Reference Detail

Ref Type

Journal Article

PMID

(34369425)

Authors

Li C, Zhao X, He Y, Li Z, Qian J, Zhang L, Ye Q, Qiu F, Lian P, Qian M, Zhang H

Title

The functional role of inherited CDKN2A variants in childhood acute lymphoblastic leukemia.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Pharmacogenetics and genomics	32	2	2022 02 01	43-50	Pharmacogenet Genomics

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Abstract Text

Genetic alterations in CDKN2A tumor suppressor gene on chromosome 9p21 confer a predisposition to childhood acute lymphoblastic leukemia (ALL). Genome-wide association studies have identified missense variants in CDKN2A associated with the development of ALL. This study systematically evaluated the effects of CDKN2A coding variants on ALL risk.We genotyped the CDKN2A coding region in 308 childhood ALL cases enrolled in CCCG-ALL-2015 clinical trials by Sanger Sequencing. Cell growth assay, cell cycle assay, MTT-based cell toxicity assay, and western blot were performed to assess the CDKN2A coding variants on ALL predisposition.We identified 10 novel exonic germline variants, including 6 missense mutations (p.A21V, p.G45A and p.V115L of p16INK4A; p.T31R, p.R90G, and p.R129L of p14ARF) and 1 nonsense mutation and 1 heterozygous termination codon mutation in exon 2 (p16INK4A p.S129X). Functional studies indicate that five novel variants resulted in reduced tumor suppressor activity of p16INK4A, and increased the susceptibility to the leukemic transformation of hematopoietic progenitor cells. Compared to other variants, p.H142R contributes higher sensitivity to CDK4/6 inhibitors.These findings provide direct insight into the influence of inherited genetic variants at the CDKN2A coding region on the development of ALL and the precise clinical application of CDK4/6 inhibitors.

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Molecular Profile	Treatment Approach
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Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role
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Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
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Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
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Gene	Variant	Impact	Protein Effect	Variant Description
CDKN2A	A21V	missense	unknown	CDKN2A A21V lies within ANK repeat 1 of the Cdkn2a protein (UniProt.org). A21V suppresses IL3-independent growth similar to wild-type Cdkn2a in the context of BCR-ABL1-expressing cells in culture (PMID: 34369425), but has not been individually characterized and therefore, its effect on Cdkn2a protein function is unknown.
CDKN2A	A36V	missense	unknown	CDKN2A A36V lies within ANK repeat 1 of the Cdkn2a protein (UniProt.org). A36V results in decreased suppression of IL3-independent growth in BCR-ABL1-expressing cells in culture (PMID: 34369425), but has not been individually characterized and therefore, its effect on Cdkn2a protein function is unknown.
CDKN2A	G45A	missense	unknown	CDKN2A G45A lies within ANK repeat 2 of the Cdkn2a protein (UniProt.org). G45A suppresses IL3-independent growth similar to wild-type Cdkn2a in BCR-ABL1-expressing cells in culture (PMID: 34369425), but has not been individually characterized and therefore, its effect on Cdkn2a protein function is unknown.
CDKN2A	A57V	missense	unknown	CDKN2A A57V lies within ANK repeat 2 of the Cdkn2a protein (UniProt.org). A57V results in a partial loss of Cdk4 binding but supports cell proliferation levels similar to wild-type Cdkn2a in culture (PMID: 19260062), demonstrates impaired ability to regulate oxidative stress and altered cell cycle distribution (PMID: 23190892), and suppresses BRC-ABL1-mediated transformation and phosphorylation of Rb and Cdk4 similar to wild-type protein in cell culture (PMID: 34369425), and therefore, its effect on Cdkn2a protein function is unknown.
CDKN2A	R99Q	missense	unknown	CDKN2A R99Q lies within ANK repeat 3 of the Cdkn2a protein (UniProt.org). R99Q results in decreased suppression of IL3-independent growth in BCR-ABL1-expressing cells in culture (PMID: 34369425), but has not been individually characterized and therefore, its effect on Cdkn2a protein function is unknown.
CDKN2A	V115L	missense	unknown	CDKN2A V115L lies within ANK repeat 4 of the Cdkn2a protein (UniProt.org). V115L suppresses IL3-independent growth similar to wild-type Cdkn2a in BCR-ABL1-expressing cells in culture (PMID: 34369425), but has not been individually characterized and therefore, its effect on Cdkn2a protein function is unknown.
CDKN2A	A127S	missense	unknown	CDKN2A A127S lies within ANK repeat 4 of the Cdkn2a protein (UniProt.org). A127S results in decreased suppression of IL3-independent growth in BCR-ABL1-expressing cells in culture (PMID: 34369425), but binding to Cdk4/6 and induction of growth arrest similar to wild-type Cdkn2a in culture (PMID: 10498896), and therefore, its effect on Cdkn2a protein function is unknown.
CDKN2A	R138G	missense	unknown	CDKN2A R138G lies within ANK repeat 4 of the Cdkn2a protein (UniProt.org). R138G suppresses IL3-independent growth similar to wild-type Cdkn2a in BCR-ABL1-expressing cells in culture (PMID: 34369425), but has not been individually characterized and therefore, its effect on Cdkn2a protein function is unknown.
CDKN2A	H142R	missense	unknown	CDKN2A H142R does not lie within any known functional domains of the Cdkn2a protein (UniProt.org). H142R results in Cdk4 and Rb phosphorylation similar to wild-type Cdkn2a but decreased suppression of IL3-independent growth of BCR-ABL1-expressing cells in culture (PMID: 34369425), and therefore, its effect on Cdkn2a protein function is unknown.
CDKN2A	A143T	missense	no effect - predicted	CDKN2A A143T does not lie within any known functional domains of the Cdkn2a protein (UniProt.org). A143T results in proliferation and cell cycle inhibition similar to wild-type Cdkn2a in culture (PMID: 35001868) and suppresses IL3-independent growth similar to wild-type Cdkn2a in BCR-ABL1-expressing cells in culture (PMID: 34369425), and therefore, is predicted to have no effect on Cdkn2a protein function.
CDKN2A	A148T	missense	unknown	CDKN2A A148T does not lie within any known functional domains of the Cdkn2a protein (UniProt.org). A148T results in inhibition of cell growth and binding to Cdk4 and Cdk6 similar to wild-type Cdkn2a (PMID: 10389768) and results in Cdk4 and Rb phosphorylation similar to wild-type Cdkn2a but decreased suppression of IL3-independent growth in BCR-ABL1-expressing cells in culture (PMID: 34369425), and therefore, its effect on Cdkn2a protein function is unknown.

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Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
CDKN2A H142R	B-cell acute lymphoblastic leukemia	sensitive	Palbociclib	Preclinical - Cell culture	Actionable	In a preclinical study, Ibrance (palbociclib) treatment inhibited viability of a B-cell acute lymphoblastic leukemia cell line expressing CDKN2A H142R in culture (PMID: 34369425).	34369425

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