Molecular Genetics of Diffuse Sclerosing Papillary Thyroid Cancer

J Clin Endocrinol Metab. 2023 Aug 18;108(9):e704-e711. doi: 10.1210/clinem/dgad185.


Context: Diffuse sclerosing papillary thyroid cancer (DSPTC) is rare, with limited data on its molecular genetics.

Objective: We studied the molecular genetics of a cohort of DSPTC.

Methods: DNA was isolated from paraffin blocks of 22 patients with DSPTC (15 females, 7 males, median age 18 years, range 8-81). We performed polymerase chain reaction-based Sanger sequencing and a next-generation sequencing (NGS) gene panel to characterize the genomic landscape of these tumors. We classified genetic alterations to definitely or probably pathogenic. Definitely pathogenic are genetic alterations that are well known to be associated with PTC (e.g., BRAFV600E). Probably pathogenic are other alterations in genes that were reported in The Cancer Genome Atlas or the poorly differentiated and anaplastic thyroid cancer datasets.

Results: Three tumors were tested only by Sanger sequencing and were negative for BRAFV600E, HRAS, KRAS, NRAS, TERT promoter, PTEN, and PIK3CA mutations. The other 19 tumors tested by NGS showed definitely pathogenic alterations in 10 patients (52.6%): 2/19 (10.5%) BRAFV600E, 5/19 (26.3%) CCDC6-RET (RET/PTC1), 1/19 (5.3%) NCOA4-RET (RET/PTC3), 1/19 (5.3%) STRN-ALK fusion, and 2/19 (10.6%) TP53 mutations. Probably pathogenic alterations occurred in 13/19 tumors (68.4%) and included variants in POLE (31.6%), CDKN2A (26%), NF1 (21%), BRCA2 (15.8%), SETD2 (5.3%), ATM (5.3%), FLT3 (5.3%), and ROS1 (5.3%). In 1 patient, the gene panel showed no alterations. No mutations were found in the RAS, PTEN, PIK3CA, or TERT promoter in all patients. There was no clear genotype/phenotype correlation.

Conclusion: In DSPTC, fusion genes are common, BRAFV600E is rare, and other usual point mutations are absent. Pathogenic and likely pathogenic variants in POLE, NF1, CDKN2A, BRCA2, TP53, SETD2, ATM, FLT3, and ROS1 occur in about two-thirds of DTPTC.

Keywords: diffuse sclerosing papillary thyroid cancer; fusion genes; gene panel; mutations; papillary thyroid cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Female
  • Humans
  • Male
  • Molecular Biology
  • Protein-Tyrosine Kinases / genetics
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins B-raf / genetics
  • Thyroid Cancer, Papillary / genetics
  • Thyroid Neoplasms* / genetics
  • Thyroid Neoplasms* / pathology


  • Protein-Tyrosine Kinases
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins B-raf