Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2025 Jun 4;13(2):101705.
doi: 10.1016/j.gendis.2025.101705. eCollection 2026 Mar.

Molecular profiling unveils genetic complexity and identifies potential new driver mechanisms in head and neck paragangliomas

Sara Mellid  1 , Eduardo Caleiras  2 , Ángel M Martínez-Montes  1 , Alicia Arenas  1 , Scherezade Jiménez  3 , María Monteagudo  1 , Rocío Letón  1 , Roberta Radu  1 , Ruth Álvarez-Díaz  4 , Ester Arroba  1 , Alberto Diaz-Talavera  1   5 , Natalia Martínez-Puente  1   5 , Cristina Álvarez-Escolá  6 , Marta Pineda  7   8 , Milagros Balbín  9 , Fátima Al-Shahrour  4 , Cristina Rodriguez-Antona  1   5   10 , Cristina Montero-Conde  1   5 , Luis J Leandro-García  1 , Emiliano Honrado  11 , Miguel Soria-Tristán  12 , Mercedes Robledo  1   5 , Alberto Cascón  1   5
Affiliations

Molecular profiling unveils genetic complexity and identifies potential new driver mechanisms in head and neck paragangliomas

Sara Mellid et al. Genes Dis. .
No abstract available

PubMed Disclaimer

Conflict of interest statement

The authors declared no conflict of interests.

Figures

Figure 1
Figure 1
Molecular profiling of head and neck paragangliomas. (A) Analysis of patients with single PPGL from our database. Sex distribution of patients according to PPGL location and the presence of mutations in PPGL-related genes. (B) Expression profiling of HNPGLs. Unsupervised hierarchical clustering of RNA-sequencing data from a series of 24 WT, 4 SDHB-mutated, 3 SDHD-mutated, 3 DNMT3A-mutated, and 1 VHL-mutated HNPGLs, together with previous RNA-sequencing data from representative C1 and C2 tumors in other locations, using a gene signature that distinguishes between PPGL molecular clusters described by Burnichon et al. Two different subgroups of HNPGLs (SDH-like and DNMT3A-like) are evidenced within the pseudohypoxic cluster. (C) Differential expression analysis between DNMT3A-like and SDH-like WT HNPGLs. Upper panel, the volcano plot showing 182 differentially expressed genes (Log2foldchange < −1.5 or > 1.5; false discovery rate < 0.01) between DNMT3A-like and SDH-like WT HNPGLs. Blue, red, and grey dots represent significantly underexpressed genes, overexpressed genes, and non-significantly differentially expressed genes, respectively. Lower panel, the EnrichR results of significantly enriched pathways related to the differentially expressed genes. The most significant hits include transcription factors SUZ12, EZH2, and MTF2, and biological processes related to nervous system development. (D) DNA methylation profile of HNPGLs. Unsupervised clustering of DNA methylation data from available HNPGLs in our series and other representative PPGLs carrying mutations in DLST, DNMT3A, HRAS, NF1, RET, and SDHx located in the head and neck region and elsewhere, using a signature of differentially methylated probes observed in the CpG island methylator phenotype (CIMP) observed in SDHB mutant renal cell carcinoma and PPGL/GIST. ∗Sample HN17, for which expression cluster assignment was not available due to poor RNA sequencing quality; +Sample HN22, which exhibited an SDH-like transcriptomic profile in the expression profiling analysis. (E) Summary of detected copy number alterations. Copy number alterations of available WT HNPGLs corresponding to the DNMT3A-like and SDH-like transcriptomic clusters compared with other representative HNPGLs with known mutations in PPGL-related genes and SDHB-mutated PPGLs with other locations (T1-T17 from left to right) are shown. ∗New sample collected from the sister of patient HN18. (F) Summary of detected variants. Alterations in SDH genes, chromatin remodeling genes, and other cancer-associated genes identified in the WT HNPGL cohort through whole-exome sequencing, exome capture RNA sequencing, and DNA methylation analysis are shown. Pathogenicity prediction was conducted using the Franklin online tool. Cluster, corresponding group according to transcriptomic profile; CIMP, CpG island methylator phenotype; VUS, variant of uncertain significance. ∗New sample collected from a sister of patient HN18. ∗∗Whole-exome sequencing was conducted on a blood sample from the patient. (G) Re-evaluation of SDHB IHC staining in the WT HNPGL series. Two expert pathologists reclassified the SDHB IHC of the samples HN16, HN17, HN18, HN19, and HN20 as dubious/inconclusive. Additionally, the samples HN21 and HN22 exhibited strong staining but low granularity and variable staining depending on the slide area, respectively. All these samples were classified as SDH-like based on transcriptomic results. C+: positive control of a tumor with positive SDHB IHC staining; C−: negative control of a tumor with negative SDHB IHC staining. ∗Tumor with embolization evidence. PPGLs, pheochromocytomas and paragangliomas; HNPGLs, head and neck paragangliomas; TAPGLs, thoracoabdominal paragangliomas; PCCs, pheochromocytomas; IHC, immunohistochemistry.
See this image and copyright information in PMC

References

    1. Sandow L., Thawani R., Kim M.S., Heinrich M.C. Paraganglioma of the head and neck: a review. Endocr Pract. 2023;29(2):141–147. - PMC - PubMed
    1. Remacha L., Currás-Freixes M., Torres-Ruiz R., et al. Gain-of-function mutations in DNMT3A in patients with paraganglioma. Genet Med. 2018;20(12):1644–1651. - PubMed
    1. Su T., Yang Y., Jiang L., et al. SDHB immunohistochemistry for prognosis of pheochromocytoma and paraganglioma: a retrospective and prospective analysis. Front Endocrinol. 2023;14
    1. Adane B., Alexe G., Seong B.K.A., et al. STAG2 loss rewires oncogenic and developmental programs to promote metastasis in ewing sarcoma. Cancer Cell. 2021;39(6):827–844.e10. - PMC - PubMed
    1. Flynn A., Benn D., Clifton-Bligh R., et al. The genomic landscape of phaeochromocytoma. J Pathol. 2015;236(1):78–89. - PubMed

LinkOut - more resources