Prognostic value of cyclin-D1 and p16 in second primary oral squamous cell
carcinoma
Christos MAGOPOULOS, Theodora KATOPODI, Fotis IORDANIDIS, Geogia THEOHARI, Alexandros LAMBROPOULOS, Ioannis DIMITRAKOPOULOS
Department of Oral and Maxillofacial Surgery, Aristotle University, Dental School, Thessaloniki, Greece.
Department of Pathology, ‘G Papanikolaou’ Hospital, Thessaloniki, Greece.
Department of General Biology and Genetics, Aristotle University, Medical School, Thessaloniki, Greece.
Hellenic Archives of Oral & Maxillofacial Surgery (2012) 1, 3-20
SUMMARY: Aim: To examine the prognostic value of cyclin-D1, p16 protein expression and other clinicopathological parameters in the evaluation of the clinical outcome and genetic profile of SPTs. Materials and methods: Immunohistochemical staining was performed in paraffin embedded specimens that were obtained from 25 patients with 80 second primary Oral Squamous Cell Carcinomas (OSCC). Results: Multivariate analysis revealed statistically significant positive relation of disease free survival (DFS) with cyclinD1 overexpression (P=.015). Overall survival (OS) was not correlated significantly to none of the clinical and IHC parameters investigated. Synergistic action of cyclin-D1 with p16 failed to reach statistical significant relation with either DFS or OS in all fashions of expression. Different mode of expression was identified between the index and the first SPTs concerning both cyclin-D1 and p16 (P<0.05). Conclusions: Patients with SPTs seem to outline a distinct entity in terms of clinicopathological behavior and genetic profile of the tumor cells. Moreover, the different prognostic value of cyclin-D1 overexpression and p16 loss of function in patients with SPTs makes our verification more potent.
KEY WORDS: Second primary tumors, cyclin-D1, p16.
REFERENCES
Akervall JA, Michalides RJ, Mineta H: Amplification of cyclin D1 in squamous cell carcinoma of the head and neck and the prognostic value of chromosomal abnormalities and cyclin D1 overexpression. Cancer 79:480–389, 1997
Ballacosa A, Almadori G, Cavallo S: Cyclin D1 gene amplification in human laryngeal squamous cell carcinomas: prognostic significance and clinical implications. Clin Cancer Res 2:175–180, 1996
Bates S, Parry D, Bonetta L, Vousden K, Dickson C, Peters G: Absence of cyclin D/cdk complexes in cells lacking functional retinoblastoma protein. Oncogene 9: 1633-1640, 1994
Bova RJ, Quinn DI, Nankervis JS, Cole IE, Sheridan BF, Jensen MJ: Cyclin D1 and p16INK4A expression predict reduced survival in carcinoma of the anterior tongue. Clin Cancer Res 5:2810-2819, 1999
Braakhuis BJ, Leemans CR, Brakenhoff RH: A genetic progression model of oral cancer: current evidence and clinical implications. J Oral Pathol Med 33: 317-322, 2004
Braakhuis BJ, Tabor MP, Leemans CR, Van Der Waal I, Snow GB, Brakenhoff RH: Second primary tumors and field cancerization in oral and oropharyngeal cancer: molecular techniques provide new insights and definitions. Head Neck 24:198–206, 2002
Califano J, Van Der Riet P, Westra W, Nawroz H, Clayman G, Plantadosi S: Genetic progression model for head and neck cancer: implications for field cancerization. Cancer Res 56:2488–92, 1996
El-Nagger AK, Lai S, Clayman GL: Expression of p16, Rb, and cyclin D1 gene products in oral and laryngeal squamous carcinoma: biological and clinical implications. Hum Pathol 30:1013–1018, 1999
Gillett C, Smith P, Gregory W, Richards M, Millis R, Peters G, Barnes D: Cyclin d1 and prognosis in human breast cancer Int J Cancer (Pred Oncol) 69: 92-99, 1996
Greenlee RT, Hill-Harmon MB, Murrary T, Thun M: Cancer statistics, 2001. CA Cancer J Clin 51:15–36, 2001
Ha PK, Califano J: The molecular biology of mucosal field cancerization of the head and neck. Crit Rev Oral Biol Med 14(5): 363- 369, 2003
Hinds PW, Dowdy SF, Eaton EN, Arnold A, Weinberg RA: Functionof a human cyclin gene as an oncogene. Proc Natl Acad Sci USA 91:709-713, 1994
Hong WK, Lippman SM, Itri LM: Prevention of second primary tumors with isotretinoinin in squamous cell carcinoma of the head and neck. N Engl J Med 323:795-801, 1990
