BRAFV600E/pTERT double mutated papillary thyroid cancers exhibit immune gene suppression

Area of Science:

• Oncology
• Immunology
• Genetics

Background:

• Papillary thyroid cancer (PTC) often harbors BRAFV600E mutations (BRAF^mut), typically associated with good prognosis.
• However, the co-occurrence of BRAF^mut and TERT-promoter mutations (pTERT^mut) in PTC (BRAF^mutpTERT^mut) is linked to more aggressive disease.
• Lymphocytic infiltration is a common feature in PTC, suggesting immune system involvement.

Purpose of the Study:

• To investigate the relationship between BRAF and pTERT mutations and immune gene dysregulation in PTC.
• To understand how these genetic alterations influence the tumor immune microenvironment.
• To elucidate the mechanisms behind the aggressive behavior of BRAF^mutpTERT^mut PTC.

Main Methods:

• Analysis of 770 immune gene transcripts in 147 PTC tumor samples using NanoString nCounter^® PanCancer Immune Profiling Panel.
• Differential gene expression analysis comparing BRAF^mutpTERT^mut and BRAF^mutpTERT wildtype (pTERT^wt) samples.
• Validation using The Cancer Genome Atlas (TCGA) PTC dataset and deconvolution analysis to assess immune cell populations.

Main Results:

• Identified 40 immune transcripts differentially expressed between BRAF^mutpTERT^mut and BRAF^mutpTERT^wt PTC.
• BRAF^mutpTERT^mut tumors showed repressed immune gene expression, including genes related to lymphoid cells, antigen-presenting cells, and cytotoxic cells.
• Deconvolution analysis revealed altered immune cell populations, such as increased M2 macrophages and decreased M1 macrophages in BRAF^mutpTERT^mut tumors.
• Immune gene pathways were enriched in BRAF^mutpTERT^wt tumors but not in BRAF^mutpTERT^mut tumors, consistent with findings of higher stromal lymphocyte infiltration in BRAF^mutpTERT^wt compared to BRAF^wtpTERT^wt.

Conclusions:

• This study is the first to report a potential link between TERT promoter mutations and the tumor immune microenvironment in PTC.
• The dysregulation of immune gene expression in BRAF^mutpTERT^mut PTC provides a molecular explanation for its aggressive clinical behavior.
• Understanding this interplay may offer new therapeutic strategies targeting the immune microenvironment in aggressive PTC.