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Molecular Genetics of Diffuse Sclerosing Papillary Thyroid Cancer
Meshael Alswailem1, Balgees Alghamdi1, Anwar Alotaibi2
1Department of Molecular Oncology, King Faisal Specialist Hospital & Research Centre, Riyadh 11211, Saudi Arabia.
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.
Insights
Diffuse sclerosing papillary thyroid cancer (DSPTC) commonly features fusion genes but rarely BRAFV600E mutations. Genetic variants in genes like POLE, NF1, and TP53 are found in about two-thirds of DSPTC cases.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Diffuse sclerosing papillary thyroid cancer (DSPTC) is a rare subtype of papillary thyroid cancer.
- Limited data exists on the molecular genetic landscape of DSPTC, hindering targeted therapeutic strategies.
Purpose of the Study:
- To investigate the molecular genetics of a cohort of diffuse sclerosing papillary thyroid cancer.
- To characterize the genomic alterations and identify potential driver mutations in DSPTC.
Main Methods:
- DNA was extracted from 22 DSPTC patient tumor samples.
- Polymerase chain reaction-based Sanger sequencing and next-generation sequencing (NGS) gene panel were employed for genomic analysis.
- Genetic alterations were classified as definitely or probably pathogenic based on established databases and literature.
Main Results:
- Fusion genes, including CCDC6-RET and NCOA4-RET, were identified in 31.6% of tumors analyzed by NGS.
- BRAFV600E mutations were rare (10.5%), and common point mutations in RAS, PTEN, PIK3CA, and TERT promoter were absent.
- Pathogenic or likely pathogenic variants in POLE, NF1, CDKN2A, BRCA2, TP53, SETD2, ATM, FLT3, and ROS1 were found in approximately 68.4% of tumors.
Conclusions:
- Fusion genes are prevalent in DSPTC, while BRAFV600E mutations are infrequent.
- A significant proportion of DSPTC cases harbor pathogenic variants in genes involved in DNA repair and tumor suppression.
- The study highlights the diverse genomic alterations in DSPTC, suggesting potential therapeutic targets beyond traditional mutations.
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