Jadayel DM, Lukas J, Nacheva E: Potential role for concurrent abnormalities of the cyclin D1, p16CDKN2 and p15CDKN2B genes in certain B cell non-Hodgkin’s lymphoma: functional studies in a cell line (Grant 519). Leukemia 11:64–72, 1997
Jang SJ, Chiba I, Hirai A, Hong WK, Mao L: Multiple oral squamous epithelial lesions: are they genetically related? Oncogene 20:2235–42, 2001
Kyomoto R, Kumazawa H, Toda Y: Cyclin D1 gene amplification is a more potent prognostic factor than its protein overexpresion in human head and neck squamous cell carcinoma. Int J Cancer 74:576–581, 1997
Leong PP, Rezai B, Koch WM: Distinguishing second primary tumors from lung metastasis in patients with head and neck squamous cell carcinoma. J Natl Cancer Inst 90: 972-977, 1998
Lukas J, Aagaard L, Strauss M, Bartek J: Oncogenic aberrations of p16INK4/CDKN2 and cyclin D1 cooperate to deregulate G1 control. Cancer Res 55:4818–4823, 1995
Michailides RJ, Van De Brekel M, Balm F: Defects in G1-S cell cycle control in head and neck cancer: a review. Head Neck 24:694–704, 2002
Miyamoto R, Uzawa N, Nagaoka S: Prognostic significance of cyclin D1 amplification and overexpression in oral squamous cell carcinomas. Oral Oncol 39:610–618, 2003
Namazie A, Alavi S, Olopade OI, Pauletti G, Aghamohamadi N, Aghamohamadi M: Cyclin D1 amplification and P16 (MTS1/CDK4I) deletion correlate with poor prognosis in head and neck tumors. Laryngoscope 112:472–481, 2002
Pande P, Mathur M, Shukla NK, Ralhan R: PRb and p16 protein alterations in human oral tumorigenesis. Oral Oncol 34:396-403, 1998
Papadimitrakopoulou V, Izzo J, Lippman SM: Frequent inactivation of p16INK4a in oral premalignant lesions. Oncogene 14:1799–1803, 1997
Parry D, Bates S, Mann DJ, Peters G: Lack of cyclin D-Cdk corn lexes in Rb-negative cells correlates with high levels of p16INK4/MTsP tumour suppressor gene product. EMBO I 14: 503-511, 1995
Pateromichelakis S, Farahini M, Phillips E, Partridge M: Molecular analysis of paired tumours: Time to start treating the field. Oral Oncol 41:916–926, 2005 Peters G, Fantl V, Smith R, Brookes S, Dickson C: Chromosome llq13 markers and D-type cyclins in breast cancer. Breast Cancer Res Treat 33:125-135, 1995 Rosin MP, Cheng X, Poh C: Use of allelic loss to predict malignant risk for low-grade oral epithelial dysplasia. Clin Cancer Res 6:357–62, 2000
Sakagushi M, Fuji Y, Hirabayashi H: Inverse correlated expression of p16 and Rb protein in non-small cell lung cancers: an immunohistochemical study. Int J Cancer 65:442–445, 1996
Sanchez-Cespedes M, Esteller M, Wu L, Nawroz-Danish H, Yoo GH, Koch WM: Gene promoter hypermethylation in tumors and serum of head and neck cancer patients. Cancer Res 60:892- 895, 2000
Sicinski P, Donaher JL, Parker SB, Li T, Fazeli A, Gardner H: Cyclin D1 provides a link between development and oncogenesis in the retina and breast. Cell 82:621-630, 1995
Slaughter DP, Southwick HW: ‘‘Field cancerization’’ in oral stratified squamous epithelium. Clinical implications of multicentric origin. Cancer 6:963–8, 1953 Tam SW, Theodoras AM, Shay JW, Draetta GF, Pagano M: Differential expression and regulation of cyclin D1 protein in normal and tumor cells: association with Cdk4 is required for cyclin D1 function in G, progression. Oncogene 9: 2663-2674, 1994
Timmermann S, Hinds P, Munger K: Elevated activity of cyclindependent kinase 6 in human squamous cell carcinoma lines. Cell Growth Diff 8:361-370, 1997 Uzawa N, Sonoda I, Myo K, Takahashi K, Miyamoto R, Amagasa T: Fluorescence in Situ Hybridization for Detecting Genomic Alterations of Cyclin D1 and p16 in Oral Squamous Cell Carcinomas. Cancer 110(10): 2230-2239, 2007
Van Oijen MG, Slootweg PJ: Oral field cancerization: carcinogeninduced independent events or micrometastatic deposits? Cancer Epidemiol Biomarkers Prev 9:249–56, 2000
Warren S, Gates O: Multiple primary malignant tumors. A survey of the literature and a statistical study. Am J Cancer 16: 1358-1414, 1932
Department of Oral and Maxillofacial Surgery, Aristotle University, Dental School, Thessaloniki, Greece.
