, associated with markedly worse OS PMID:38864854.
  • In 397 sequenced resected PAAD patients (MSK pancreas_msk_2024), CDKN2A mutations were enriched in KRASG12R tumors (40%) versus KRASG12D (22.1%, p=0.046); overall CDKN2A mutation rate 24% (95/397); CDKN2A/B deep deletions were notably under-detected on MSK-IMPACT in this PDAC cohort PMID:39214094.
  • In the MSK-CHORD 24,950-patient real-world dataset, CDKN2A was flagged among genes with significant metastasis associations in LUAD pathway/gene-level analyses, with alterations linked to metastasis at all four organ sites (CNS, bone, liver, lung) PMID:39506116.
  • In 2,336 PDAC patients sequenced with MSK-IMPACT (pdac_msk_2024), CDKN2A/CDKN2B alteration rate climbed with stage from 44% (resectable) to 60% (metastatic), P = 6.9 × 10⁻⁵; this stage-dependent increase identifies CDKN2A/B loss as a marker of disease progression in PDAC PMID:39753968.
  • CDKN2A/CDKN2B deletions were nearly universal in RT-MPNST (92% vs 44% sporadic), present in 29% of RT-MFH (UPS) and 33% of RT-OS, but almost absent in RT-ANGS (2%) in a comparative genomic analysis of 82 radiation-associated sarcomas PMID:37350195.
  • Homozygous deletion of the CDKN2A/CDKN2B locus is extremely common (over 50%) in GBM; part of the p53 pathway (as p14ARF, 49% altered) and RB pathway (as p16INK4A) PMID:18772890.
  • 9 mutations plus frequent focal deletions identified in 188 primary LUAD tumours (TSP cohort). PMID:18948947
  • CDKN2A deletions in 14% and mutations in 9% of GBC; part of frequent oncogenic CNAs PMID:36228155
  • CDKN2A deletion/loss detected in HNSCC by whole-exome sequencing of 74 tumor-normal pairs (Broad Institute cohort) PMID:21798893
  • CDKN2A deletion recurrently observed in HNSCC by whole-exome sequencing of 32 primary tumors (Johns Hopkins cohort) PMID:21798897
  • Homozygous deletions identified as rare but potentially significant events in the METABRIC breast cancer cohort (2,000 tumors) PMID:22522925
  • CDKN2A deletion is among the most frequent somatic alterations in melanoma across 121 tumors (Broad WES cohort), consistent with homozygous loss driving RB and p53 pathway inactivation PMID:22817889
  • CDKN2A is recurrently deleted in 147 melanoma tumors (Yale WES cohort), with homozygous loss being one of the most common alterations across the landscape PMID:22842228
  • Deleted/mutated in SCLC WES/WGS study (JHU, 36 tumors) with SOX2 amplification PMID:22941189
  • Homozygously deleted and mutated at high frequency in TCGA lung squamous cell carcinoma cohort (178 tumors); identified as one of the most significantly altered genes PMID:22960745
  • Deleted/mutated in lung adenocarcinoma WES study (Broad, 183 tumors) PMID:22980975
  • Deleted/mutated in pancreatic cancer (ICGC WES, 142 tumors); CDKN2A homozygous deletion is among the most frequent alterations in pancreatic ductal adenocarcinoma, abrogating p16-mediated cell cycle control PMID:23103869
  • Deleted in ALL (St. Jude WGS/WES, 44 tumors); CDKN2A deletion identified as a recurrent alteration promoting cell-cycle dysregulation in pediatric acute lymphoblastic leukemia PMID:23334668
  • Focal deletion in OSCC; combined with CCND1 amplification yields cell-cycle pathway alteration in 94% (33/35) of tumors PMID:23619168
  • Second most significantly mutated gene in EAC; recurrent point mutations are the dominant lesion in the 14% of EACs with point-mutation-driven cell-cycle disruption PMID:23525077
  • Increased expression in copy-number-high endometrial carcinoma cluster; cited as a feature distinguishing serous from endometrioid carcinoma PMID:23636398
  • Truncating frameshift mutation in ACC; 3 additional cases with LOH encompassing CDKN2A without nearby NFIB involvement, suggesting a CDKN2A role independent of the MYB-NFIB fusion event PMID:23778141
  • Focal 9p21 deletion in CCRCC (TCGA, n=446); enriched in mRNA subtype m3 (53% vs 26%, p<0.0001) PMID:23792563
  • 9p21.3 homozygous deletion in ~24–25% of high-grade bladder tumors PMID:23897969
  • Homozygous deletion in 57.8% of GBM pathway-analysis cohort; mutually exclusive with TP53 mutation (p=1.99e-7) PMID:24120142
