p14ARF protein expression is a predictor of both relapse and survival in squamous cell carcinoma of the anterior tongue.
OBJECTIVE
The INK4A-ARF locus at chromosome 9p21 is frequently altered in head and neck squamous cell carcinoma (SCC) and encodes two distinct tumor suppressors, p16(INK4A) and p14(ARF). This study addressed the role of p14(ARF) as a potential prognostic marker in this disease.


METHODS
p14(ARF) protein expression was assessed by immunohistochemistry in a cohort of 140 patients with SCC of the anterior tongue. Using univariate and multivariate Cox's proportional hazards models, the outcomes examined were time to disease recurrence or death, with or without clinicopathologic covariates, including nodal status, disease stage, treatment status, Ki-67 staining, and molecular markers with known functional or genetic relationships with p14(ARF) (p16(INK4A), p53, pRb, p21(WAF1/CIP1), E2F-1).


RESULTS
On multivariate analysis, p14(ARF) positivity (nucleolar p14(ARF) staining and/or nuclear p14(ARF) staining in >/=30% of tumor cells) was an independent predictor of improved disease-free survival (DFS; P = 0.002) and overall survival (OS; P = 0.002). This was further enhanced when p14(ARF) positivity was cosegregated with positive (>/=1%) p16(INK4A) staining (DFS, P < 0.001; OS, P < 0.001). Patients whose cancers were p14(ARF) negative and p53 positive (>50%) had the poorest outcome (DFS, P < 0.001; OS, P < 0.001) of any patient subgroup analyzed.


CONCLUSIONS
These data show that in patients with SCC of the tongue, combined nuclear and nucleolar expression of p14(ARF) protein predicts for improved DFS and OS independent of established prognostic markers.
Kwong
Rhonda A
RA
Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.
Kalish
Larry H
LH
Nguyen
Tuan V
TV
Kench
James G
JG
Bova
Ronaldo J
RJ
Cole
Ian E
IE
Musgrove
Elizabeth A
EA
Sutherland
Robert L
RL
D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000473:pathology*; D018797:Cell Cycle Proteins / Q000032:analysis; D015331:Cohort Studies; D019938:Cyclin D1 / Q000032:analysis; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000096:biosynthesis; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004268:DNA-Binding Proteins / Q000032:analysis; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D006801:Humans; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000032:analysis; D015999:Multivariate Analysis; D009364:Neoplasm Recurrence, Local; D009367:Neoplasm Staging; D011237:Predictive Value of Tests; D011379:Prognosis; D016016:Proportional Hazards Models; D016160:Retinoblastoma Protein / Q000032:analysis; D016019:Survival Analysis; D014062:Tongue Neoplasms / Q000378:metabolism / Q000473:pathology*; D014157:Transcription Factors / Q000032:analysis; D025803:Tumor Suppressor Protein p14ARF / Q000096:biosynthesis*; D016159:Tumor Suppressor Protein p53 / Q000032:analysis
C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D019394:Ki-67 Antigen; D016160:Retinoblastoma Protein; D014157:Transcription Factors; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53; D019938:Cyclin D1