Department of Pathology, ‘G Papanikolaou’ Hospital, Thessaloniki, Greece.
Department of General Biology and Genetics, Aristotle University, Medical School, Thessaloniki, Greece.
Hellenic Archives of Oral & Maxillofacial Surgery (2012) 1, 3-20
SUMMARY: Aim: To examine the prognostic value of cyclin-D1, p16 protein expression and other clinicopathological parameters in the evaluation of the clinical outcome and genetic profile of SPTs. Materials and methods: Immunohistochemical staining was performed in paraffin embedded specimens that were obtained from 25 patients with 80 second primary Oral Squamous Cell Carcinomas (OSCC). Results: Multivariate analysis revealed statistically significant positive relation of disease free survival (DFS) with cyclinD1 overexpression (P=.015). Overall survival (OS) was not correlated significantly to none of the clinical and IHC parameters investigated. Synergistic action of cyclin-D1 with p16 failed to reach statistical significant relation with either DFS or OS in all fashions of expression. Different mode of expression was identified between the index and the first SPTs concerning both cyclin-D1 and p16 (P<0.05). Conclusions: Patients with SPTs seem to outline a distinct entity in terms of clinicopathological behavior and genetic profile of the tumor cells. Moreover, the different prognostic value of cyclin-D1 overexpression and p16 loss of function in patients with SPTs makes our verification more potent.
KEY WORDS: Second primary tumors, cyclin-D1, p16.
REFERENCES
Akervall JA, Michalides RJ, Mineta H: Amplification of cyclin D1 in squamous cell carcinoma of the head and neck and the prognostic value of chromosomal abnormalities and cyclin D1 overexpression. Cancer 79:480–389, 1997
Ballacosa A, Almadori G, Cavallo S: Cyclin D1 gene amplification in human laryngeal squamous cell carcinomas: prognostic significance and clinical implications. Clin Cancer Res 2:175–180, 1996
Bates S, Parry D, Bonetta L, Vousden K, Dickson C, Peters G: Absence of cyclin D/cdk complexes in cells lacking functional retinoblastoma protein. Oncogene 9: 1633-1640, 1994
Bova RJ, Quinn DI, Nankervis JS, Cole IE, Sheridan BF, Jensen MJ: Cyclin D1 and p16INK4A expression predict reduced survival in carcinoma of the anterior tongue. Clin Cancer Res 5:2810-2819, 1999
Braakhuis BJ, Leemans CR, Brakenhoff RH: A genetic progression model of oral cancer: current evidence and clinical implications. J Oral Pathol Med 33: 317-322, 2004
Braakhuis BJ, Tabor MP, Leemans CR, Van Der Waal I, Snow GB, Brakenhoff RH: Second primary tumors and field cancerization in oral and oropharyngeal cancer: molecular techniques provide new insights and definitions. Head Neck 24:198–206, 2002
Califano J, Van Der Riet P, Westra W, Nawroz H, Clayman G, Plantadosi S: Genetic progression model for head and neck cancer: implications for field cancerization. Cancer Res 56:2488–92, 1996
El-Nagger AK, Lai S, Clayman GL: Expression of p16, Rb, and cyclin D1 gene products in oral and laryngeal squamous carcinoma: biological and clinical implications. Hum Pathol 30:1013–1018, 1999
Gillett C, Smith P, Gregory W, Richards M, Millis R, Peters G, Barnes D: Cyclin d1 and prognosis in human breast cancer Int J Cancer (Pred Oncol) 69: 92-99, 1996
Greenlee RT, Hill-Harmon MB, Murrary T, Thun M: Cancer statistics, 2001. CA Cancer J Clin 51:15–36, 2001
Ha PK, Califano J: The molecular biology of mucosal field cancerization of the head and neck. Crit Rev Oral Biol Med 14(5): 363- 369, 2003
Hinds PW, Dowdy SF, Eaton EN, Arnold A, Weinberg RA: Functionof a human cyclin gene as an oncogene. Proc Natl Acad Sci USA 91:709-713, 1994
Hong WK, Lippman SM, Itri LM: Prevention of second primary tumors with isotretinoinin in squamous cell carcinoma of the head and neck. N Engl J Med 323:795-801, 1990
