AI Summary
The study aimed to characterize the genetic alterations of infiltrative follicular variant of papillary thyroid carcinoma (IFVPTC) through whole-exome sequencing. The results revealed that endogenous processes dominated the genome shaping, with BRAF V600E being a common trunk mutation. Subcloning analysis showed multiple coexisting clones in most samples, while somatic copy number alterations (sCNAs) highlighted amplifications of human leukocyte antigen C (HLA-C) and HLA-A. Immunohistochemistry (IHC) indicated the potential of HLA-C to differentiate IFVPTC and invasive encapsulated follicular variant of PTC (I-EFVPTC) from noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). The study enhances understanding of IFVPTC's molecular features for improved diagnosis and management.
Abstract
Background
Infiltrative 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.
Methods
Whole-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).
Results
This 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.
Conclusions
This 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.