Top

Published in:

01-05-2007

Clinicopathological Roles of Alterations of Tumor Suppressor Gene p16 in Papillary Thyroid Carcinoma

Authors: Alfred King Yin Lam, MBBS, MD, PhD, FRCPA, Chung Yau Lo, MBBS, MS, FRCS (Edin.), FACS, Pauline Leung, BSc, Brian Hung Hin Lang, MBBS, FRACS, Wai Fun Chan, MBBS, FRCS (Edin.), John M. Luk, DMedSc

Published in: Annals of Surgical Oncology | Issue 5/2007

Abstract

Background

Alterations of the p16 gene are common in human cancers, but their roles in thyroid cancers have not been clearly defined. The aim of the present study was to investigate the clinicopathological roles of the p16 gene in papillary thyroid carcinoma (PTC).

Methods

p16 gene alterations were investigated in 44 patients with PTC (9 men, 35 women) by immunohistochemistry, reverse transcriptase–polymerase chain reaction and methylation-specific polymerase chain reaction. The findings were correlated with their clinicopathological features.

Results

p16 protein expression, mRNA alterations, and promoter methylation were detected in 89% (n = 39), 77% (n = 33), and 41% (n = 18) of patients with PTC, respectively. There was no marked relationship between p16 protein expression, mRNA alteration, and promoter methylation. In follicular variant of PTC (FVPTC), there was a frequent lack of p16 protein expression and promoter methylation. PTCs showing p16 promoter methylation were often associated with a high AMES (age, metastasis to distant sites, extrathyroidal invasion, size) risk group and advanced pTNM (tumor–lymph node–metastasis) stages.

Conclusions

p16 gene alterations are common and correlate with histological features and biological aggressiveness in PTC, suggesting that they might play an important role in its pathogenesis.

Larsen CJ. Contribution of the dual coding capacity of the p16INK4a/MTS1/CDKN2 locus to human malignancies. Prog Cell Cycle Res 1997; 3:109–24PubMed

Oue N, Mitani Y, Motoshita J, et al. Accumulation of DNA methylation is associated with tumour stage in gastric cancer. Cancer 2006; 106:1250–9PubMedCrossRef

Mihic-Probst D, Mnich CD, Oberholzer PA, et al. p16 expression in primary malignant melanoma is associated with prognosis and lymph node status. Int J Cancer 2006; 118:2262–8PubMedCrossRef

Sabah M, Cummins R, Leader M, Kay E. Loss of p16INK4A expression is associated with allelic imbalance/loss of heterozygosity of chromosome 9 p16 in microdissected synovial sarcomas. Virchows Arch 2005; 447:842–8PubMedCrossRef

Tsirigotis P, Pappa V, Labropoulos S, et al. Mutational and methylation analysis of the cyclin-dependent kinase 4 inhibitor (p16INK4A) gene in chronic lymphocytic leukemia. Eur J Haematol 2006; 76:230–6PubMedCrossRef

Auerkari EI. Methylation of tumour suppressor genes p16 (INK4a), p16 (Kip1) and E-cadherin in carcinogenesis. Oral Oncol 2006; 42:5–13PubMedCrossRef

Lam AK, Lo CY, Lam KS. Papillary carcinoma of thyroid: a 30-yr clinicopathological review of the histological variants. Endocr Pathol 2005; 16:323–30PubMedCrossRef

Ciampi R, Nikiforov YE. Alterations of the BRAF gene in thyroid tumours. Endocr Pathol 2005; 16:163–72PubMedCrossRef

Lam KY, Lo CY, Leung PS. High prevalence of RET proto-oncogene activation (RET/PTC) in papillary thyroid carcinomas. Eur J Endocrinol 2002; 147:741–5PubMedCrossRef

10.

Jarzab B, Wloch J, Wiench M. Molecular changes in thyroid neoplasia. Folia Histochem Cytobiol 2001; 39(Suppl 2):26–7PubMed

11.

LiVolsi VA, Albores-Saavedra J, Asa SL, et al. Papillary carcinoma. In: DeLellis RA, Llyod RV, Heitz PU, Eng C, eds. World Health Organization Classification of Tumours: Pathology and Genetics—Tumours of Endocrine Organs. Lyon: IARC, 2004:57–66

12.

Cady B, Sedgwick MD, Meissner WA, Wool MS, Salzman FA, Werber J. Risk factor analysis in differentiated thyroid cancer. Cancer 1979; 43:810–20PubMedCrossRef

13.

Jukkola A, Bloigu R, Ebeling T, Salmela P, Blanco G. Prognostic factors in differentiated thyroid carcinomas and their implications for current staging classifications. Endocr Relat Cancer 2004; 11:571–9PubMedCrossRef

14.

Lo CY, Chan WF, Lam KY, Wan KY. Optimizing the treatment of AMES high-risk papillary thyroid carcinoma. World J Surg 2004; 28:1103–9PubMedCrossRef

15.

Armes JE, Lourie R, de Silva M, et al. Abnormalities of the RB1 pathway in ovarian serous papillary carcinoma as determined by overexpression of the p16 (INK4A) protein. Int J Gynecol Pathol 2005; 24:363–8PubMedCrossRef

16.

Cui X, Shirai Y, Wakai T, Yokoyama N, Hirano S, Hatakeyama K. Aberrant expression of pRb and p16 (INK4), alone or in combination, indicates poor outcome after resection in patients with colorectal carcinoma. Hum Pathol 2004; 35:1189–95PubMedCrossRef

17.

