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Differential Roles of P16 and P14 Genes in Prognosis of Oral

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Differential Roles of P16 and P14 Genes in Prognosis of Oral 414 Differential Roles of p16INK4A and p14ARF Genes in Prognosis of Oral Carcinoma R. Sailasree,1 A. Abhilash,1 K.M. Sathyan,1 K.R. Nalinakumari,2 Shaji Thomas,3 and S. Kannan1 1Laboratory of Cell Cycle Regulation and Molecular Oncology, Division of Cancer Research, 2Division of Dental Surgery, and 3Division of Surgical Oncology, Regional Cancer Center, Thiruvananthapuram, Kerala, India Abstract INK4A Background: Oral cancer patients are found to have observed in 30% of the cases. p16 deletion was poor clinical outcome and high disease recurrence associated with aggressive tumors, as evidenced by the rate, in spite of an aggressive treatment regimen. The nodal involvement of the disease. Low or absence of inactivation of INK4A/ARF loci is reported to be second p16INK4A protein adversely affected the initial treat- INK4A to p53 inactivation in human cancers. The purpose of ment response. Promoter methylation of p16 was this study was to assess the prognostic significance of associated with increased disease recurrence and acts the molecular aberrations in the INK4A locus for as an independent predictor for worse prognosis. ARF effective identification of aggressive oral carcinoma Surprisingly, p14 methylation associated with cases needing alternate therapy. lower recurrence rate in oral cancer patients with a Materials and Methods: The study composed of 116 good clinical outcome. Overall survival of these patients freshly diagnosed with oral carcinoma. The patients was associated with tumor size, nodal disease, INK4A genetic and epigenetic status of the p16 and and p16INK4A protein expression pattern. Our results ARF INK4A ARF p14 genes was evaluated. The relation between indicate that p16 and p14 alterations constitute these genic alterations and different treatment end a major molecular abnormality in oral cancer cases. points, such as residual disease (initial response), Conclusion: The molecular profile of INK4A/ARF locus, disease recurrence, and overall survival, along with both at DNA and protein level, could be used as a the standard clinical markers, were analyzed. prognostic biomarker for assessing the aggressiveness INK4A Results: 62% of the study cases had p16 gene of disease in oral carcinoma patients. The study further abnormalities, with deletion accounting for 33% and shows the opposing clinical effect of these two genes, ARF methylation for 29%. Alterations in p14 gene transcribed from the same locus, in oral cancer patients. either by deletion (12%) and/or methylation (18%) were (Cancer Epidemiol Biomarkers Prev 2008;17(2):414–20) Introduction Head and neck squamous cell carcinoma represents the metastasis system supplemented with conventional sixth most common cancer worldwide and accounts for histopathologic tumor grading, which has proved to be 500,000 new cases annually. In some European and unsatisfactory prognostic indicators in the present Southeast Asian countries, including India, oral cancer scenario. Determination of the biological behavior and prevails to be the leading formof cancer (1, 2). In oral identification of prognostic biomarkers is important for carcinoma cases, poor survival outcome with a proba- the early detection of relapse, as well as for stratification bility of survival at 5 years being <50% is seen, in spite of of patients before enrollment onto their treatment adopting the most aggressive multimodal treatment regimen. INK4A strategies (3). High recurrence rate leading to treatment The INK4A locus, harboring the p16 gene, is a INK4A failure seems to be a major drawback in the patient major aberration hotspot in oral carcinoma. The p16 treatment protocol. The current cornerstone of thera- gene functions as negative regulator of the cell cycle peutic decision-making is based on the tumor-node- progression through its inhibition of cdk4/6 and subse- quent blockage of the cyclin-dependent phosphorylation of the Rb (4). Genetic alterations of p16INK4A lead to loss Received 3/28/07; revised 11/13/07; accepted 11/20/07. of control of the restriction point in the G1 phase of the Grant support: Department of Science and Technology, Government of India grant cell cycle and favor cellular transformation (5). In our SP/SO/B64/2001. INK4A The costs of publication of this article were defrayed in part by the payment of page earlier study, it is found that p16 expression loss charges. This article must therefore be hereby marked advertisement in accordance defines a subgroup of oral cancer patients with worse with 18 U.S.C. Section 1734 solely to indicate this fact. clinical outcome (6). The present study aimed at Note: R. Sailasree and A. Abhilash contributed equally to this study. deciphering the molecular alterations involved in Abhilash is a recipient of Senior Research Fellowship of the Council of Scientific and