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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 Pharmacogenetics and genomics
Vol 32
Issue 2
Date 2022 02 01
URL
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
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
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 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.
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 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 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 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.
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