O’Neill CJ, McCluggage WG. p16 expression in the female genital tract and its value in diagnosis. Adv Anat Pathol 2006; 13:8–15PubMedCrossRef

18.

Dray M, Russell P, Dalrymple C, et al. p16 (INK4a) as a complementary marker of high-grade intraepithelial lesions of the uterine cervix. I: experience with squamous lesions in 189 consecutive cervical biopsies. Pathology 2005; 37:112–24PubMed

19.

Boltze C, Zack S, Quednow C, Bettge S, Roessner A, Schneider-Stock R. Hypermethylation of the CDKN2/ p16INK4A promotor in thyroid carcinogenesis. Pathol Res Pract 2003; 199:399–404PubMedCrossRef

20.

Ferenc T, Lewinski A, Lange D, et al. Analysis of p161NK4A protein expression in follicular thyroid tumours. Pol J Pathol 2004; 55:143–8PubMed

21.

Schagdarsurengin U, Gimm O, Hoang-Vu C, Dralle H, Pfeifer GP, Dammann R. Frequent epigenetic silencing of the CpG island promoter of RASSF1A in thyroid carcinoma. Cancer Res 2002; 62:3698–701PubMed

22.

Elisei R, Shiohara M, Koeffler HP, Fagin JA. Genetic and epigenetic alterations of the cyclin-dependent kinase inhibitors p16INK4b and p16INK4a in human thyroid carcinoma cell lines and primary thyroid carcinomas. Cancer 1998; 83:2185–93PubMedCrossRef

23.

Schulte KM, Staudt S, Niederacher D, et al. Rare loss of heterozygosity of the MTS1 and MTS2 tumor suppressor genes in differentiated human thyroid cancer. Horm Metab Res 1998; 30:549–54PubMedCrossRef

24.

Ivan M, Wynford-Thomas D, Jones CJ. Abnormalities of the p16INK4A gene in thyroid cancer cell lines. Eur J Cancer 1996; 32A:2369–70PubMedCrossRef

25.

Calabro V, Strazzullo M, La Mantia G, et al. Status and expression of the p16INK4 gene in human thyroid tumors and thyroid-tumor cell lines. Int J Cancer 1996; 67:29–34PubMedCrossRef

26.

Yane K, Konishi N, Kitahori Y, et al. Lack of p16/CDKN2 alterations in thyroid carcinomas. Cancer Lett 1996; 101:85–92PubMedCrossRef

27.

Jones CJ, Shaw JJ, Wyllie FS, Gaillard N, Schlumberger M, Wynford-Thomas D. High frequency deletion of the tumour suppressor gene p16INK4a (MTS1) in human thyroid cancer cell lines. Mol Cell Endocrinol 1996; 116:115–9PubMedCrossRef

28.

Yane K, Konishi N, Kitahori Y, Hiasa Y, et al. Lack of p16/CDKN2 alterations in thyroid carcinomas. Cancer Lett 1996; 101:85–92PubMedCrossRef

29.

Lang BH, Lo CY, Chan WF, Lam AK, Wan KY. Classical and follicular variant of papillary thyroid carcinoma: a comparative study on clinicopathologic features and long-term Outcome. World J Surg 2006; 30:752–8PubMedCrossRef

30.

Lloyd RV, Erickson LA, Casey MB, et al. Observer variation in the diagnosis of follicular variant of papillary thyroid carcinoma. Am J Surg Pathol 2004; 28:1336–40PubMedCrossRef

31.

Lo CY, Lam KY, Leung PP, Luk JM. High prevalence of cyclooxygenase 2 expression in papillary thyroid carcinoma. Eur J Endocrinol 2005; 152:545–50PubMedCrossRef

32.

Lam AK, Montone KT, Nolan KA, Livolsi VA. Ret oncogene activation in papillary thyroid carcinoma: prevalence and implication on the histological parameters. Hum Pathol 1998; 29:565–8PubMedCrossRef

Title: Clinicopathological Roles of Alterations of Tumor Suppressor Gene p16 in Papillary Thyroid Carcinoma
Authors: Alfred King Yin Lam, MBBS, MD, PhD, FRCPA
Chung Yau Lo, MBBS, MS, FRCS (Edin.), FACS
Pauline Leung, BSc
Brian Hung Hin Lang, MBBS, FRACS
Wai Fun Chan, MBBS, FRCS (Edin.)
John M. Luk, DMedSc
Publication date: 01-05-2007
Publisher: Springer-Verlag
Published in: Annals of Surgical Oncology / Issue 5/2007
Print ISSN: 1068-9265
Electronic ISSN: 1534-4681
DOI: https://doi.org/10.1245/s10434-006-9280-9

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Clinicopathological Roles of Alterations of Tumor Suppressor Gene p16 in Papillary Thyroid Carcinoma

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 5/2007

Regional Nodal Metastatic Disease Is the Strongest Predictor of Survival in Patients with Thin Vertical Growth Phase Melanomas: A Case for SLN Staging Biopsy in These Patients

Analysis of Early Postoperative Morbidity Among Patients with Rectal Cancer Treated with and without Neoadjuvant Chemoradiotherapy

Diffusion of Surgical Techniques in Early Stage Breast Cancer: Variables Related to Adoption and Implementation of Sentinel Lymph Node Biopsy

Carcinoid of the Rectum Risk Stratification (CaRRs): A Strategy for Preoperative Outcome Assessment

Local Recurrence in Soft Tissue Sarcoma: More About the Tumor, Less About the Surgeon

A Phase II Trial of Image-Guided Radiofrequency Ablation of Small Invasive Breast Carcinomas: Use of Saline-Cooled Tip Electrode