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Cell-Cycle Gene Alterations in 4,864 Tumors Analyzed by Next-Generation Sequencing: Implications for Targeted

Teresa Helsten1, Shumei Kato2, Maria Schwaederle1

  • 1Center for Personalized Cancer Therapy, UC San Diego Moores Cancer Center, La Jolla, California.

Molecular Cancer Therapeutics
|May 20, 2016
PubMed

Insights

Cell-cycle pathway gene alterations are common in 39% of cancers, impacting drug development. Specific gene aberrations like CDKN2A/B and RB1 vary by cancer type, offering insights for targeted therapies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Cell-cycle regulation is crucial for preventing uncontrolled cell growth.
  • Alterations in the cyclin-dependent kinase (CDK)-retinoblastoma (RB) pathway are frequently observed in various cancers.
  • Targeting the CDK-RB pathway is a key strategy in cancer drug development.

Purpose of the Study:

  • To determine the frequency and spectrum of abnormalities in key cell-cycle genes across a large cohort of diverse human cancers.
  • To identify specific cancer types and histologies most affected by cell-cycle pathway aberrations.
  • To analyze the co-occurrence and mutual exclusivity of genetic alterations within the cell-cycle pathway to inform therapeutic strategies.

Main Methods:

  • Next-generation sequencing was employed to analyze the frequency of aberrations in cell-cycle pathway genes (including CDKN2A/B, RB1, CCND1, CCNE1, CDK4, CCND3, CCND2, and CDK6) across 4,864 tumor samples.
  • Statistical analyses, including multivariate analysis, were used to assess the associations between different gene alterations and their frequencies across various cancer types and histologies.

Main Results:

  • Aberrations in the cell-cycle pathway were identified in 39% of the analyzed cancers, highlighting its common involvement in tumorigenesis.
  • Specific gene frequencies included CDKN2A/B (20.1%), RB1 (7.6%), CCND1 (6.1%), CCNE1 (3.6%), CDK4 (3.2%), CCND3 (1.8%), CCND2 (1.7%), and CDK6 (1.7%).
  • Significant associations were observed, such as positive correlations between CCND1/2/3 and CDK6, and negative correlations between RB1 and genes like CCND1, CDK4, and CDKN2A/B.

Conclusions:

  • The cell-cycle pathway is frequently altered in a wide range of cancers, representing a significant target for therapeutic intervention.
  • The distinct patterns of gene alterations within this pathway across different cancer types and histologies provide valuable information for the development of targeted drugs.
  • Understanding these genetic landscapes is essential for optimizing precision medicine approaches in oncology.

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