CCND1

Overview

CCND1 encodes Cyclin D1, a key regulator of the G1-to-S phase cell cycle transition. It activates CDK4/6 to phosphorylate and inactivate RB1, thereby promoting cell cycle progression. CCND1 amplification is a recurrent oncogenic event in esophagogastric cancers and several other malignancies, where it is associated with treatment resistance and poor prognosis.

Alterations observed in the corpus

  • Alterations (amplification/overexpression) associated with inferior progression-free survival on univariate analysis in metastatic esophagogastric cancer treated with pembrolizumab + trastuzumab + chemotherapy PMID:37406106.
  • Expressed preferentially in differentiated (non-stem) tumor cells of grade II oligodendroglioma (IDH-mutant, 1p19q-codeleted); cyclin switching from CCND2 (stem/progenitor) to CCND1/CCND3 (differentiated) observed across 4,347 single cells from 6 tumors PMID:27806376.
  • CCND1 alterations enriched after prior therapy in hormone-receptor-positive BRCA patients, confirming the endocrine-resistance signature, in the MSK-CHORD real-world cohort (n=42,655 patients) PMID:39506116.
  • Identified as mutated/amplified in LUAD (TSP, n=188); cell cycle pathway member; part of CDK4/6-CCND1 axis disrupted alongside CDKN2A/B loss. PMID:18948947
  • CCND1 amplification in 10% of metastatic UC samples (UC-GENOME cohort) PMID:36333289
  • CCND1 amplification detected in HNSCC by whole-exome sequencing of 74 tumor-normal pairs (Broad Institute cohort) PMID:21798893
  • CCND1 amplification recurrently observed in HNSCC by whole-exome sequencing of 32 primary tumors (Johns Hopkins cohort) PMID:21798897
  • Amplification at 11q13.3 defines IntClust 2 (39/45 cases) as part of the 11q13/14 amplicon cassette in the METABRIC breast cancer cohort (2,000 tumors) PMID:22522925
  • CCND1 amplifications detected in breast cancer WES of 100 tumors, contributing to cell cycle dysregulation PMID:22722201
  • CCND1 copy-number amplification is observed in the Broad melanoma WES cohort of 121 tumors, implicating cell cycle dysregulation as a cooperating event with BRAF/NRAS mutations PMID:22817889
  • CCND1 amplification is detected in the Yale melanoma WES cohort of 147 tumors, consistent with its role in cell cycle entry and co-amplification with CDK4 PMID:22842228
  • Amplified/mutated in TCGA lung squamous cell carcinoma cohort (178 tumors) PMID:22960745
  • Amplified in breast cancer (TCGA, 510 tumors); CCND1 amplification enriched in luminal B and HER2-enriched subtypes, driving cell-cycle progression via CDK4/6 PMID:23000897
  • Focal high-level amplification in 22% (8/38) of OSCC; strongly correlated with gene expression (p=5.66e-9); combined with CDKN2A deletion yields cell-cycle alteration in 94% of tumors PMID:23619168
  • Frequently focally amplified in esophageal adenocarcinoma (EAC), contributing to cell-cycle deregulation PMID:23525077
  • HIF2A cooperates with PAX8 to upregulate CCND1 (cyclin D1) in ccRCC, as cited in the context of proximal tubule dedifferentiation and VHL-null proliferation PMID:23797736
  • Focal amplification at 11q13.2–13.3 in 14% of high-grade bladder tumors; mutually exclusive with CCNE1 amplification and inversely correlated with RB1 loss PMID:23897969
  • Recurrent focal amplification in GBM; subtype-correlated alongside CCND2 and CCNE2 PMID:24120142
  • Focal amplification observed in bladder TCC (transitional cell carcinoma); part of a set of recurrently amplified oncogenes PMID:24121792
  • Exon-1 mutations in 10/29 (35%) WES mantle cell lymphoma cases; enriched in SOX11-negative (86%) and IGHV-mutated (58%) MCL, consistent with acquisition in the germinal-center microenvironment PMID:24145436
  • Single nonsense mutation p.Cys285Ter (suspected germline) in sinonasal AdCC; flagged as possible germline variant based on allele fraction, not validated against matched normal tissue PMID:24418857
  • 39 coding and non-coding mutations in multiple myeloma (MM); co-occurs with t(11;14) translocation — likely a somatic-hypermutation hotspot driven by AID; part of the significantly mutated cell-cycle gene set PMID:24434212
  • Low-frequency (1%) mitotic-checkpoint/cell-cycle hit in rhabdomyosarcoma (RMS) pediatric genomic landscape study PMID:24436047
  • Focal amplification in 10% of muscle-invasive bladder carcinomas (BLCA, n=131); identified by GISTIC 2.0 analysis of TCGA bladder urothelial carcinoma cohort PMID:24476821
  • Most frequent focal amplification peak (11q13.2) in ESCC; drives cell-cycle dysregulation; identified by SCNV analysis across 184 ESCC samples PMID:24686850
  • High-level focal amplification in 7% of HCCs (SNP-array, n=704); part of the proliferation class molecular signature PMID:24798001
