CCND3

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bibliography: 'morinlab.bib' csl: 'NLM.csl' link-citations: true

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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).[@richterRecurrentMutationID32012; @morinFrequentMutationHistonemodifying2011]

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.[@schmitzBurkittLymphomaPathogenesis2012]

Relevance tier by entity

Entity	Tier	Description
	1	high-confidence MZL gene[@jalladesExomeSequencingIdentifies2017]
	2	relevance in PMBL/cHL/GZL not firmly established[@deschGenotypingCirculatingTumor2020]
	1	high-confidence BL gene [@richterRecurrentMutationID32012]
	1	high-confidence DLBCL gene[@morinFrequentMutationHistonemodifying2011]
	1	high-confidence FL gene [@morinFrequentMutationHistonemodifying2011]

Mutation incidence in large patient cohorts (GAMBL reanalysis)

include:DLBCL_CCND3.md include:FL_CCND3.md include:BL_CCND3.md

Mutation pattern and selective pressure estimates

include:dnds_CCND3.md

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

include:browser_CCND3.md

Expression

include:mermaid_CCND3.md

References