Widespread Chromosomal Losses and Mitochondrial DNA Alterations as Genetic Drivers in Hürthle Cell Carcinoma

Gopal, Raj K.; Kübler, Kirsten; Calvo, Sarah E.; Polak, Paz; Livitz, Dimitri; Rosebrock, Daniel; Sadow, Peter M.; Campbell, Braidie; Donovan, Samuel E.; Amin, Salma; Gigliotti, Benjamin J.; Grabarek, Zenon; Hess, Julian M.; Stewart, Chip; Braunstein, Lior Z.; Arndt, Peter F.; Mordecai, Scott; Shih, Angela R.; Cháves, Frances; Zhan, Tiannan; Lubitz, Carrie C.; Kim, Jiwoong; Iafrate, A. John; Wirth, Lori J.; Parangi, Sareh; Leshchiner, Ignaty; Daniels, Gilbert H.; Mootha, Vamsi K.; Dias‐Santagata, Dora; Getz, Gad; McFadden, David G.

doi:10.1016/j.ccell.2018.06.013

Cited by 190 publications

(200 citation statements)

References 86 publications

Supporting

Mentioning

187

Contrasting

Unclassified

Order By: Relevance

“…Mutations in tumor suppressor genes such as TP53, as well as PTEN, were shown to be enriched in HCC with widespread loss of heterozygosity (LOH). 31 The one case in our study with TP53 mutation was also a Hürthle cell carcinoma.…”

Section: Resultsmentioning

confidence: 56%

“…The reported prevalence of TERT mutations is approximately 0% in benign lesions, 12%‐14% in PTC and FTC, and 38%‐46% in poorly differentiated thyroid carcinoma (PDTC) and ATC . TERT promoter mutations are often identified in advanced thyroid cancers, including HCC, and are associated with metastasis and aggressive disease . The two TERT mutated lesions in our study were malignant on surgical follow‐up, both consisting of Hürthle cell carcinomas.…”

Section: Discussionmentioning

confidence: 68%

“…29 TERT promoter mutations are often identified in advanced thyroid cancers, including HCC, and are associated with metastasis and aggressive disease. 30,31 The two TERT mutated lesions in our study were malignant on surgical follow-up, both consisting of Hürthle cell carcinomas. Interestingly, there were two secondary TERT mutations associated with NRAS mutations; however, they did not have available histologic followup.…”

Section: Resultsmentioning

confidence: 83%

See 2 more Smart Citations

Hürthle cell lesions on thyroid fine needle aspiration cytology: Molecular and histologic correlation

Schatz-Siemers

Brandler

Oweity

et al. 2019

Diagnostic Cytopathology

View full text Add to dashboard Cite

Background Hürthle cell lesions often pose diagnostic challenges, despite their common occurrence on thyroid fine‐needle aspiration cytology (FNAC). The associated molecular alterations are also not well understood. Therefore, our study aimed to delineate the molecular profile of Hürthle cell lesions classified as Bethesda Categories III or IV (atypia of undetermined significance (AUS) or suspicious for follicular neoplasm (SFN)) on FNAC and to correlate this molecular profile with surgical resection findings. Methods This study consisted of 188 Hürthle cell lesions with indeterminate cytology and ThyroSeq® v2/v3 molecular testing results. Surgical follow‐up was available for 33 cases. Results The majority of indeterminate Hürthle cell lesions had negative ThyroSeq® results (61%) and were benign on available surgical follow‐up. The most prevalent mutations involved the RAS gene (21%), which were associated with benign lesions, non‐invasive follicular thyroid neoplasms with papillary‐like nuclear features (NIFTP), and malignancy. The remaining mutations involved less than 18% of the cases, including PAX8/PPARG (3.7%), TSHR (3.7%), EIF1AX (2.7%), MET (2.1%), PTEN (1.6%), clonal copy number alteration (1.6%), TERT (1.1%), and 0.5% each of GNAS, PIK3CA, and TP53 mutations. On follow‐up, 45% were benign, 24% were NIFTP, and 30% were malignant. The malignant cases had different molecular alterations. Conclusion No single molecular alteration defines cytologically indeterminate Hürthle cell lesions; the majority of cases have low‐risk or no molecular alterations and are benign on follow‐up. These findings suggest that molecular testing may be useful, but is not definitive, in determining which cases may be managed conservatively; additional studies are needed to fully determine the negative predictive value in ruling out malignancy.

