Loss of p16INK4A Expression and Homozygous CDKN2A Deletion Are Associated with Worse Outcome and Younger Age in Thymic Carcinomas

J Thorac Oncol. 2017 May;12(5):860-871. doi: 10.1016/j.jtho.2017.01.028. Epub 2017 Feb 5.

Abstract

Introduction: Thymic carcinomas are aggressive tumors. Biomarkers and alternative treatment modalities are needed. We studied the expression of p16 and cytogenetic abnormalities of cyclin-dependent kinase inhibitor 2A gene (CDKN2A) and correlated findings with clinical features and outcome in a large cohort of thymic carcinomas.

Methods: Thymic carcinomas (1963-2013) were stained with p16. Fluorescence in situ hybridization was utilized to assess for the presence of CDKN2A gene (at 9p21). Statistical analysis was performed.

Results: A total of 27 patients (including 15 men) with thymic carcinoma at a median age of 51.7 years at time of surgery and available follow-up information were included. Loss of p16 expression was found in 12 of 26 cases (46.2%) and was associated with worse recurrence and metastasis-free survival (p = 0.01), which in multivariate analysis was independent of resection status (p = 0.007) and T stage (p = 0.01). Four of 22 tumors (18.2%) showed homozygous CDKN2A deletion that was correlated with loss of p16 expression (p=0.02). In tumors of the squamous cell carcinoma subtype, loss of p16 expression was associated with worse recurrence and metastasis-free survival (p = 0.006) and overall survival (p = 0.0009). Patients with thymic squamous cell carcinomas lacking p16 expression were younger (p = 0.006). Although similar trends for younger age were noted in patients with thymic squamous cell carcinomas with homozygous CDKN2A deletion, the small number of such cases (n = 2) did not allow for statistical analysis.

Conclusions: Loss of p16 expression and homozygous deletion of CDKN2A are promising prognostic biomarkers in thymic carcinoma. On the basis of our findings, a subset of thymic carcinomas have the potential to respond to CDK4/6 inhibitors; however, further functional studies are needed.

Keywords: CDKN2A; Fluorescence in situ hybridization; Thymic carcinoma; p16(INK4A).

MeSH terms

  • Adult
  • Age Factors
  • Aged
  • Aged, 80 and over
  • Base Sequence*
  • Biomarkers, Tumor / genetics
  • Carcinoma, Squamous Cell / genetics*
  • Carcinoma, Squamous Cell / secondary
  • Carcinoma, Squamous Cell / surgery
  • Cyclin-Dependent Kinase Inhibitor p16 / genetics*
  • Disease-Free Survival
  • Female
  • Gene Expression
  • Homozygote
  • Humans
  • In Situ Hybridization, Fluorescence
  • Male
  • Middle Aged
  • Neoplasm Recurrence, Local / genetics*
  • Neoplasm Staging
  • Sequence Deletion*
  • Survival Rate
  • Thymoma / genetics*
  • Thymoma / secondary
  • Thymoma / surgery
  • Thymus Neoplasms / genetics*
  • Thymus Neoplasms / pathology
  • Thymus Neoplasms / surgery
  • Tumor Suppressor Protein p14ARF / genetics*
  • Young Adult

Substances

  • Biomarkers, Tumor
  • Cyclin-Dependent Kinase Inhibitor p16
  • Tumor Suppressor Protein p14ARF