  • Homozygous focal deletion at 9p21 in 50/99 (50%) of bladder TCC tumors PMID:24121792
  • Only gene with recurrent homozygous deletions in MCL (mantle cell lymphoma); no somatic point mutations detected PMID:24145436
  • Sporadic alteration included in the intrahepatic cholangiocarcinoma/gallbladder carcinoma prevalence-screen panel PMID:24185509
  • Homozygous deletion in 4/23 (17%) pancreatic acinar carcinomas, including 2/3 mixed acinar-ductal carcinomas PMID:24293293
  • Homozygous deletion together with CDKN2B in PanNEN patient PN16; supported CDK4/6-inhibitor therapy recommendation in WGTA-guided therapy study PMID:24326773
  • TMZ-associated P114L mutation acquired in patients 05 and 10 during low-grade glioma treatment; abrogates CDK4 inhibition and cell-cycle arrest, contributing to malignant progression to GBM in TMZ-driven hypermutated recurrences PMID:24336570
  • Homozygous deletion in 3% of rhabdomyosarcoma (RMS) cases; 9p21.3 LOH in 9% (PAX-fusion-negative-skewed); part of 12q15 amplicon context with MDM2/FRS2 alterations PMID:24436047
  • Focal homozygous deletion in 47% of muscle-invasive bladder carcinomas (BLCA, n=131); most common focal deletion at 9p21.3; correlated with reduced mRNA expression; mutually exclusive with RB1 loss PMID:24476821
  • Mutated in ESCC; cited as part of the canonical ESCC genomic landscape alongside TP53, RB1, PIK3CA, NOTCH1, and NFE2L2 in a microbiome-focused ESCC review PMID:24670651
  • Focal deletion and mutation in ESCC; contributes to cell-cycle dysregulation; identified by SCNV and targeted deep-sequencing analysis of 139 paired ESCC samples PMID:24686850
  • Inactivated in the G3 proliferative HCC subgroup (Boyault classification); part of the 13-gene RT-PCR panel distinguishing dysplastic nodules from early HCC; G3 subgroup (TP53 mutation + CDKN2A inactivation) was most accurate single signature for predicting post-resection recurrence PMID:24735922
  • Loss-of-function mutation in 2% and homozygous deletion in 5% of HCCs (WES/SNP-array); epigenetic silencing also reported PMID:24798001
  • Recurrent mutations in thymic carcinomas PMID:24974848
  • Promoter hypermethylation in all EBV-positive gastric tumours; focal deletion in CIN subtype; hypermethylation associated with low ploidy, low mutation rate, and SETD2 mutation PMID:25079317
  • Mutated in 4% of LUAD; most significant deletion peak in copy-number data; hypermethylated in CIMP-H tumours; methylation associated with low ploidy, low mutation rate, and SETD2 mutation PMID:25079552
  • Alterations independently associated with worse recurrence-free survival (HR=5.76) and cancer-specific survival (HR=2.94) in muscle-invasive urothelial carcinoma after radical cystectomy; authors propose rationale for CDK4 inhibitor trials PMID:25092538
  • Epigenetically silenced in 4/66 chromophobe RCC cases PMID:25155756
  • Biallelic loss in MSK-PCa3 and MSK-PCa6 prostate cancer cell lines as an alternative RB-pathway hit PMID:25201530
  • Focal 9p21 deletions in 12% of Ewing sarcoma tumors; mutually exclusive with STAG2 mutation; STAG2 may regulate CDKN2A epigenetically via CTCF-cohesin insulation PMID:25223734
  • Homozygous deletion (most common) or heterozygous loss in 81% of MPNSTs; co-occurs with NF1 and PRC2 (EED/SUZ12) loss PMID:25240281
  • Mutated/deleted in 43.6% of cSCC; significant by all four driver-detection methods PMID:25303977
  • Deletion/mutation in 15–27% of intrahepatic CCA and 19% of extrahepatic CCA; mediates acquired resistance to FGFR inhibitors in FGFR2 fusion-positive iCCA, associated with shorter time to progression and poorer overall survival PMID:25526346
  • 9p21 top GISTIC deletion peak in cutaneous squamous cell carcinoma; CDKN2A altered by mutation plus homozygous loss in 14/29 (48%) of cSCC tumors PMID:25589618
  • Inactivation in 22% of HNSCC overall (58% in HPV(-), 0% in HPV(+) on pathway analysis); co-occurs with TP53 loss in smoking-related tumors; falls in significant deletion peak at 9p21 (279-tumor TCGA cohort) PMID:25631445
  • CDKN2A loss enriched in alcohol-related HCC; independently associated with poor survival PMID:25822088