show abstract

Section: Resultsmentioning

confidence: 56%

Section: Discussionmentioning

confidence: 68%

Section: Resultsmentioning

confidence: 83%

See 1 more Smart Citation

Hürthle cell lesions on thyroid fine needle aspiration cytology: Molecular and histologic correlation

Schatz-Siemers

Brandler

Oweity

et al. 2019

Diagnostic Cytopathology

View full text Add to dashboard Cite

show abstract

“…Somatic genomic alterations in Hürthle cell carcinomas are different from those in PTC and FTC. Hürthle cell carcinomas have MADCAM1, EIF1AX, NRAS, DAXX, PT53 and NF1 mutations , but no BRAF mutations and a lower frequency of NRAS mutation than FTC . Somatic recurrent mitochondrial mutations occur in 71% of Hürthle cell carcinomas.…”

Section: Genetic Profiles and Molecular Diagnosis Of Thyroid Tumorsmentioning

confidence: 99%

“…H€ urthle cell carcinomas have MADCAM1, EIF1AX, NRAS, DAXX, PT53 and NF1 mutations, but no BRAF mutations and a lower frequency of NRAS mutation than FTC. 201,205 Somatic recurrent mitochondrial mutations occur in 71% of H€ urthle cell carcinomas. Unique chromosomal landscapes in H€ urthle cell carcinomas involve wholechromosome duplication of chromosomes 5 and 7, and widespread loss of chromosomes resulting in near-haploid chromosomal content.…”

Section: Genetic Profiles and Molecular Diagnosis Of Thyroid Tumorsmentioning

confidence: 99%

The new 4th edition World Health Organization classification for thyroid tumors, Asian perspectives

Kakudo

Bychkov

Bai

et al. 2018

Pathology International

View full text Add to dashboard Cite

Thyroid Cancer

Boucai,

Zafereo,

Cabanillas

2024

JAMA

View full text Add to dashboard Cite

ImportanceApproximately 43 720 new cases of thyroid carcinoma are expected to be diagnosed in 2023 in the US. Five-year relative survival is approximately 98.5%. This review summarizes current evidence regarding pathophysiology, diagnosis, and management of early-stage and advanced thyroid cancer.ObservationsPapillary thyroid cancer accounts for approximately 84% of all thyroid cancers. Papillary, follicular (≈4%), and oncocytic (≈2%) forms arise from thyroid follicular cells and are termed well-differentiated thyroid cancer. Aggressive forms of follicular cell-derived thyroid cancer are poorly differentiated thyroid cancer (≈5%) and anaplastic thyroid cancer (≈1%). Medullary thyroid cancer (≈4%) arises from parafollicular C cells. Most cases of well-differentiated thyroid cancer are asymptomatic and detected during physical examination or incidentally found on diagnostic imaging studies. For microcarcinomas (≤1 cm), observation without surgical resection can be considered. For tumors larger than 1 cm with or without lymph node metastases, surgery with or without radioactive iodine is curative in most cases. Surgical resection is the preferred approach for patients with recurrent locoregional disease. For metastatic disease, surgical resection or stereotactic body irradiation is favored over systemic therapy (eg, lenvatinib, dabrafenib). Antiangiogenic multikinase inhibitors (eg, sorafenib, lenvatinib, cabozantinib) are approved for thyroid cancer that does not respond to radioactive iodine, with response rates 12% to 65%. Targeted therapies such as dabrafenib and selpercatinib are directed to genetic mutations (BRAF, RET, NTRK, MEK) that give rise to thyroid cancer and are used in patients with advanced thyroid carcinoma.ConclusionsApproximately 44 000 new cases of thyroid cancer are diagnosed each year in the US, with a 5-year relative survival of 98.5%. Surgery is curative in most cases of well-differentiated thyroid cancer. Radioactive iodine treatment after surgery improves overall survival in patients at high risk of recurrence. Antiangiogenic multikinase inhibitors and targeted therapies to genetic mutations that give rise to thyroid cancer are increasingly used in the treatment of metastatic disease.

show abstract

Widespread Chromosomal Losses and Mitochondrial DNA Alterations as Genetic Drivers in Hürthle Cell Carcinoma

Cited by 190 publications

References 86 publications

Hürthle cell lesions on thyroid fine needle aspiration cytology: Molecular and histologic correlation

Hürthle cell lesions on thyroid fine needle aspiration cytology: Molecular and histologic correlation

The new 4th edition World Health Organization classification for thyroid tumors, Asian perspectives

Thyroid Cancer

Contact Info

Product

Resources

About