Chordoma Foundation

CDKN2A (p16)

The CDKN2A gene produces the p16 protein. The protein is a critical player in the cell cycle, blocking a cell’s progression through the G1-S checkpoint.

Location: CDKN2A, Chromosome 9p21.3
Substrates: CDK4/6

p16 is a tumor suppressor that functions by binding to cyclin-dependent kinases (CDK4/6) and preventing their phosphorylation. Inactivation of CDKN2A in normal cells leads to loss of p16 and ultimately to centrosome dysfunction and genomic instability. It is thought to be an important event in early tumorigenesis.1

CDKN2A and p16 in Chordoma

Frequent loss of all or part of chromosome 9, and particularly of the region containing CDKN2A, is reported in chordoma tumors and cell lines. Furthermore, expression of the p16 protein produced by CDKN2A gene is absent in nearly all chordoma tumors tested. CDKN2A and p16 are critical to normal cell growth and proliferation, and loss of the gene and protein have been associated with aggressive behavior in other cancers.2 Some researchers believe that pharmaceutical inhibitors of CDKs may be able to neutralize the consequences of CDKN2A/p16 loss and improve patient outcomes.

Molecular Evidence

Chromosome and Gene Abnormalities

  • Losses of the entirety of chromosome 9 or of the region of 9p where CDKN2A resides are among the most common chromosomal aberrations reported in chordoma samples.2 3 4 5 6 7 8 9 10 11
  • Chromosome 9 loss appears to be more common in sacral than in clival chordomas.12
  • Homozygous deletion of 9p21 was found to be predictive of overall progression-free survival after surgery (PFSS) as well as progression-free survival after radiotherapy (PFSR) in clival chordoma.13
  • Chordoma cell lines U-CH1, U-CH2, and MUG-Chor1 show biallelic losses of the region of 9p that contains the CDKN2A gene.14 15 Nine recently established U-CH lines also show mono- or biallelic losses of the CDKN2A locus.16 17
  • Heterozygous loss of chromosome 9 (including CDKN2A) was preserved in a patient-derived xenograft (PDX) model of clival chordoma.18

Somatic Mutations

  • Two samples taken from the same patient at different anatomical locations each had the same mutations in CDKN2A and SMARCB1 (also implicated as a therapeutic target in chordoma).19

Protein Expression

  • p16 expression is absent in the majority of chordoma samples analyzed by immunohistochemistry or western blot.1 7 20 21 22

Pathway Activation

  • 80% of chordoma tissue samples were found to have what researchers proposed is a potential responder phenotype (characterized by protein expression of CDKN2A substrates CD4/6 as well as pRb) for inhibition of the CDK4/6 cyclin dependent kinase pathways by pharmacological agents.16

Preclinical Evidence

In-vitro Efficacy

  • Palbociclib: Treatment of cell lines with CDK4/6 inhibitor palbociclib inhibited cellular proliferation. Follow-up analysis in U-CH1 and U-CH2 found no evidence that treatment induced apoptosis.4
  • Abemaciclib: Treatment of U-CH1 and U-CH2 with CDK4/6 inhibitor Abemaciclib (LY2835219) reduced cell viability.4

