Genomic Characterization of Papillary Thyroid Cancer Reveals Germline Mutations Associated With Congenital Hypothyroidism
PURPOSEThyroid dyshormonogenesis, a form of congenital hypothyroidism, is characterized by defects in thyroid hormone synthesis genes, affecting both children and adults. However, the potential link between such genetic defects and the development of papillary thyroid cancer (PTC) remains unclear.ME...
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| Format: | Article |
| Language: | English |
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American Society of Clinical Oncology
2025-05-01
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| Series: | JCO Global Oncology |
| Online Access: | https://ascopubs.org/doi/10.1200/GO-25-00043 |
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| author | Vaishakhi Trivedi Hitesh Kore Disha Poojary Vanita Noronha Munita Bal Pratik Chandrani Anuradha Choughule Priyanka Pange Vinod Gupta Nandini Menon Vijay Patil Minit Shah Pankaj Chaturvedi Kumar Prabhash Amit Dutt |
| author_facet | Vaishakhi Trivedi Hitesh Kore Disha Poojary Vanita Noronha Munita Bal Pratik Chandrani Anuradha Choughule Priyanka Pange Vinod Gupta Nandini Menon Vijay Patil Minit Shah Pankaj Chaturvedi Kumar Prabhash Amit Dutt |
| author_sort | Vaishakhi Trivedi |
| collection | DOAJ |
| description | PURPOSEThyroid dyshormonogenesis, a form of congenital hypothyroidism, is characterized by defects in thyroid hormone synthesis genes, affecting both children and adults. However, the potential link between such genetic defects and the development of papillary thyroid cancer (PTC) remains unclear.METHODSWe conducted whole-exome sequencing on 100 (N = 100) tumor-normal paired and orphan tumor samples of PTC from Indian patients, characterizing both germline and somatic molecular alterations.RESULTSWe identified significant germline mutations in the DUOX2 gene (approximately 8.8%), commonly associated with congenital hypothyroidism and thyroid dyshormonogenesis, and found these mutations to correlate with poor prognosis in PTC. Additionally, hallmark somatic mutations were detected in genes such as BRAF (35.4%), KRAS (3.8%), HRAS (5.1%), and NRAS (17.7%), which are well-known drivers of PTC. Importantly, we identified a distinct molecular subtype termed independent of BRAF-RAS (iBR), characterized by nonhallmark alterations and associated with a higher recurrence rate and poorer recurrence-free survival in Indian patients with PTC, highlighting the clinical significance of these molecular insights in prognosis and treatment strategies.CONCLUSIONOur analysis of PTC among Indians revealed novel genetic alterations and molecular subtypes. We identified a germline mutation in the DUOX2 gene, associated with congenital hypothyroidism, as a potential risk factor of PTC. Additionally, we characterized distinct molecular subtypes, BRAF-RAS driven and iBR driven, and their clinical implications. These findings provide valuable insights into the genetic landscape of thyroid cancer in Indian patients and offer potential avenues for targeted therapies. |
| format | Article |
| id | doaj-art-3ac10644e7774e59bbd388c9ce1663fd |
| institution | OA Journals |
| issn | 2687-8941 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | American Society of Clinical Oncology |
| record_format | Article |
| series | JCO Global Oncology |
| spelling | doaj-art-3ac10644e7774e59bbd388c9ce1663fd2025-08-20T02:34:33ZengAmerican Society of Clinical OncologyJCO Global Oncology2687-89412025-05-011110.1200/GO-25-00043Genomic Characterization of Papillary Thyroid Cancer Reveals Germline Mutations Associated With Congenital HypothyroidismVaishakhi Trivedi0Hitesh Kore1Disha Poojary2Vanita Noronha3Munita Bal4Pratik Chandrani5Anuradha Choughule6Priyanka Pange7Vinod Gupta8Nandini Menon9Vijay Patil10Minit Shah11Pankaj Chaturvedi12Kumar Prabhash13Amit Dutt14Department of Medical Oncology, Tata Memorial Hospital, Parel, IndiaDepartment of Anatomy and Physiology, The University of Melbourne, Melbourne, AustraliaMedical