Jadayel DM, Lukas J, Nacheva E: Potential role for concurrent abnormalities of the cyclin D1, p16CDKN2 and p15CDKN2B genes in certain B cell non-Hodgkin’s lymphoma: functional studies in a cell line (Grant 519). Leukemia 11:64–72, 1997
Jang SJ, Chiba I, Hirai A, Hong WK, Mao L: Multiple oral squamous epithelial lesions: are they genetically related? Oncogene 20:2235–42, 2001
Kyomoto R, Kumazawa H, Toda Y: Cyclin D1 gene amplification is a more potent prognostic factor than its protein overexpresion in human head and neck squamous cell carcinoma. Int J Cancer 74:576–581, 1997
Leong PP, Rezai B, Koch WM: Distinguishing second primary tumors from lung metastasis in patients with head and neck squamous cell carcinoma. J Natl Cancer Inst 90: 972-977, 1998
Lukas J, Aagaard L, Strauss M, Bartek J: Oncogenic aberrations of p16INK4/CDKN2 and cyclin D1 cooperate to deregulate G1 control. Cancer Res 55:4818–4823, 1995
Michailides RJ, Van De Brekel M, Balm F: Defects in G1-S cell cycle control in head and neck cancer: a review. Head Neck 24:694–704, 2002
Miyamoto R, Uzawa N, Nagaoka S: Prognostic significance of cyclin D1 amplification and overexpression in oral squamous cell carcinomas. Oral Oncol 39:610–618, 2003
Namazie A, Alavi S, Olopade OI, Pauletti G, Aghamohamadi N, Aghamohamadi M: Cyclin D1 amplification and P16 (MTS1/CDK4I) deletion correlate with poor prognosis in head and neck tumors. Laryngoscope 112:472–481, 2002
Pande P, Mathur M, Shukla NK, Ralhan R: PRb and p16 protein alterations in human oral tumorigenesis. Oral Oncol 34:396-403, 1998
Papadimitrakopoulou V, Izzo J, Lippman SM: Frequent inactivation of p16INK4a in oral premalignant lesions. Oncogene 14:1799–1803, 1997
Parry D, Bates S, Mann DJ, Peters G: Lack of cyclin D-Cdk corn lexes in Rb-negative cells correlates with high levels of p16INK4/MTsP tumour suppressor gene product. EMBO I 14: 503-511, 1995
Pateromichelakis S, Farahini M, Phillips E, Partridge M: Molecular analysis of paired tumours: Time to start treating the field. Oral Oncol 41:916–926, 2005 Peters G, Fantl V, Smith R, Brookes S, Dickson C: Chromosome llq13 markers and D-type cyclins in breast cancer. Breast Cancer Res Treat 33:125-135, 1995 Rosin MP, Cheng X, Poh C: Use of allelic loss to predict malignant risk for low-grade oral epithelial dysplasia. Clin Cancer Res 6:357–62, 2000
Sakagushi M, Fuji Y, Hirabayashi H: Inverse correlated expression of p16 and Rb protein in non-small cell lung cancers: an immunohistochemical study. Int J Cancer 65:442–445, 1996
Sanchez-Cespedes M, Esteller M, Wu L, Nawroz-Danish H, Yoo GH, Koch WM: Gene promoter hypermethylation in tumors and serum of head and neck cancer patients. Cancer Res 60:892- 895, 2000
Sicinski P, Donaher JL, Parker SB, Li T, Fazeli A, Gardner H: Cyclin D1 provides a link between development and oncogenesis in the retina and breast. Cell 82:621-630, 1995
Slaughter DP, Southwick HW: ‘‘Field cancerization’’ in oral stratified squamous epithelium. Clinical implications of multicentric origin. Cancer 6:963–8, 1953 Tam SW, Theodoras AM, Shay JW, Draetta GF, Pagano M: Differential expression and regulation of cyclin D1 protein in normal and tumor cells: association with Cdk4 is required for cyclin D1 function in G, progression. Oncogene 9: 2663-2674, 1994
Timmermann S, Hinds P, Munger K: Elevated activity of cyclindependent kinase 6 in human squamous cell carcinoma lines. Cell Growth Diff 8:361-370, 1997 Uzawa N, Sonoda I, Myo K, Takahashi K, Miyamoto R, Amagasa T: Fluorescence in Situ Hybridization for Detecting Genomic Alterations of Cyclin D1 and p16 in Oral Squamous Cell Carcinomas. Cancer 110(10): 2230-2239, 2007
Van Oijen MG, Slootweg PJ: Oral field cancerization: carcinogeninduced independent events or micrometastatic deposits? Cancer Epidemiol Biomarkers Prev 9:249–56, 2000
Warren S, Gates O: Multiple primary malignant tumors. A survey of the literature and a statistical study. Am J Cancer 16: 1358-1414, 1932
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