Prognostic significance of p16INK4a alterations and 9p21 loss of heterozygosity in locally advanced laryngeal squamous cell carcinoma.
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.
Bazan
Viviana
V
Section of Molecular Oncology, University of Palermo, Italy.
Zanna
Ines
I
Migliavacca
Manuela
M
Sanz-Casla
Maria Teresa
MT
Maestro
Maria Luisa
ML
Corsale
Simona
S
Macaluso
Marcella
M
Dardanoni
Gabriella
G
Restivo
Salvatore
S
Quintela
Paloma López
PL
Bernaldez
Ricardo
R
Salerno
Sergio
S
Morello
Vincenza
V
Tomasino
Rosa Maria
RM
Gebbia
Nicola
N
Russo
Antonio
A
D001483:Base Sequence; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000473:pathology; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics*; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000737:chemistry / Q000235:genetics; D019942:Genes, p16; D006801:Humans; D007822:Laryngeal Neoplasms / Q000235:genetics* / Q000473:pathology; D019656:Loss of Heterozygosity; D015999:Multivariate Analysis; D011003:Ploidies; D017354:Point Mutation; D011379:Prognosis; D016016:Proportional Hazards Models; D011446:Prospective Studies; D016196:S Phase
D004273:DNA, Neoplasm