Sommer J, Itani D, Homlar K, et al. Methylthioadenosine phosphorylase and activated insulin-like growth factor-1 receptor/insulin receptor: potential therapeutic targets in chordoma. J Pathol. 2010;220(5):608-617. [PubMed]
Horbinski C, Oakley G, Cieply K, et al. The prognostic value of Ki-67, p53, epidermal growth factor receptor, 1p36, 9p21, 10q23, and 17p13 in skull base chordomas. Arch Pathol Lab Med. 2010;134(8):1170-1176. [PubMed]
Ribeiro MFSA, de Sousa MC, Hanna SA, et al. Tumor Reduction with Pazopanib in a Patient with Recurrent Lumbar Chordoma. Case Reports in Oncological Medicine. 2018;2018:1-7. doi:10.1155/2018/4290131
Hallor K, Staaf J, Jönsson G, et al. Frequent deletion of the CDKN2A locus in chordoma: analysis of chromosomal imbalances using array comparative genomic hybridisation. Br J Cancer. 2008;98(2):434-442. [PubMed]
Rinner B, Weinhaeusel A, Lohberger B, et al. Chordoma characterization of significant changes of the DNA methylation pattern. PLoS One. 2013;8(3):e56609. [PubMed]
Dewaele B, Maggiani F, Floris G, et al. Frequent activation of EGFR in advanced chordomas. Clin Sarcoma Res. 2011;1(1):4. [PubMed]
Le L, Nielsen G, Rosenberg A, et al. Recurrent chromosomal copy number alterations in sporadic chordomas. PLoS One. 2011;6(5):e18846. [PubMed]
Wang L, Zehir A, Nafa K, et al. Genomic aberrations frequently alter chromatin regulatory genes in chordoma. Genes Chromosomes Cancer. 2016;55(7):591-600. [PubMed]
Stephens P, Greenman C, Fu B, et al. Massive Genomic Rearrangement Acquired in a Single Catastrophic Event during Cancer Development. Cell. 2011;144(1):27-40. [PMC]
Tarpey P, Behjati S, Young M, et al. The driver landscape of sporadic chordoma. Nat Commun. 2017;8:890. [PMC]
Ribeiro M, de S, Hanna S, et al. Tumor Reduction with Pazopanib in a Patient with Recurrent Lumbar Chordoma. Case Rep Oncol Med. 2018;2018:4290131. [PubMed]
Diaz R, Guduk M, Romagnuolo R, et al. High-resolution whole-genome analysis of skull base chordomas implicates FHIT loss in chordoma pathogenesis. Neoplasia. 2012;14(9):788-798. [PubMed]
Zenonos G, Mukherjee D, Chang Y, et al. Prospective validation of a molecular prognostication panel for clival chordoma. J Neurosurg. June 2018:1-10. [PubMed]
Brüderlein S, Sommer J, Meltzer P, et al. Molecular characterization of putative chordoma cell lines. Sarcoma. 2010;2010:630129. [PubMed]
Rinner B, Froehlich E, Buerger K, et al. Establishment and detailed functional and molecular genetic characterisation            of a novel sacral chordoma cell line, MUG-Chor1. Int J Oncol. 2012;40(2):443-451. [PubMed]
von W, Goerttler L, Marienfeld R, et al. Preclinical Characterization of Novel Chordoma Cell Systems and Their Targeting by Pharmocological Inhibitors of the CDK4/6 Cell-Cycle Pathway. Cancer Res. 2015;75(18):3823-3831. [PubMed]
Jäger D, Lechel A, Tharehalli U, et al. U-CH17P, -M and -S, a new cell culture system for tumor diversity and progression in chordoma. Int J Cancer. November 2017. [PubMed]
Diaz R, Luck A, Bondoc A, et al. Characterization of a clival chordoma xenograft model reveals tumor genomic instability. Am J Pathol. September 2018. [PubMed]
Choy E, MacConaill L, Cote G, et al. Genotyping cancer-associated genes in chordoma identifies mutations in oncogenes and areas of chromosomal loss involving CDKN2A, PTEN, and SMARCB1. PLoS One. 2014;9(7):e101283. [PubMed]
Presneau N, Shalaby A, Idowu B, et al. Potential therapeutic targets for chordoma: PI3K/AKT/TSC1/TSC2/mTOR pathway. Br J Cancer. 2009;100(9):1406-1414. [PubMed]
Naka T, Boltze C, Kuester D, et al. Alterations of G1-S checkpoint in chordoma: the prognostic impact of p53 overexpression. Cancer. 2005;104(6):1255-1263. [PubMed]
Liu T, Shen J, Choy E, et al. CDK4 expression in chordoma: A potential therapeutic target. J Orthop Res. November 2017. [PubMed]

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