Prognostic significance of p16^INK4a alterations and 9p21 loss of heterozigosity in locally advanced laryngeal squamous cell carcinoma

Abstract

The p16INK4a gene, localized within chromosome 9p21, has been identified as a cyclin-dependent kinase inhibitor and may negatively regulate the cell cycle acting as a tumor suppressor. Genetic alterations involving the 9p21 region are common in human cancers. A consecutive series of 64 untreated patients (median of follow up 53 months) undergoing surgical resection for locally advanced laryngeal squamous-cell carcinomas (LSCCs) has been studied prospectively. Our purpose was to investigate p16 alterations (9p21 allelic loss, hypermethylation and point mutations) and their possible association with clinico-pathological data and flow cytometric variables (DNA-ploidy and S-phase fraction (SPF)), and to determine the possible prognostic role of this gene in these tumors. PCR-based techniques were used for investigating 9p21 loss of heterozygosity (LOH) and methylation promoter status of the p16 gene. p16 mutations were detected by PCR-SSCP (single strand conformation polymorphism) and sequencing. 9p21 LOH was detected in 16/62 (26%) informative tumors, point mutations in 5% (3/64) and hypermethylation in 9% (6/64) of the cases. p16 alterations were significantly associated with high SPF and DNA-aneuploidy. By univariate analysis, poor histologic differentiation, stage IV, DNA-aneuploidy and p16 point mutations proved to be significantly related to quicker relapse, whereas these same factors, and in addition high SPF, 9p21 LOH and any p16 alterations were significantly related to shorter overall survival. By Cox proportional hazards analysis only histologic grade (G3) and p16 point mutations were independently related to both disease relapse and death. Our study has identified p16 point mutations as important biomolecular indicators in LSCCs.

CDKN2A but not TP53 mutations nor HPV presence predict poor outcome in metastatic squamous cell carcinoma of the skin

“…CDKN2A and TP53 mutations have been shown to be of prognostic value in different tumor types. [13][14][15][16] For instance, in head and neck SCCs, mutations in the CDKN2A and TP53 gene are shown to have a negative effect on survival. 13,14,28 In CSCCs, the prognostic effect of these genes has not been explored yet.…”

“…CDKN2A and TP53 mutations have been shown to have a prognostic effect in different tumor types. [13][14][15][16] In CSCC, the influence of …”

“…CDKN2A and TP53 mutations have been shown to have a prognostic effect in different tumor types. [13][14][15][16] In CSCC, the influence of CDKN2A and TP53 mutations on survival has not been investigated yet. One of the purposes of this study is to investigate the role of these genes on survival in a group of metastatic CSCCs.…”

Prognostic implications of loss of heterozygosity at 8p21 and 9p21 in head and neck squamous cell carcinoma

“…Since then, several other authors have found loss at 9p21, known to house the TSG CDKN2A. 10,11 In this study, we test for associations between LOH and survival using 26 microsatellite repeat polymorphism (MSRP) markers at 8 different regions in the genome that contain known or suspected tumor suppressor genes. …”

TP53 mutations and S‐phase fraction but not DNA‐ploidy are independent prognostic indicators in laryngeal squamous cell carcinoma

“…Mutations within the H-K-N-Ras and TP53 genes were detected by SSCP analysis following PCR amplification of the exon 1 for H-K-Ras, exons 1-2 for N-Ras, and of the exons 5-8 for TP53, respectively (Table 1), performed as previously described (Bazan et al, 2002a;Russo et al, 2002) controls were amplified by PCR and included in the experiment. In all PCR assays, aerosol-resistant pipette tips were used to avoid crosscontamination.…”