INK4A Industrial Research, Government of India. p16 down-regulation and to assess the prognostic INK4A Requests for reprints: S. Kannan, Laboratory of Cell Cycle Regulation and implications of p16 gene alterations in oral carcino- Molecular Oncology, Division of Cancer Research, Regional Cancer Center, ma. As instability of this locus is reporxted to be high in Thiruvananthapuram695011, India. Phone: 91-471-2522338; Fax: 91-471-2447454. carcinoma, we analyzed p16INK4A and its alternate E-mail: [email protected] or [email protected] ARF ARF Copyright D 2008 American Association for Cancer Research. spliced product—p14 at molecular level. The p14 doi:10.1158/1055-9965.EPI-07-0284 tumor suppressor gene has a unique first exon that Cancer Epidemiol Biomarkers Prev 2008;17(2). February 2008 Downloaded from cebp.aacrjournals.org on September 26, 2021. © 2008 American Association for Cancer Research. Cancer Epidemiology, Biomarkers & Prevention 415 INK4A splices into exons 2 and 3 of p16 gene in a different 1 unit Taq polymerase, 2.5% DMSO, and 80 to 100 ng of reading frame, thus translating a distinct protein that genomic DNA. PCR was done for 30 to 35 cycles having bears no amino acid homology to the p16INK4A gene annealing temperature of 58 to 60jC for 1 min. The PCR product. p14ARF acts by binding to mdm2, a negative products were separated on agarose gel, and ethidium regulator of p53, causing stabilization of p53 and leading bromide–stained fragments were recorded by the gel to cell cycle arrest (7). INK4A ARF Major inactivation of the p16 /p14 genes results from promoter methylation, homozygous deletion, and Table 1. Characteristics of oral carcinoma patients intragenic mutation. These genetic and epigenetic alter- ations have been detected frequently in a variety of Factors Frequency (%) human cancers, including head and neck cancer (8, 9). Sex The alteration affecting the INK4A/ARF locus can Male 82 (70.7) potentially disrupt the two main tumor suppression Female 34 (29.3) INK4A ARF Age, mean F SD (range) pathways, p16 -Rb and p14 -p53. In this study, F we did a comprehensive genetic and epigenetic analysis Male 58 9 (37-80) Female 61 F 10 (36-85) of both the genes to identify whether these genes can be Oral habits used as a prognostic biomarker in oral carcinoma. The ARF INK4A None 10 (8.6) results indicate p14 and p16 genes to have strong Chewing alone 34 (29.3) clinical implications but with differential roles in oral Smoking alone 3 (2.6) carcinoma. Alcohol alone 1 (0.9) Chewing with smoking 18 (15.5) Chewing with alcohol 9 (7.8) Smoking with alcohol 9 (7.8) Materials and Methods Chewing + smoking + alcohol 32 (27.6) T status Patient Characteristics and Tissue Sample. The 1 8 (7.0) present study population of 116 oral cancer patients 2 45 (39.1) was selected fromour original cohort of 348 patients 3 19 (16.5) previously described (6). Availability of tumor tissue for 4 43 (37.4) NA 1 DNA isolation was the criteria for selecting the present N status cohort fromour original one. Informationon patient 0 64 (56.1) characteristics, both personal and clinical, is given in 1 40 (35.1) Table 1. Fromeach patient, an incision biopsy was 2 8 (7.0) collected fromthe lesion and divided into two bits. One 3 2 (1.8) bit was immediately snap frozen in liquid nitrogen and NA 2 À j Composite stage stored at 80 C for molecular work-up, and the other bit I 6 (5.2) was used for histopathologic reporting and immunohis- II 28 (24.3) tochemical analyses. The histopathologic grading and III 36 (31.3) staging of the lesion were done as per the WHO criteria IV 45 (39.1) (10). The Institutional Review Board approved the NA 1 Histopathology experimental design, specimen collection procedure, WDSCC 35 (30.0) and scope of this study. Mean age of the patients at MDSCC 73 (62.9) diagnosis was 59 years (range, 36-85 years). Genderwise, PDSCC 6 (5.2) 82 cases (71%) were male and 34 (29%) were female. Verrucous carcinoma 2 (1.7) More than 60% of the patients were presented with Treatment extensive lesion at the time of diagnosis. Radiation alone Radiotherapy 61 (52.6) Surgery 1 (0.9) or in combination with surgery was the main mode of Chemotherapy 2 (1.7) treatment given. Clinical follow-up for 50 months was Radiotherapy + surgery 23 (19.8) conducted with a median follow-up of 23 months. Chemotherapy + radiotherapy 11 (9.5) Chemotherapy + surgery 1 (0.9) DNA Extraction. The genomic DNA from tumor and Chemotherapy + radiotherapy + surgery 14 (12.1) normal samples were extracted by standard phenol- None 3 (2.6) chloroformmethod.Briefly, tissues were pulverized and Residual disease treated with proteinase K followed by phenol-chloroform No 80 (71.4) extraction. Ethanol precipitation was carried out, and Yes 32 (28.6) NA 4 DNA was dissolved in Tris-EDTA buffer (pH 8.0). Disease recurrence Homozygous Deletion Analysis. To assess the homo- No 49 (62.8) Yes 29 (37.2) zygous deletion status of these two genes, competitive ARF NA 2 multiplex PCR was carried out.
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