Role of CDKN2C Copy Number in Sporadic Medullary Thyroid Carcinoma

Abstract

Background: The cyclin-dependent-kinase inhibitors (CDKN)/retinoblastoma (RB1) pathway has been implicated as having a role in medullary thyroid carcinoma (MTC) tumorigenesis. CDKN2C loss has been associated with RET-mediated MTC in humans but with minimal phenotypic correlation provided. The objective of this study was to evaluate the association between tumor RET mutation status, CDKN2C loss, and aggressiveness of MTC in a cohort of patients with sporadic disease.

Methods: Tumors from patients with sporadic MTC treated at a single institution were evaluated for somatic RET^M918T mutation and CDKN2C copy number loss. These variables were compared to patient demographics, pathology detail, clinical course, and disease-specific and overall survival.

Results: Sixty-two MTC cases with an initial surgery date ranging from 1983 to 2009 met the inclusion criteria, of whom 36 (58%) were male. The median age at initial surgery was 53 years (range 22-81 years). The median tumor size was 30 mm (range 6-145 mm) with 29 (57%) possessing extrathyroidal extension. Nodal and/or distant metastasis at presentation was found in 47/60 (78%) and 12/61 (20%) patients, respectively. Median follow-up time was 10.5 years (range 1.1-27.8 years) for the censored observations. The presence of CDKN2C loss was associated with worse M stage and overall AJCC stage. Median overall survival of patients with versus without CDKN2C loss was 4.14 [confidence interval (CI) 1.93-NA] versus 18.27 [CI 17.24-NA] years (p < 0.0001). Median overall survival of patients with a combined somatic RET^M918T mutation and CDKN2C loss versus no somatic RET^M918T mutation and CDKN2C loss versus somatic RET^M918T mutation and CDKN2C 2N versus no somatic RET^M918T mutation and CDKN2C 2N was 2.38 [CI 1.67-NA] years versus 10.81 [CI 2.46-NA] versus 17.24 [CI 9.82-NA] versus not reached [CI 13.46-NA] years (p < 0.0001).

Conclusions: The detection of somatic CDKN2C loss is associated with the presence of distant metastasis at presentation as well decreased overall survival, a relationship enhanced by concomitant RET^M918T mutation. Further defining the genes involved in the progression of metastatic MTC will be an important step toward identifying pathways of disease progression and new therapeutic targets.

Keywords: CDKN2C; RET; Rb pathway; haploinsufficiency; medullary thyroid carcinoma.

FIG. 1.

Molecular pathways associated with thyroid cancer. Mutations in the RET/MAPK signaling pathway are known to drive tumorigenesis. This activation causes the enhanced progression of Cyclin D, which interacts with CDK4/6 to phosphorylate Rb. pRb is required for cell cycle progression. The members of the INK4/CDKN2 family (CDKN2A [p15], CDKN2B [p16], CDKN2C [p18], and CDKN2D [p19]) are cyclin-dependent kinase inhibitors that block the progression of the cell cycle by interacting with CDK4 or CDK6 to prevent activation of the Cyclin D-CDK4/6 complex.

FIG. 2.

Overall survival (OS) of medullary thyroid carcinoma (MTC) patients with somatic CDKN2C copy number loss versus those patients with somatic tumor CDKN2C 2N. Median follow-up 10.5 years; median OS CDKN2C copy number loss versus CDKN2C 2N 4.14 [confidence interval (CI) 1.93–NA] versus 18.27 [CI 13.46–NA] years (p < 0.0001).

FIG. 3.

OS of MTC patients with a combined somatic CDKN2C copy number loss and somatic RET^M918T mutation versus somatic CDKN2C copy number loss and wild type (WT) somatic RET^M918T versus somatic CDKN2C 2N and somatic RET^M918T mutation versus somatic CDKN2C 2N and WT somatic RET^M918T. Median follow-up 10.5 years; median OS of patients with a combined somatic CDKN2C copy number loss and RET^M918T mutation versus CDKN2C copy number loss and WT somatic RET^M918T versus CDKN2C 2N and RET^M918T mutation versus CDKN2C 2N and WT somatic RET^M918T was 2.38 [CI 1.67–NA] years versus 10.81 [CI 2.46–NA] versus 17.24 [CI 9.82–NA] versus 18.27 [CI 13.46–NA] years (p < 0.0001).