BRAF, TERT and HLA-G Status in the Papillary Thyroid Carcinoma: A Clinicopathological Association Study

As BRAF, TERT, HLA-G, and microRNAs have been individually associated with papillary thyroid carcinoma (PTC), we aimed to evaluate the individual and collaborative role of these markers in PTC in the same patient cohort. HLA-G and BRAF tumor expression was evaluated by immunohistochemistry. Using molecular methods, BRAFV600E and TERT promoter mutations were evaluated in thyroid fine needle aspirates. MicroRNA tumor profiling was investigated using massively parallel sequencing. We observed strong HLA-G (67.96%) while BRAF (62.43%) staining was observed in PTC specimens. BRAF overexpression was associated with poor response to therapy. The BRAFV600E (52.9%) and TERTC228T (13%) mutations were associated with extrathyroidal extension, advanced-age, and advanced-stage cancer. The TERT rs2853669 CC+TC genotypes (38%) were overrepresented in metastatic tumors. Nine modulated microRNAs targeting the BRAF, TERT, and/or HLA-G genes were observed in PTC and involved with cancer-related signaling pathways. The markers were individually associated with PTC features, emphasizing the synergistic effect of BRAFV600E and TERTC228T; however, their collaborative role on PTC outcome was not fully demonstrated. The differentially expressed miRNAs targeting the BRAF and/or HLA-G genes may explain their increased expression in the tumor milieu.

[1]  Chenyue Zhang,et al.  TERT mutations correlate with higher TMB value and unique tumor microenvironment and may be a potential biomarker for anti‐CTLA4 treatment , 2020, Cancer medicine.

[2]  L. C. Conti de Freitas,et al.  Plasma levels of soluble HLA‐G and cytokines in papillary thyroid carcinoma before and after thyroidectomy , 2020, International journal of clinical practice.

[3]  T. Fujiwara,et al.  Upregulation of microRNA-31 is associated with poor prognosis in patients with advanced colorectal cancer , 2020, Oncology letters.

[4]  H. Kamma,et al.  Clinicopathological significance of the single nucleotide polymorphism, rs2853669 within the TERT promoter in papillary thyroid carcinoma , 2020, Pathology international.

[5]  Randle Aaron M. Villanueva,et al.  ggplot2: Elegant Graphics for Data Analysis (2nd ed.) , 2019, Measurement: Interdisciplinary Research and Perspectives.

[6]  D. G. Pinheiro,et al.  Post-transcriptional markers associated with clinical complications in Type 1 and Type 2 diabetes mellitus , 2019, Molecular and Cellular Endocrinology.

[7]  A. Moslem,et al.  Epidemiology, incidence and mortality of thyroid cancer and their relationship with the human development index in the world: An ecology study in 2018 , 2019, Advances in Human Biology.

[8]  M. A. Arruda,et al.  Preoperative detection of TERT promoter and BRAFV600E mutations in papillary thyroid carcinoma in high-risk thyroid nodules. , 2019, Archives of endocrinology and metabolism.

[9]  E. Donadi,et al.  MicroRNA expression profiles discriminate childhood T‐ from B‐acute lymphoblastic leukemia , 2018, Hematological oncology.

[10]  L. Kowalski,et al.  Loss of DNA methylation is related to increased expression of miR-21 and miR-146b in papillary thyroid carcinoma , 2018, Clinical Epigenetics.

[11]  Xiao-mei Zhang,et al.  Prognostic value of a two‐microRNA signature for papillary thyroid cancer and a bioinformatic analysis of their possible functions , 2018, Journal of cellular biochemistry.

[12]  F. Guo,et al.  MicroRNA-9-5p functions as a tumor suppressor in papillary thyroid cancer via targeting BRAF. , 2018, Oncology letters.

[13]  J. Liu,et al.  Young age increases the risk of lymph node positivity in papillary thyroid cancer patients: a SEER data-based study , 2018, Cancer management and research.

[14]  Hong Yang,et al.  Downregulation of miR-486-5p in papillary thyroid carcinoma tissue: A study based on microarray and miRNA sequencing , 2018, Molecular medicine reports.