  • Frequently deleted in PDAC (36% in pathway analysis); dominant RB-pathway lesion co-occurring with CDK4/CCND1 amplification and RB1 loss PMID:25855536
  • 9p21.3 deletion in 83% of PCNSL (homozygous in 55%), the dominant copy-number event in primary CNS lymphoma PMID:25991819
  • Cell-cycle pathway aberration in mCRPC; potential CDK4 inhibitor candidate PMID:26000489
  • Alterations evenly distributed across BRAF/RAS/NF1 melanoma subtypes PMID:26091043
  • Recurrent focal homozygous deletion in SCLC (110 tumors, WGS); co-occurs with TP53/RB1 bi-allelic loss as an accessory alteration PMID:26168399
  • Recurrently altered in upper-tract urothelial carcinoma (UTUC) alongside other p15/p16 pathway events; identified in 300-gene MSK-IMPACT panel sequencing (n=83 UTUC) PMID:26278805
  • Focal deletions in 11 desmoplastic melanoma cases; also LOF mutations and one germline mutation in a sun-shielded tumor; p16 loss confirmed by IHC PMID:26343386
  • Homozygous loss drove the recurrent clone in medulloblastoma patient MB-REC-12 after the PTCH1-driven primary clone was eliminated by therapy; acquired alongside CDKN2B loss PMID:26760213
  • Mentioned in study PMID:26804919
  • Mentioned in study PMID:26824661
  • Single-case CDKN2A mutation observed in PDTC/ATC thyroid cancer targeted sequencing (IMPACT panel, 117 tumors), consistent with prior WES ATC findings PMID:26878173
  • CDKN2A was significantly mutated in both lung ADC and SqCC; significantly more frequently mutated in SqCC than ADC (p<0.01, Fisher’s exact); one of only six genes significantly mutated in both NSCLC histologies PMID:27158780.
  • CDKN2A homozygous deletions found in 53/2,087 breast tumors (most common HD target); confirmed as Mut-driver TSG in both ER+ and ER- breast cancer; identified among 40 Mut-driver genes in the METABRIC 2,433-tumor cohort PMID:27161491.
  • CDKN2A mutation/deletion in 37% of HPV-negative versus 5% of HPV-positive recurrent/metastatic head and neck squamous cell carcinoma PMID:27442865
  • 9p21 codeletion (with CDKN2B and MTAP) defines CN Cluster A in urothelial carcinoma; in patient WCM117, CDKN2A progressed from sub-clonal heterozygous deletion in the primary to clonal homozygous deletion in distant metastases (FISH-confirmed) PMID:27749842
  • CDKN2A is a significantly mutated driver in metastatic breast cancer (mBC), also recurrent in early breast cancer (eBC); identified by MutSig analysis of 216 mBC whole-exome sequences PMID:28027327
  • CDKN2A inactivated in 76% of EAC and 76% of ESCC (by mutation, deletion, or epigenetic silencing); significantly mutated in EAC; combined CDKN2A loss and CCND1/CDK6 amplification in ESCC supports CDK4/6 inhibitor evaluation PMID:28052061
  • CDKN2A — deletions identified in advanced LUAD; no patient with CDKN2A deletion as the highest actionable alteration received matched therapy in this precision oncology cohort PMID:28336552
  • CDKN2A — recurrent deletion on Chr 9 in acral lentiginous melanoma (ALM), retained significance in both primary and metastatic tumor subsets PMID:28373299
  • CDKN2A W110 mutation in 1/19 sequenced anaplastic oligodendroglioma tumors; deletion also observed alongside PTEN loss and CDKN2B deletion in a false-positive 1p/19q FISH case with glioblastoma-like signature (ODG cohort, odg_msk_2017) PMID:28472509
  • Cell-cycle gene alterations including CDKN2A increased significantly with stage (p = 0.028) and grade (p = 0.009) across 105 BLCA NMIBC tumors profiled by MSK-IMPACT; grouped with RB1, CCND1, CDKN1A as a cell-cycle pathway unit PMID:28583311
  • Recurrent focal deletion in CCA (n=17 of 71 WGS cases), among the most frequent recurrent deletions in the cohort alongside UTY and KDM5D PMID:28667006.
  • Second most frequently altered tumor suppressor in the MET500 metastatic pan-cancer cohort (80/500, 16%) PMID:28783718.
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  • Recurrent mutation in HPV(−) vulvar squamous cell carcinomas (n=15 WES cohort); consistent with the established TP53/CDKN2A/HRAS mutation pattern of HPV(−) vulvar SCC PMID:29422544

