376645480cbbde1397972fcd7feed590 pmc_33922635.pdf f8dfa0ccdf4915868526e97a427bc3ad061a135e pmc_33922635.pdf aa74a671aec7626948750bb271f365fc86d035e98eccd77e6921d856a804ccb7 pmc_33922635.pdf Title: Genetic Determinants for Prediction of Outcome of Patients with Papillary Thyroid Carcinoma Subject: 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 TERTpmut showed increased risk of structural disease (HR = 7.0, p < 0.001) and DSM (HR = 10.1, p = 0.001). Combined genotypes, BRAFwt/TERTpmut (HR = 6.8, p = 0.003), BRAFmut/TERTpmut (HR = 3.2, p = 0.056) and BRAFmut/TERTpwt (HR = 2.2, p = 0.023) showed increased risk of recurrent/persistent disease. Patients with tumors BRAFwt/TERTpmut (HR = 24.2, p < 0.001) and BRAFmut/TERTpmut (HR = 11.5, p = 0.002) showed increased risk of structural disease. DSM was significantly increased in patients with TERTpmut regardless of BRAF status (BRAFmut/TERTpmut, log-rank p < 0.001; BRAFwt/TERTpmut, log-rank p < 0.001). Our results indicate that molecular markers may have a role in predicting PTC patients’ outcome. BRAFmut/TERTpwt tumors were prone to associate with local aggressiveness (recurrent/persistent disease), whereas TERTpmut tumors were predisposed to recurrent structural disease and DSM. Keywords: thyroid cancer; papillary thyroid carcinoma; prognosis; BRAF; RAS; TERT; patient outcome; recurrent/persistent disease; structural disease; PTC-specific mortality Author: Antónia Afonso Póvoa, Elisabete Teixeira, Maria Rosa Bella-Cueto, Rui Batista, Ana Pestana, Miguel Melo, Thalita Alves, Mafalda Pinto, Manuel Sobrinho-Simões, Jorge Maciel and Paula Soares Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Sun Apr 25 08:35:42 2021 CEST ModDate: Sun Apr 25 08:39:30 2021 CEST Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 16 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 1728101 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- LQVUEJ+VnURWPalladioL Type 1 Custom yes yes no 10 0 LOFVZG+URWPalladioL-Ital Type 1 Custom yes yes no 15 0 GLNTTZ+URWPalladioL-Bold Type 1 Custom yes yes no 20 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no 155 0 ABCDEE+Palatino Linotype,Italic TrueType WinAnsi yes yes no 159 0 ABCDEE+Palatino Linotype CID TrueType Identity-H yes yes yes 163 0 ABCDEE+Palatino Linotype,Bold TrueType WinAnsi yes yes no 182 0 ABCDEE+Palatino Linotype TrueType WinAnsi yes yes no 186 0 ABCDEE+Palatino Linotype,Italic TrueType WinAnsi yes yes no 190 0 ABCDEE+Palatino Linotype CID TrueType Identity-H yes yes yes 194 0 ABCDEE+Palatino Linotype,BoldItalic TrueType WinAnsi yes yes no 201 0 Jhove (Rel. 1.22.1, 2019-04-17) Date: 2023-10-21 02:38:22 CEST RepresentationInformation: pmc_33922635.pdf ReportingModule: PDF-hul, Rel. 1.12.1 (2019-04-17) LastModified: 2023-03-31 12:09:51 CEST Size: 1728101 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 497 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@262b2c86 Item: Title: Materials and Methods Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@371a67ec Children: Item: Title: Patient Samples Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@5ed828d Item: Title: Patient Follow-Up and Risk Stratification Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@50d0686 Item: Title: DNA Extraction Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7a3d45bd Item: Title: PCR and Sanger Sequencing Analysis Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1e7c7811 Item: Title: Statistical Analysis Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@77ec78b9 Item: Title: Results Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1a3869f4 Children: Item: Title: Description of the Patients Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@a38d7a3 Item: Title: Primary Tumors’ Genetic Characterization Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@77f99a05 Item: Title: Metastatic Lesions’ Genetic Characterization and Molecular Profile Concordance Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@63440df3 Item: Title: Molecular Alterations in Recurrent/Persistent Disease Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@3aeaafa6 Item: Title: Molecular Alterations in Structural Disease Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@76a3e297 Item: Title: Molecular Alterations in Disease-Specific Mortality Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@4d3167f4 Item: Title: Discussion Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@ed9d034 Item: Title: Conclusions Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@6121c9d6 Item: Title: References Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@87f383f Info: Title: Genetic Determinants for Prediction of Outcome of Patients with Papillary Thyroid Carcinoma Author: Antónia Afonso Póvoa, Elisabete Teixeira, Maria Rosa Bella-Cueto, Rui Batista, Ana Pestana, Miguel Melo, Thalita Alves, Mafalda Pinto, Manuel Sobrinho-Simões, Jorge Maciel and Paula Soares Subject: 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 TERTpmut showed increased risk of structural disease (HR = 7.0, p < 0.001) and DSM (HR = 10.1, p = 0.001). Combined genotypes, BRAFwt/TERTpmut (HR = 6.8, p = 0.003), BRAFmut/TERTpmut (HR = 3.2, p = 0.056) and BRAFmut/TERTpwt (HR = 2.2, p = 0.023) showed increased risk of recurrent/persistent disease. Patients with tumors BRAFwt/TERTpmut (HR = 24.2, p < 0.001) and BRAFmut/TERTpmut (HR = 11.5, p = 0.002) showed increased risk of structural disease. DSM was significantly increased in patients with TERTpmut regardless of BRAF status (BRAFmut/TERTpmut, log-rank p < 0.001; BRAFwt/TERTpmut, log-rank p < 0.001). Our results indicate that molecular markers may have a role in predicting PTC patients’ outcome. BRAFmut/TERTpwt tumors were prone to associate with local aggressiveness (recurrent/persistent disease), whereas TERTpmut tumors were predisposed to recurrent structural disease and DSM. 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Annotation: Subtype: Link Rect: 476, 663, 513, 674 Annotation: Subtype: Link Rect: 455, 640, 492, 651 Annotation: Subtype: Link Rect: 499, 640, 535, 651 Annotation: Subtype: Link Rect: 177, 595, 215, 605 Annotation: Subtype: Link Rect: 496, 571, 534, 582 Annotation: Subtype: Link Rect: 362, 548, 400, 559 Annotation: Subtype: Link Rect: 406, 548, 442, 559 Annotation: Subtype: Link Rect: 145, 515, 182, 525 Annotation: Subtype: Link Rect: 380, 491, 417, 502 Annotation: Subtype: Link Rect: 424, 491, 460, 502 Annotation: Subtype: Link Rect: 396, 468, 433, 479 Annotation: Subtype: Link Rect: 439, 468, 475, 479 Checksum: 559eefa9 Type: CRC32 Checksum: 376645480cbbde1397972fcd7feed590 Type: MD5 Checksum: f8dfa0ccdf4915868526e97a427bc3ad061a135e Type: SHA-1