  • Recurrent focal amplification in CIN gastric adenocarcinoma; suggests CDK4/6 inhibitor evaluation in this subtype PMID:25079317
  • Recurrent focal amplification in LUAD; identified as one of multiple significant amplification peaks in the TCGA lung adenocarcinoma dataset (n=230) PMID:25079552
  • Focal 11q amplification observed in cSCC cohort PMID:25303977
  • Recurrent copy-number gain in 4 of 29 cutaneous squamous cell carcinoma samples by GISTIC analysis PMID:25589618
  • 11q13 co-amplification cassette with FADD and CTTN in 31% of HPV(-) HNSCC vs. 3% of HPV(+) tumors (279-tumor TCGA cohort) PMID:25631445
  • Co-amplified at 11q13.3 locus with FGF3/FGF4/FGF19 (~4% FDA-targetable) in HCC; focal amplification appears at advanced stages and is independently associated with poor survival PMID:25822088
  • Amplification in 6% of PDA (RB-pathway alteration); co-occurs with CDK4 amplification (9%) and CDKN2A/B deletion; part of RB-pathway lesion cluster PMID:25855536
  • Cell-cycle pathway aberration in mCRPC; potentially actionable via CDK4 inhibition; part of RB1/CDKN2A/B/CDK4/CCND1/CDKN1B cluster PMID:26000489
  • Focal amplifications enriched in Triple-WT melanoma subtype; part of CDK4/CCND1 co-amplification pattern PMID:26091043
  • Retained and overexpressed in 2 SCLC tumors with wild-type RB1 due to chromothripsis; proposed as an alternative mechanism of Rb-pathway inactivation when RB1 is intact PMID:26168399
  • Significant association with T stage in upper-tract urothelial carcinoma (UTUC) in a 300-gene panel sequencing study (MSK-IMPACT cohort, n=83 UTUC vs 102 UCB) PMID:26278805
  • Focal amplification (IHC-confirmed) in desmoplastic melanoma; found in 1–3 cases alongside CDK4, MDM2, YAP1, and MYC amplifications PMID:26343386
  • Recurrent focal amplification in 2% of primary prostate cancer tumors (TCGA prostate cohort) PMID:26544944
  • CCND1 is part of a co-amplification event at 11q13-14 with PAK1 that defines IntClust2 in lung cancer genomics context; novel focal amplifications at the CCND3/MIR21 locus were identified in lung ADC PMID:27158780.
  • CCND1 co-amplification with PAK1 at 11q13-14 defines IntClust2 in breast cancer; this co-amplification represents a single early clonal driver event and explains paradoxically low intra-tumor heterogeneity (MATH) despite poor outcomes; IntClust2 tumors show resistance to neo-adjuvant cytotoxic chemotherapy PMID:27161491.
  • CCND1 amplification at 11q13.2 with overexpression in hepatoblastoma (LIHB) used as a good-prognosis indicator in the PIPseq pediatric precision-oncology cohort PMID:28007021
  • CCND1 recurrent amplification in metastatic breast cancer (mBC), consistent with primary breast cancer profiles; identified in WES of 216 mBC samples vs TCGA primary tumors PMID:28027327
  • CCND1 amplified in 57% of ESCC and 15% of EAC in the TCGA esophageal carcinoma study; combined CDKN2A loss and CCND1 amplification in ESCC supports CDK4/6 inhibitor evaluation PMID:28052061
  • CCND1 amplification discussed as a previously reported alteration in acral lentiginous melanoma (ALM) based on cited literature PMID:28373299
  • K114del mutation observed in 1/19 (5.3%) sequenced anaplastic oligodendroglioma tumors profiled by MSK-IMPACT 410 in the odg_msk_2017 cohort PMID:28472509
  • Cell-cycle gene alterations including CCND1 increased significantly with stage (p = 0.028) and grade (p = 0.009) in 105 nonmuscle invasive bladder cancer (BLCA) tumors profiled by MSK-IMPACT PMID:28583311
  • Recurrent oncogene amplification in CCA (n=7 of 71 WGS cases); co-amplified with MYC, MDM2, and EGFR in a subset of Fluke-associated cholangiocarcinomas PMID:28667006.
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Cancer types (linked)

  • EGC/STAD/ESCA/GEJ: CCND1 alterations were identified as a negative prognostic factor for PFS in the context of HER2-directed plus PD-1 blockade combination therapy PMID:37406106.
  • ODG — CCND1 marks the differentiated compartment of oligodendroglioma; cyclin switching (CCND2-high in stem/progenitors, CCND1/CCND3-high in differentiated cells) mirrors a normal developmental gradient PMID:27806376.

Co-occurrence and mutual exclusivity

  • Observed co-occurring with ERBB2 amplification in esophagogastric cancers; represents a parallel cell-cycle activating mechanism PMID:37406106.

Therapeutic relevance

  • CCND1 alterations were associated with inferior PFS, suggesting they may mediate resistance to HER2-directed and immune checkpoint therapy; CDK4/6 inhibitors are a potential co-targeting strategy PMID:37406106.

Open questions

  • Whether CCND1 alterations confer resistance specifically to trastuzumab, to pembrolizumab, or to both in the HER2+ EGC setting has not been dissected.

Sources

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