Comprehensive genomic profiling of infiltrative follicular variant of papillary thyroid carcinoma

Author:

Wu Quanyou12ORCID,Hu Chunfang3,Feng Lin2,Yang Xin3,Cui Ying3,Zhao Huan3,Xiao Ting2,Guo Huiqin34

Affiliation:

1. Division of Abdominal Cancer Department of Medical Oncology Cancer Center and Laboratory of Molecular Targeted Therapy in Oncology West China Hospital Sichuan University Chengdu China

2. State Key Laboratory of Molecular Oncology Department of Etiology and Carcinogenesis National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical College Beijing China

3. Department of Pathology National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical College Beijing China

4. Department of Pathology National Cancer Center/National Clinical Research Center for Cancer/Hebei Cancer Hospital Chinese Academy of Medical Sciences Langfang China

Abstract

AbstractBackgroundInfiltrative follicular variant of papillary thyroid carcinoma (IFVPTC) exhibits nuclear characteristics typical of papillary thyroid carcinoma (PTC) but demonstrates a follicular growth pattern. The diagnosis of IFVPTC presenting with atypical nuclear features of PTC poses challenges for both preoperative cytopathology and postoperative histopathology. In such cases, molecular markers are needed to serve as diagnostic aids. Given the limited knowledge of IFVPTC's genomic features, this study aimed to characterize its genetic alterations and identify clinically relevant molecular markers.MethodsWhole‐exome sequencing of 50 IFVPTC tumor–normal pairs identified single‐nucleotide variants, somatic copy number alterations (sCNAs), and subclonal architecture. Key mutations were verified via polymerase chain reaction and Sanger sequencing, whereas valuable biomarkers were validated via immunohistochemistry (IHC).ResultsThis study found that endogenous processes rather than exogenous mutagens dominated the shaping of the genome of IFVPTC during tumorigenesis. BRAF V600E was the only common trunk mutation and significantly mutated gene in IFVPTC. Subcloning analysis found that most IFVPTC samples harbored two or more coexisting clones. sCNA analysis revealed that human leukocyte antigen C (HLA‐C) and HLA‐A were significantly amplified. Subsequent IHC investigations indicated that HLA‐C shows promise in averting the misclassification of challenging‐to‐interpret IFVPTC and invasive encapsulated follicular variant of PTC (I‐EFVPTC) as noninvasive follicular thyroid neoplasm with papillary‐like nuclear features (NIFTP). Although there were several similarities between classic PTC and IFVPTC, they differed significantly in their sCNA patterns.ConclusionsThis study provides valuable insights into IFVPTC's genetic alterations and highlights the potential of HLA‐C IHC to distinguish challenging‐to‐interpret IFVPTC and I‐EFVPTC from NIFTP, which will enhance the understanding of its molecular features for improved diagnosis and management.

Funder

National Natural Science Foundation of China

Publisher

Wiley

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