Role of CDKN2C Copy Number in Sporadic Medullary Thyroid Carcinoma.

BACKGROUND The cyclin-dependent-kinase inhibitors (CDKN)/retinoblastoma (RB1) pathway has been implicated as having a role in medullary thyroid carcinoma (MTC) tumorigenesis. CDKN2C loss has been associated with RET-mediated MTC in humans but with minimal phenotypic correlation provided. The objective of this study was to evaluate the association between tumor RET mutation status, CDKN2C loss, and aggressiveness of MTC in a cohort of patients with sporadic disease. METHODS Tumors from patients with sporadic MTC treated at a single institution were evaluated for somatic RETM918T mutation and CDKN2C copy number loss. These variables were compared to patient demographics, pathology detail, clinical course, and disease-specific and overall survival. RESULTS Sixty-two MTC cases with an initial surgery date ranging from 1983 to 2009 met the inclusion criteria, of whom 36 (58%) were male. The median age at initial surgery was 53 years (range 22-81 years). The median tumor size was 30 mm (range 6-145 mm) with 29 (57%) possessing extrathyroidal extension. Nodal and/or distant metastasis at presentation was found in 47/60 (78%) and 12/61 (20%) patients, respectively. Median follow-up time was 10.5 years (range 1.1-27.8 years) for the censored observations. The presence of CDKN2C loss was associated with worse M stage and overall AJCC stage. Median overall survival of patients with versus without CDKN2C loss was 4.14 [confidence interval (CI) 1.93-NA] versus 18.27 [CI 17.24-NA] years (p < 0.0001). Median overall survival of patients with a combined somatic RETM918T mutation and CDKN2C loss versus no somatic RETM918T mutation and CDKN2C loss versus somatic RETM918T mutation and CDKN2C 2N versus no somatic RETM918T mutation and CDKN2C 2N was 2.38 [CI 1.67-NA] years versus 10.81 [CI 2.46-NA] versus 17.24 [CI 9.82-NA] versus not reached [CI 13.46-NA] years (p < 0.0001). CONCLUSIONS The detection of somatic CDKN2C loss is associated with the presence of distant metastasis at presentation as well decreased overall survival, a relationship enhanced by concomitant RETM918T mutation. Further defining the genes involved in the progression of metastatic MTC will be an important step toward identifying pathways of disease progression and new therapeutic targets.

[1]  James X. Sun,et al.  Comprehensive Genomic Profiling of Clinically Advanced Medullary Thyroid Carcinoma , 2016, Oncology.

[2]  A. Lazar,et al.  Somatic Copy Number Alterations at Oncogenic Loci Show Diverse Correlations with Gene Expression , 2016, Scientific Reports.

[3]  V. Leite,et al.  RAS proto-oncogene in medullary thyroid carcinoma. , 2015, Endocrine-related cancer.

[4]  E. Mayer.  Targeting Breast Cancer with CDK Inhibitors , 2015, Current Oncology Reports.

[5]  G. Cote,et al.  Treating medullary thyroid cancer in the age of targeted therapy. , 2014, International journal of endocrine oncology.

[6]  Zhonglei Lu,et al.  Antitumor mechanisms when pRb and p53 are genetically inactivated , 2014, Oncogene.

[7]  Mingming Jia,et al.  COSMIC: exploring the world's knowledge of somatic mutations in human cancer , 2014, Nucleic Acids Res..

[8]  M. Dickson.  Molecular Pathways Molecular Pathways : CDK 4 Inhibitors for Cancer Therapy , 2014 .

[9]  O. Griffith,et al.  COSMIC (Catalogue of Somatic Mutations in Cancer) , 2014 .

[10]  M. Banerjee,et al.  The effect of extent of surgery and number of lymph node metastases on overall survival in patients with medullary thyroid cancer. , 2014, The Journal of clinical endocrinology and metabolism.

[11]  S. Elledge,et al.  Cumulative Haploinsufficiency and Triplosensitivity Drive Aneuploidy Patterns and Shape the Cancer Genome , 2013, Cell.

[12]  M. Kreissl,et al.  Cabozantinib in progressive medullary thyroid cancer. , 2013, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[13]  G. McArthur,et al.  The Cell-Cycle Regulator CDK4: An Emerging Therapeutic Target in Melanoma , 2013, Clinical Cancer Research.

[14]  Giovanni Tesoriere,et al.  RB1 in cancer: Different mechanisms of RB1 inactivation and alterations of pRb pathway in tumorigenesis , 2013, Journal of cellular physiology.

[15]  S. Sherman.  Lessons learned and questions unanswered from use of multitargeted kinase inhibitors in medullary thyroid cancer. , 2013, Oral oncology.

[16]  S. Grant,et al.  Cyclin-dependent kinase inhibitor therapy for hematologic malignancies , 2013, Expert opinion on investigational drugs.

[17]  L. Wood,et al.  Exomic sequencing of medullary thyroid cancer reveals dominant and mutually exclusive oncogenic mutations in RET and RAS. , 2013, The Journal of clinical endocrinology and metabolism.

[18]  M. Speicher,et al.  High‐resolution analysis of alterations in medullary thyroid carcinoma genomes , 2012, International journal of cancer.

[19]  E. Baudin,et al.  Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial. , 2012, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[20]  J. Akey.  Analysis of 2,440 human exomes highlights the evolution and functional impact of rare coding variation , 2011, Genome Biology.

