p16MTS1/CDK4I mutations and concomitant loss of heterozygosity at 9p21-23 are frequent events in squamous cell carcinoma of the larynx.
We have examined the presence of p16MTS1/CDK4I gene deletions, mutations and methylation status, and 9p21-23 deletions in a series of 46 squamous cell carcinomas of the larynx and paired normal mucosa previously characterized for cyclin D1 gene amplification and overexpression. pRb expression was also examined by immunohistochemistry. p16MTS1/CDK4I mutations were found in 10/46 (22%) carcinomas and hypermethylation in 2/31 (7%). Loss of heterozygosity at 9p21-23 was found in 24 out of 42 (57%) carcinomas examined. All p16MTS1/CDK4I mutated cases and the two hypermethylated carcinomas showed 9p21-23 loss of heterozygosity. The loss of heterozygosity correlated with advanced local invasion (P=0.0045), lymph node metastases (P=0.0326), stage IV of the tumors (P=0.0058), and existence of cyclin D1 amplification/overexpression (P < 0.03). Only one out of 37 carcinomas was negative for pRb expression. No alterations in p16 gene or 9p21-23 loss of heterozygosity were detected in this case. These findings indicate that p16MTS1/CDK4I is frequently inactivated by gene mutation, hypermethylation, and allelic deletions in a significant subset of squamous cell carcinomas of larynx. Since 9p21-23 loss of heterozygosity was more frequently detected than p16MTS1/CDK4I mutations, and mutated carcinomas invariably had loss of heterozygosity, allelic losses probably precede the p16MTS1/CDK4I mutations. Their association with cyclin D1 deregulation in advanced carcinomas could indicate a possible cooperative effect in the progression of these neoplasms.
Jares
P
P
Department of Anatomic Pathology, Hospital Clínic i Provincial, University of Barcelona, Spain.
Fernández
P L
PL
Nadal
A
A
Cazorla
M
M
Hernández
L
L
Pinyol
M
M
Hernández
S
S
Traserra
J
J
Cardesa
A
A
Campo
E
E
D000368:Aged; D019943:Amino Acid Substitution; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000473:pathology; D002874:Chromosome Mapping; D002899:Chromosomes, Human, Pair 9; D019938:Cyclin D1 / Q000032:analysis / Q000096:biosynthesis; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D005260:Female; D016368:Frameshift Mutation; D006801:Humans; D007822:Laryngeal Neoplasms / Q000235:genetics* / Q000473:pathology; D019656:Loss of Heterozygosity; D008207:Lymphatic Metastasis; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D009154:Mutation; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D012326:RNA Splicing; D017384:Sequence Deletion
D019941:Cyclin-Dependent Kinase Inhibitor p16; D019938:Cyclin D1