Cancer types (linked)

  • Peripheral T-cell lymphoma (notably MEITL) — CDKN2A deletion is a rare but very high-risk OS marker PMID:37078708.
  • LUAD — CDKN2A loss shortens time to metastasis and is enriched in CNS/liver mets PMID:37084736.
  • NSCLC brain metastasis — CDKN2A/B deletions are enriched vs primaries, marking cell-cycle dysregulation as near-obligate for BM development PMID:37591896.
  • Extremity alveolar RMS — CDKN2A deletion is recurrent and adverse PMID:37315267.
  • PAAD — CDKN2A mutation rate is KRAS-allele-dependent, enriched in KRASG12R relative to KRASG12D tumors; alteration rate increases from 44% (resectable) to 60% (metastatic) in the 2,336-patient pdac_msk_2024 cohort PMID:39214094 PMID:39753968.
  • LUAD — CDKN2A alterations associated with metastasis to CNS, bone, liver, and lung in multivariate analysis of MSK-CHORD PMID:39506116.
  • MPNST — CDKN2A/B deletions in 92% of RT-MPNST (vs 44% sporadic), making it the most enriched alteration in RT-MPNST PMID:37350195.
  • MFH (UPS) — CDKN2A/B deletions in 29% of RT-UPS PMID:37350195.
  • OS — CDKN2A/B deletions in 33% of RT-OS PMID:37350195.
  • ANGS — CDKN2A/B deletions rare (2%) in RT-AS, distinguishing it from other RT-sarcoma histotypes PMID:37350195.
  • EGC (EGC/STAD/ESCA) — enriched in average-onset disease (22% vs 11%); associated with inferior PFS and OS PMID:37406106 PMID:37699004.
  • CSCC — recurrent in actinic keratoses and early cSCC; 9p allelic imbalance PMID:39091884.
  • DIFG/ASTR — homozygous deletion is a WHO grade 4 diagnostic marker; associated with radiotherapy-driven epigenetic evolution PMID:38117484.
  • CESC — genomic driver in gastric-type cervical adenocarcinoma PMID:37643132.
  • HCC — 8% frequency by cfDNA (MSK-ACCESS); cell cycle pathway alteration PMID:37769223.
  • LMS/ULMS — deletions more common in ULMS (10%) than STLMS (2.6%) PMID:38488807.
  • PLMESO — classical DPM driver; not enriched in GNH mesothelioma subset PMID:38630790.
  • THAP — deleted in 42% of ATCs; rare in PTCs (~5%); co-occurs with TP53 mutations in ATC PMID:38412093.
  • PTAD — loss acquired at recurrence in aggressive pituitary neuroendocrine tumor (co-occurring with CCND3 amplification) PMID:38758238.

Co-occurrence and mutual exclusivity

  • CDKN2A deletion is mutually exclusive with CDK4 amplification in extremity ARMS PMID:37315267.
  • CDKN2A/CDKN2B co-altered as a pair in NSCLC brain metastases, together driving cell-cycle pathway enrichment PMID:37591896.

Therapeutic relevance

  • CDKN2A/B loss in NSCLC BM is proposed as rationale for CDK4/6-directed strategies in CNS-tropic disease, though not tested in the corpus PMID:37591896.
  • Extremity RMS authors similarly raise CDK4/6 inhibition as a candidate strategy for CDKN2A-deleted tumors PMID:37315267.

Open questions

Sources

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