Differential roles of p16INK4A and p14ARF genes in prognosis of oral carcinoma.
BACKGROUND
Oral cancer patients are found to have poor clinical outcome and high disease recurrence rate, in spite of an aggressive treatment regimen. The inactivation of INK4A/ARF loci is reported to be second to p53 inactivation in human cancers. The purpose of this study was to assess the prognostic significance of the molecular aberrations in the INK4A locus for effective identification of aggressive oral carcinoma cases needing alternate therapy.


METHODS
The study composed of 116 patients freshly diagnosed with oral carcinoma. The genetic and epigenetic status of the p16(INK4A) and p14(ARF) genes was evaluated. The relation between these genic alterations and different treatment end points, such as residual disease (initial response), disease recurrence, and overall survival, along with the standard clinical markers, were analyzed.


RESULTS
62% of the study cases had p16(INK4A) gene abnormalities, with deletion accounting for 33% and methylation for 29%. Alterations in p14(ARF) gene either by deletion (12%) and/or methylation (18%) were observed in 30% of the cases. p16(INK4A) deletion was associated with aggressive tumors, as evidenced by the nodal involvement of the disease. Low or absence of p16(INK4A) protein adversely affected the initial treatment response. Promoter methylation of p16(INK4A) was associated with increased disease recurrence and acts as an independent predictor for worse prognosis. Surprisingly, p14(ARF) methylation associated with lower recurrence rate in oral cancer patients with a good clinical outcome. Overall survival of these patients was associated with tumor size, nodal disease, and p16(INK4A) protein expression pattern. Our results indicate that p16(INK4A) and p14(ARF) alterations constitute a major molecular abnormality in oral cancer cases.


CONCLUSIONS
The molecular profile of INK4A/ARF locus, both at DNA and protein level, could be used as a prognostic biomarker for assessing the aggressiveness of disease in oral carcinoma patients. The study further shows the opposing clinical effect of these two genes, transcribed from the same locus, in oral cancer patients.
Sailasree
R
R
Laboratory of Cell Cycle Regulation and Molecular Oncology, Division of Cancer Research, Regional Cancer Center, Thiruvananthapuram 695011, India.
Abhilash
A
A
Sathyan
K M
KM
Nalinakumari
K R
KR
Thomas
Shaji
S
Kannan
S
S
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016009:Chi-Square Distribution; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D019175:DNA Methylation; D005260:Female; D017353:Gene Deletion; D006801:Humans; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D009062:Mouth Neoplasms / Q000235:genetics* / Q000473:pathology; D009364:Neoplasm Recurrence, Local / Q000235:genetics; D017354:Point Mutation; D011379:Prognosis; D016016:Proportional Hazards Models; D016019:Survival Analysis; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics*
D019941:Cyclin-Dependent Kinase Inhibitor p16; D025803:Tumor Suppressor Protein p14ARF