Table of Contents

Overview

CCND3 (Cyclin D3) is a gene that encodes a protein involved in the regulation of the cell cycle. Mutations in CCND3 are implicated in various types of B-cell lymphomas, including Burkitt lymphoma and diffuse large B-cell lymphoma (DLBCL).1,2

Experimental Evidence

Somatic mutations in CCND3 often stabilize the Cyclin D3 protein by altering the phosphorylation motif, which is crucial for proteasomal degradation. These mutations are associated with an increase in Cyclin D3 protein stability and oncogenic potential.3

Relevance tier by entity

Entity Tier Description
BL 1 High-confidence BL gene
DLBCL 1 High-confidence DLBCL gene
FL 1 High-confidence FL gene
MZL 1 High-confidence MZL gene
PMBL 2 Role of CCND3 mutations in PMBL requires confirmation

Mutation incidence in large patient cohorts (GAMBL reanalysis)

DLBCL

Entity Collection N mutated Incidence 95% CI
DLBCL GAMBL without Reddy 1,089 80 0.0735 [0.058,0.089]
DLBCL GAMBL with Reddy 2,088 118 0.0565 [0.0466,0.0664]
DLBCL BC 231 14 0.0606 [0.0298,0.0914]
DLBCL Dana-Farber 303 14 0.0462 [0.0226,0.0698]
DLBCL NCI 470 46 0.0979 [0.071,0.1247]
DLBCL Reddy 999 38 0.0380 [0.0262,0.0499]
DLBCL DLBCL_ICGC 85 6 0.0706 [0.0161,0.125]

FL

pathology Collection N mutated Incidence CI
FL GAMBL without Crouch 642 20 0.0312 [0.0177,0.0446]
FL GAMBL with Crouch 1,189 54 0.0454 [0.0336,0.0573]
FL BC 379 12 0.0317 [0.014,0.0493]
FL Kalmbach 164 7 0.0427 [0.0117,0.0736]
FL Crouch 547 34 0.0622 [0.0419,0.0824]
FL FL_ICGC 99 1 0.0101 [0,0.0298]

BL

pathology Collection N mutated Incidence CI
BL GAMBL without Panea 309 94 0.3017 [0.2507,0.3527]
BL GAMBL without ICGC/Zhou 320 80 0.2444 [0.1976,0.2912]
BL GAMBL with Panea 410 113 0.2666 [0.2242,0.3089]
BL BLGSP 219 61 0.2785 [0.2192,0.3379]
BL Zhou/ICGC 90 33 0.3667 [0.2671,0.4662]
BL Panea 101 19 0.1881 [0.1119,0.2643]

Mutation pattern and selective pressure estimates

Entity Missense dN/dS Nonsense dN/dS Q value
BL 50.8413 153.2128 0
FL 17.6496 16.0260 0
DLBCL 3.8116 12.3120 0

CCND3 Hotspots

Exon 5 Hotspot

T283 (Threonine 283): One of the most frequently mutated sites in CCND3. Mutations at this site can result in enhanced cyclin D3 stability and increased cell cycle progression.

I290 (Isoleucine 290): Another common mutation in exon 5. Mutations here are associated with similar functional impacts as E283, promoting uncontrolled cell proliferation.

Exon 1 and Exon 2

While exon 5 is the primary hotspot, mutations in exon 1 and exon 2 have also been observed, though less frequently. These mutations can affect the regulatory regions of the gene, potentially increasing levels of CCND3 by promoting stability of the protein.

Functional Impact of CCND3 Mutations

Cell Cycle Dysregulation: CCND3, along with other cyclins, regulates the transition from the G1 phase to the S phase of the cell cycle. Mutations in CCND3 can lead to its overexpression or increased stability, resulting in accelerated cell cycle progression and uncontrolled cell division.

Increased Protein Stability: Mutations at E283 and D290 often result in the increased stability of the cyclin D3 protein, preventing its degradation. This leads to sustained activation of CDK4/6 (cyclin-dependent kinases), further driving cell cycle progression.

Oncogenic Potential: The dysregulation of CCND3 due to these mutations contributes to the oncogenic potential of B-cell lymphomas. By promoting continuous cell proliferation, these mutations help lymphoma cells evade normal growth control mechanisms.

Chromosome Coordinate (hg19) ref>alt HGVSp
chr6 41903736 C>G S274T
chr6 41903731 G>A Q276*
chr6 41903719 G>A Q280*
chr6 41903710 T>G T283P
chr6 41903710 T>C T283A
chr6 41903710 T>A T283S
chr6 41903709 G>A T283I
chr6 41903707 G>A P284S
chr6 41903706 G>C P284R
chr6 41903706 G>A P284L
chr6 41903694 G>C T288R
chr6 41903692 C>G A289P
chr6 41903691 G>C A289G
chr6 41903688 A>T I290K
chr6 41903688 A>G I290T
chr6 41903688 A>C I290R
chr6 41903682 A>T L292Q
chr6 41903682 A>C L292R

Visualizations

Protein

View coding variants in ProteinPaint hg19 or hg38

Genome

View all variants in GenomePaint hg19 or hg38

Expression

History

%%{init: { 'logLevel': 'debug', 'theme': 'dark' } }%% timeline title Publication timing 2011-07-27 : Morin : DLBCL 2012-03-06 : Lohr : DLBCL 2012-11-11 : Richter : BL 2017-07-27 : Jallades : MZL 2017-10-10 : Reddy : DLBCL 2018-05-01 : Chapuy : DLBCL 2018-10-01 : Arthur : DLBCL 2019-08-20 : Desch : PMBL 2021-05-05 : Hubschmann : DLBCL

References

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Citing

If you use the information or data from this site, please cite

Krysta Coyle, Kostiantyn Dreval, Daniel Hodson and Ryan D. Morin. Audit of B-cell cancer genes. Blood Adv (2025) 9 (8): 2019–2031.

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