[21]  V. Leite,et al.  High prevalence of RAS mutations in RET-negative sporadic medullary thyroid carcinomas. , 2011, The Journal of clinical endocrinology and metabolism.

[22]  L. Santarpia,et al.  The evolving field of tyrosine kinase inhibitors in the treatment of endocrine tumors. , 2010, Endocrine reviews.

[23]  C. Compton,et al.  The American Joint Committee on Cancer: the 7th Edition of the AJCC Cancer Staging Manual and the Future of TNM , 2010, Annals of Surgical Oncology.

[24]  Jean Y. J. Wang,et al.  Targeting the RB-pathway in Cancer Therapy , 2010, Clinical Cancer Research.

[25]  D. Farley,et al.  Need for a revised staging consensus in medullary thyroid carcinoma. , 2009, Archives of surgery.

[26]  L. Santarpia,et al.  Beyond RET: potential therapeutic approaches for advanced and metastatic medullary thyroid carcinoma , 2009, Journal of internal medicine.

[27]  Rene H Medema,et al.  P18 is a tumor suppressor gene involved in human medullary thyroid carcinoma and pheochromocytoma development , 2009, International journal of cancer.

[28]  L. Santarpia,et al.  High resolution array-comparative genomic hybridization profiling reveals deoxyribonucleic acid copy number alterations associated with medullary thyroid carcinoma. , 2008, The Journal of clinical endocrinology and metabolism.

[29]  D. Franklin,et al.  Synergistic effect of oncogenic RET and loss of p18 on medullary thyroid carcinoma development. , 2008, Cancer research.

[30]  S. Hauptmann,et al.  Locoregional recurrence and death from medullary thyroid carcinoma in a contemporaneous series: 5-year results. , 2007, European journal of endocrinology.

[31]  P. Pandolfi,et al.  p18Ink4c and Pten Constrain a Positive Regulatory Loop between Cell Growth and Cell Cycle Control , 2006, Molecular and Cellular Biology.

[32]  F. Zindy,et al.  The CDK Inhibitor p18Ink4c is a Tumor Suppressor in Medulloblastoma , 2006, Cell cycle.

[33]  Chiaki Takahashi,et al.  Genetic Interaction between Rb and K-ras in the Control of Differentiation and Tumor Suppression , 2004, Molecular and Cellular Biology.

[34]  D. Marsh,et al.  Genome-wide copy number imbalances identified in familial and sporadic medullary thyroid carcinoma. , 2003, The Journal of clinical endocrinology and metabolism.

[35]  V. Godfrey,et al.  Haploinsufficiency of p18INK4c Sensitizes Mice to Carcinogen-Induced Tumorigenesis , 2003, Molecular and Cellular Biology.

[36]  C. Larsson,et al.  CGH alterations in medullary thyroid carcinomas in relation to the RET M918T mutation and clinical outcome. , 2001, International journal of oncology.

[37]  V. Godfrey,et al.  Functional Collaboration between Different Cyclin-Dependent Kinase Inhibitors Suppresses Tumor Growth with Distinct Tissue Specificity , 2000, Molecular and Cellular Biology.

[38]  K. Franssila,et al.  DNA copy number changes in thyroid carcinoma. , 1999, The American journal of pathology.

[39]  F. Kaye,et al.  RET cooperates with RB/p53 inactivation in a somatic multi-step model for murine thyroid cancer , 1998, Oncogene.

[40]  L. Donehower,et al.  Mice deficient in both p53 and Rb develop tumors primarily of endocrine origin. , 1995, Cancer research.

[41]  T. Jacks,et al.  Cooperative tumorigenic effects of germline mutations in Rb and p53 , 1994, Nature Genetics.

[42]  C. Mathew,et al.  Genetic events in tumour initiation and progression in multiple endocrine neoplasia type 2 , 1993, Genes, chromosomes & cancer.

[43]  P. White,et al.  Consistent association of 1p loss of heterozygosity with pheochromocytomas from patients with multiple endocrine neoplasia type 2 syndromes. , 1992, Cancer research.

[44]  Samaan Na,et al.  Deletion mapping on the distal third region of chromosome 1p in multiple endocrine neoplasia type IIA. , 1990 .

[45]  C. Mathew,et al.  Deletion of genes on chromosome 1 in endocrine neoplasia , 1987, Nature.

[46]  M. Hofmann,et al.  Thyroid C-Cell Biology and Oncogenic Transformation. , 2015, Recent results in cancer research. Fortschritte der Krebsforschung. Progres dans les recherches sur le cancer.

[47]  A. Jemal,et al.  Cancer statistics, 2015 , 2015, CA: a cancer journal for clinicians.

[48]  S. Chellappan,et al.  The Rb-E2F transcriptional regulatory pathway in tumor angiogenesis and metastasis. , 2014, Advances in cancer research.

[49]  D. Goodrich,et al.  RB1, development, and cancer. , 2011, Current topics in developmental biology.

[50]  P. Pandolfi,et al.  p18 Ink4c and Pten constrain a positive regulatory loop between cell growth and cell cycle control. , 2006, Molecular and cellular biology.

[51]  C. Nguyen,et al.  Deletion mapping on the distal third region of chromosome 1p in multiple endocrine neoplasia type IIA. , 1990, Anticancer research.

[52]  Steven P Weitzman Maria E Cabanillas,et al.  Cancer Management and Research Dovepress the Treatment Landscape in Thyroid Cancer: a Focus on Cabozantinib , 2022 .