[15]  K. J. Na,et al.  Immune landscape of papillary thyroid cancer and immunotherapeutic implications. , 2018, Endocrine-related cancer.

[16]  E. Chmielik,et al.  Dynamic risk stratification in the follow-up of thyroid cancer: what is still to be discovered in 2017? , 2017, Endocrine-related cancer.

[17]  P. Vitti,et al.  Differences in miRNA expression profiles between wild-type and mutated NIFTPs. , 2017, Endocrine-related cancer.

[18]  Latife Arzu Aral,et al.  Plasma human leukocyte antigen-G (HLA-G) in patients with thyroid cancer , 2017, Turkish journal of medical sciences.

[19]  Nancy D Perrier,et al.  Updated American Joint Committee on Cancer/Tumor-Node-Metastasis Staging System for Differentiated and Anaplastic Thyroid Cancer (Eighth Edition): What Changed and Why? , 2017, Thyroid : official journal of the American Thyroid Association.

[20]  J. Strominger,et al.  HLA-G: At the Interface of Maternal-Fetal Tolerance. , 2017, Trends in immunology.

[21]  N. Shen,et al.  Association between rs2853669 in TERT gene and the risk and prognosis of human cancer: a systematic review and meta-analysis. , 2017, OncoTarget.

[22]  M. Barczyński,et al.  BRAF V600E mutation in prognostication of papillary thyroid cancer (PTC) recurrence. , 2016, Gland surgery.

[23]  S. Balasubramanian,et al.  Systematic Review of Trends in the Incidence Rates of Thyroid Cancer. , 2016, Thyroid : official journal of the American Thyroid Association.

[24]  Ju Han Kim,et al.  Significance of the BRAF mRNA Expression Level in Papillary Thyroid Carcinoma: An Analysis of The Cancer Genome Atlas Data , 2016, PloS one.

[25]  R. Calado,et al.  Acquired TERT promoter mutations stimulate TERT transcription in mantle cell lymphoma , 2016, American journal of hematology.

[26]  Jun S. Song,et al.  Understanding TERT Promoter Mutations: A Common Path to Immortality , 2016, Molecular Cancer Research.

[27]  M. Xing,et al.  BRAF and TERT promoter mutations in the aggressiveness of papillary thyroid carcinoma: a study of 653 patients , 2016, Oncotarget.

[28]  Gal Omry-Orbach.  Risk Stratification in Differentiated Thyroid Cancer: An Ongoing Process , 2016, Rambam Maimonides medical journal.

[29]  J. Fang,et al.  Decreased expression of tumor suppressive miR-874 and its clinical significance in human osteosarcoma. , 2015, Genetics and molecular research : GMR.

[30]  A. Lam,et al.  Clinical pathological impacts of microRNAs in papillary thyroid carcinoma: A crucial review. , 2015, Experimental and molecular pathology.

[31]  V. Detours,et al.  New global analysis of the microRNA transcriptome of primary tumors and lymph node metastases of papillary thyroid cancer , 2015, BMC Genomics.

[32]  A. Lin,et al.  Human Leukocyte Antigen-G (HLA-G) Expression in Cancers: Roles in Immune Evasion, Metastasis and Target for Therapy , 2015, Molecular medicine.

[33]  J. Perales-Patón,et al.  The miR-146b-3p/PAX8/NIS Regulatory Circuit Modulates the Differentiation Phenotype and Function of Thyroid Cells during Carcinogenesis. , 2015, Cancer research.

[34]  É. C. de Paula,et al.  BRAF overexpression is associated with BRAF V600E mutation in papillary thyroid carcinomas. , 2015, Genetics and molecular research : GMR.

[35]  Li Yang,et al.  miR-874 functions as a tumor suppressor by inhibiting angiogenesis through STAT3/VEGF-A pathway in gastric cancer , 2015, Oncotarget.

[36]  J. Bishop,et al.  BRAF V600E and TERT promoter mutations cooperatively identify the most aggressive papillary thyroid cancer with highest recurrence. , 2014, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[37]  R. Tuttle,et al.  Update on differentiated thyroid cancer staging. , 2014, Endocrinology and metabolism clinics of North America.

