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Genetic Determinants for Prediction of Outcome of Patients with Papillary Thyroid Carcinoma.

ABSTRACT: Papillary thyroid carcinoma (PTC) usually presents an excellent prognosis, but some patients present with aggressive metastatic disease. BRAF, RAS, and TERT promoter (TERTp) genes are altered in PTC, and their impact on patient outcomes remains controversial. We aimed to determine the role of genetic alterations in PTC patient outcomes (recurrent/persistent disease, structural disease, and disease-specific mortality (DSM)). The series included 241 PTC patients submitted to surgery, between 2002-2015, in a single hospital. DNA was extracted from tissue samples of 287 lesions (primary tumors and metastases). Molecular alterations were detected by Sanger sequencing. Primary tumors presented 143 BRAF, 16 TERTp, and 13 RAS mutations. Isolated TERTp^mut showed increased risk of structural disease (HR = 7.0, p < 0.001) and DSM (HR = 10.1, p = 0.001). Combined genotypes, BRAF^wt/TERTp^mut (HR = 6.8, p = 0.003), BRAF^mut/TERTp^mut (HR = 3.2, p = 0.056) and BRAF^mut/TERTp^wt (HR = 2.2, p = 0.023) showed increased risk of recurrent/persistent disease. Patients with tumors BRAF^wt/TERTp^mut (HR = 24.2, p < 0.001) and BRAF^mut/TERTp^mut (HR = 11.5, p = 0.002) showed increased risk of structural disease. DSM was significantly increased in patients with TERTp^mut regardless of BRAF status (BRAF^mut/TERTp^mut, log-rank p < 0.001; BRAF^wt/TERTp^mut, log-rank p < 0.001). Our results indicate that molecular markers may have a role in predicting PTC patients' outcome. BRAF^mut/TERTp^wt tumors were prone to associate with local aggressiveness (recurrent/persistent disease), whereas TERTp^mut tumors were predisposed to recurrent structural disease and DSM.

SUBMITTER: Povoa AA

PROVIDER: S-EPMC8122921 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundPersistent or recurrent papillary thyroid carcinoma (PTC) occurs in some patients after initial thyroid surgery and often, radioactive iodine treatment. Here, we identify the efficacy, safety, and long-term outcome of our current surgical management paradigm for persistent/recurrent PTC in the central compartment in an interdisciplinary thyroid cancer clinical and research program at a tertiary thyroid cancer referral center.MethodsWe retrospectively analyzed our standardized approach of comprehensive bilateral level VI/VII lymph node dissection (SND [VI, VII]) for cytologically confirmed PTC in the central compartment.ResultsFrom 1994 to 2004, 210 patients, median age 42 (range 12-82) underwent SND (VI, VII). Most patients (106, 51%) had already undergone ≥2 surgical procedures for persistent or recurrent disease, and 31 (15%) had distant metastases at presentation. Postoperatively, 104 (71%) of the 146 patients who were thyroglobulin (Tg) positive had no evidence of disease. Anti-Tg antibodies were present in 38 patients (18%), 17 of whom (53%) did not have anti-Tg antibodies postoperatively. Fourteen patients (7%) were hypoparathyroid at presentation, and 2 more (1%) became permanently hypoparathyroid after surgery. Four patients (2%) experienced recurrent laryngeal nerve paralysis (RLNP) of a previously functioning nerve. Unanticipated RLNP was observed in only one nerve at risk. External beam radiation was given to 33 patients (17%). An additional 17 patients (8%) developed distant metastases during follow-up. At the last follow-up, 130 (66%) of the 196 patients had no detectable Tg; of these, 99 (76%) had no further evidence of disease. A median of 7.25 years after surgery, 167 (90%) of the 185 patients were without evidence of central disease, and 18 (10%) had developed central compartment recurrences within a median interval of 24.3 months. Of those with recurrence, 16 out of 18 patients (89%) underwent a subsequent surgical procedure, thus resulting in an overall 98% central compartment control rate. Kaplan-Meier disease-specific survival at 10 years was 98.9% for patients <45 years old and 77.9% for those ≥45 years old (log-rank p<0.00001). The only predictor of central compartment recurrence was malignancy in a thyroid remnant noted within the central compartment surgical specimen.ConclusionsBilateral comprehensive level VI/VII dissections are safe and effective for long-term control of recurrent/persistent PTC in the central lymphatic compartment.

Project description:Although the mortality rate of papillary thyroid carcinoma (PTC) is relatively low, the recurrence rates of PTC remain high. The high recurrence rates are related to the difficulties in treatment. Gene expression profiles has provided novel insights into potential therapeutic targets and molecular biomarkers of PTC. The aim of the present study was to identify mRNA signatures which may categorize PTCs into high-and low-risk subgroups and aid with the predictions for prognoses. The mRNA expression profiles of PTC and normal thyroid tissue samples were obtained from The Cancer Genome Atlas (TCGA) database. Differentially expressed mRNAs were identified using the 'EdgeR' software package. Gene signatures associated with the overall survival of PTC were selected, and enrichment analysis was performed to explore the biological pathways and functions of the prognostic mRNAs using the Database for Visualization, Annotation and Integration Discovery. A signature model was established to investigate a specific and robust risk stratification for PTC. A total of 1,085 differentially expressed mRNAs were identified between the PTC and normal thyroid tissue samples. Among them, 361 mRNAs were associated with overall survival (P<0.05). A 5-mRNA prognostic signature for PTC (ADRA1B, RIPPLY3, PCOLCE, TEKT1 and SALL3) was identified to classify the patients into high-and low-risk subgroups. These prognostic mRNAs were enriched in Gene Ontology terms such as 'calcium ion binding', 'enzyme inhibitor activity', 'carbohydrate binding', 'transcriptional activator activity', 'RNA polymerase II core promoter proximal region sequence-specific binding' and 'glutathione transferase activity', and Kyoto Encyclopedia of Genes and Genomes signaling pathways such as 'pertussis', 'ascorbate and aldarate metabolism', 'systemic lupus erythematosus', 'drug metabolism-cytochrome P450 and 'complement and coagulation cascades'. The 5-mRNA signature model may be useful during consultations with patients with PTC to improve the prediction of their prognosis. In addition, the prognostic signature identified in the present study may reveal novel therapeutic targets for patients with PTC.

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Genetic Determinants for Prediction of Outcome of Patients with Papillary Thyroid Carcinoma.

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