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Cyclin-dependent kinase pathway aberrations in diverse malignancies: clinical and molecular characteristics

Shumei Kato1, Maria Schwaederle, Gregory A Daniels

  • 1a Center for Personalized Cancer Therapy and Division of Hematology and Oncology ; Department of Medicine; UC San Diego Moores Cancer Center ; La Jolla , CA USA.

Cell Cycle (Georgetown, Tex.)
|February 20, 2015
PubMed

Insights

Cancer cell cycle aberrations in cyclin-dependent kinase (CDK) pathways are common and linked to genomic instability. These CDK pathway alterations are associated with poorer survival and impact treatment outcomes, warranting further investigation.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Cell cycle regulation by cyclin-dependent kinases (CDKs) is crucial for preventing genomic instability and uncontrolled tumor proliferation.
  • Aberrations in CDK pathways, including CDK4/6 and CDKN2A/B, are implicated in various cancers and are targets for novel therapeutics.
  • Understanding the clinical significance of these aberrations across diverse malignancies is essential for advancing cancer treatment.

Purpose of the Study:

  • To investigate the clinical correlates of CDK4/6 and CDKN2A/B abnormalities in a diverse range of cancer types.
  • To determine the frequency and associations of CDK pathway aberrations with other genetic alterations.
  • To evaluate the prognostic and predictive impact of CDK aberrations on patient survival and treatment response.

Main Methods:

  • Retrospective review of 347 patients with various cancers who underwent molecular profiling using targeted next-generation sequencing (Foundation Medicine).
  • Analysis of gene alterations in CDK4/6, CDKN2A/B, TP53, PTEN, EGFR, and ARID1A.
  • Statistical analysis including univariate and multivariate analyses to assess associations with survival and treatment outcomes.

Main Results:

  • Aberrations in CDK4/6 or CDKN2A/B were identified in 22.8% (79/347) of patients, with TP53 mutations being more frequent.
  • CDK aberrations were most common in glioblastomas (81%) and absent in colorectal cancers.
  • Aberrant CDK elements were independently associated with EGFR and ARID1A abnormalities (P < 0.0001 and P = 0.01) and showed a trend toward poorer overall survival (HR = 1.67, P = 0.09).
  • PTEN and TP53 aberrations were independently associated with poorer survival in multivariate analysis.
  • A trend towards worse progression-free survival (PFS) on platinum-containing regimens was observed in patients with abnormal CDK elements (3.5 vs. 5.0 months, P = 0.13).

Conclusions:

  • Aberrations in the CDK pathway are frequent in cancer and are associated with alterations in EGFR and ARID1A.
  • Patients with abnormal CDK pathway genes exhibit a trend towards poorer survival and worse PFS with platinum-based chemotherapy.
  • Further research is warranted to elucidate the prognostic and predictive value of CDK alterations across different cancer types.
Keywords:
CDK4/6CDKN2A/Bcancercyclin-Dependent Kinasenext generation sequencing

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