[38]  E. Donadi,et al.  Transcriptional and Posttranscriptional Regulations of the HLA-G Gene , 2014, Journal of immunology research.

[39]  E. Donadi,et al.  HLA-G is differentially expressed in thyroid tissues. , 2014, Thyroid : official journal of the American Thyroid Association.

[40]  Zi-ming Yuan,et al.  Deregulation of microRNA expression in thyroid tumors , 2014, Journal of Zhejiang University SCIENCE B.

[41]  Jennifer M. Carr,et al.  RNA sequencing identifies multiple fusion transcripts, differentially expressed genes, and reduced expression of immune function genes in BRAF (V600E) mutant vs BRAF wild-type papillary thyroid carcinoma. , 2014, The Journal of clinical endocrinology and metabolism.

[42]  A. Fusco,et al.  Deregulation of microRNA expression in thyroid neoplasias , 2014, Nature Reviews Endocrinology.

[43]  J. Bishop,et al.  Highly prevalent TERT promoter mutations in aggressive thyroid cancers. , 2013, Endocrine-related cancer.

[44]  Simone Mocellin,et al.  Telomerase and the search for the end of cancer. , 2013, Trends in molecular medicine.

[45]  E. Carosella,et al.  The immunosuppressive molecule HLA-G and its clinical implications , 2012, Critical reviews in clinical laboratory sciences.

[46]  Rajvir Dahiya,et al.  MicroRNA-708 induces apoptosis and suppresses tumorigenicity in renal cancer cells. , 2011, Cancer research.

[47]  C. Sander,et al.  Integrative genomic profiling of human prostate cancer. , 2010, Cancer cell.

[48]  L. Excoffier,et al.  Arlequin suite ver 3.5: a new series of programs to perform population genetics analyses under Linux and Windows , 2010, Molecular ecology resources.

[49]  Hadley Wickham,et al.  ggplot2 - Elegant Graphics for Data Analysis (2nd Edition) , 2017 .

[50]  M. Haymart.  Understanding the relationship between age and thyroid cancer. , 2009, The oncologist.

[51]  Brad T. Sherman,et al.  Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists , 2008, Nucleic acids research.

[52]  Brett Kahr.  Tissues , 2008, On Practising Therapy at 1.45 A.M..

[53]  S. Asa,et al.  Enhanced B-Raf protein expression is independent of V600E mutant status in thyroid carcinomas. , 2007, Human pathology.

[54]  Yu Liang,et al.  BMC Genomics , 2007 .

[55]  N. Rouas-Freiss,et al.  Immuno-tolerogenic functions of HLA-G: relevance in transplantation and oncology. , 2005, Autoimmunity reviews.

[56]  M. Xing,et al.  BRAF mutation in thyroid cancer. , 2005, Endocrine-related cancer.

[57]  E. Blackburn,et al.  Telomeres and telomerase: their mechanisms of action and the effects of altering their functions , 2005, FEBS letters.

[58]  D. Geraghty,et al.  Analysis of HLA-E expression in human tumors , 2003, Immunogenetics.

[59]  E. Thompson,et al.  Performing the exact test of Hardy-Weinberg proportion for multiple alleles. , 1992, Biometrics.

[60]  Kaliszewski,et al.  American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer : The American Thyroid Association Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid Cancer , 2017 .

[61]  Rajiv Kumar,et al.  TERT promoter mutations in telomere biology. , 2017, Mutation research.

[62]  L. Marshall.  Follicular cell-derived thyroid cancer , 2015, Nature Reviews Disease Primers.

[63]  R Core Team,et al.  R: A language and environment for statistical computing. , 2014 .

[64]  Shen Lv,et al.  Utility of BRAF protein overexpression in predicting the metastasis potential of papillary thyroid carcinoma. , 2011, Oncology letters.

[65]  D. Wallace,et al.  Telomere diseases. , 2010, The New England journal of medicine.

[66]  J. Klein,et al.  The HLA system. First of two parts. , 2000, The New England journal of medicine.