Oncology Molecular Laboratory, Tata Memorial Hospital, Parel, IndiaDepartment of Medical Oncology, Tata Memorial Hospital, Parel, IndiaDepartment of Pathology, Tata Memorial Hospital, Parel, IndiaHomi Bhabha National Institute, Training School Complex, Mumbai, IndiaDepartment of Medical Oncology, Tata Memorial Hospital, Parel, IndiaDepartment of Medical Oncology, Tata Memorial Hospital, Parel, IndiaDepartment of Medical Oncology, Tata Memorial Hospital, Parel, IndiaDepartment of Medical Oncology, Tata Memorial Hospital, Parel, IndiaDepartment of Medical Oncology, Tata Memorial Hospital, Parel, IndiaDepartment of Medical Oncology, Tata Memorial Hospital, Parel, IndiaHomi Bhabha National Institute, Training School Complex, Mumbai, IndiaDepartment of Medical Oncology, Tata Memorial Hospital, Parel, IndiaIntegrated Cancer Genomics Laboratory, Department of Genetics (Biotech Centre), University of Delhi South Campus, New Delhi, IndiaPURPOSEThyroid dyshormonogenesis, a form of congenital hypothyroidism, is characterized by defects in thyroid hormone synthesis genes, affecting both children and adults. However, the potential link between such genetic defects and the development of papillary thyroid cancer (PTC) remains unclear.METHODSWe conducted whole-exome sequencing on 100 (N = 100) tumor-normal paired and orphan tumor samples of PTC from Indian patients, characterizing both germline and somatic molecular alterations.RESULTSWe identified significant germline mutations in the DUOX2 gene (approximately 8.8%), commonly associated with congenital hypothyroidism and thyroid dyshormonogenesis, and found these mutations to correlate with poor prognosis in PTC. Additionally, hallmark somatic mutations were detected in genes such as BRAF (35.4%), KRAS (3.8%), HRAS (5.1%), and NRAS (17.7%), which are well-known drivers of PTC. Importantly, we identified a distinct molecular subtype termed independent of BRAF-RAS (iBR), characterized by nonhallmark alterations and associated with a higher recurrence rate and poorer recurrence-free survival in Indian patients with PTC, highlighting the clinical significance of these molecular insights in prognosis and treatment strategies.CONCLUSIONOur analysis of PTC among Indians revealed novel genetic alterations and molecular subtypes. We identified a germline mutation in the DUOX2 gene, associated with congenital hypothyroidism, as a potential risk factor of PTC. Additionally, we characterized distinct molecular subtypes, BRAF-RAS driven and iBR driven, and their clinical implications. These findings provide valuable insights into the genetic landscape of thyroid cancer in Indian patients and offer potential avenues for targeted therapies.https://ascopubs.org/doi/10.1200/GO-25-00043 |
| spellingShingle | Vaishakhi Trivedi Hitesh Kore Disha Poojary Vanita Noronha Munita Bal Pratik Chandrani Anuradha Choughule Priyanka Pange Vinod Gupta Nandini Menon Vijay Patil Minit Shah Pankaj Chaturvedi Kumar Prabhash Amit Dutt Genomic Characterization of Papillary Thyroid Cancer Reveals Germline Mutations Associated With Congenital Hypothyroidism JCO Global Oncology |
| title | Genomic Characterization of Papillary Thyroid Cancer Reveals Germline Mutations Associated With Congenital Hypothyroidism |
| title_full | Genomic Characterization of Papillary Thyroid Cancer Reveals Germline Mutations Associated With Congenital Hypothyroidism |
| title_fullStr | Genomic Characterization of Papillary Thyroid Cancer Reveals Germline Mutations Associated With Congenital Hypothyroidism |
| title_full_unstemmed | Genomic Characterization of Papillary Thyroid Cancer Reveals Germline Mutations Associated With Congenital Hypothyroidism |
| title_short | Genomic Characterization of Papillary Thyroid Cancer Reveals Germline Mutations Associated With Congenital Hypothyroidism |
| title_sort | genomic characterization of papillary thyroid cancer reveals germline mutations associated with congenital hypothyroidism |
| url | https://ascopubs.org/doi/10.1200/GO-25-00043 |
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