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Mutation Profile of Aggressive Pheochromocytoma and Paraganglioma with Comparison of TCGA Data
Yun Mi Choi1, Jinyeong Lim2, Min Ji Jeon3
1Department of Internal Medicine, Hallym University Dongtan Sacred Heart Hospital, Hallym University College of Medicine, Gyeonggi-Do 18450, Korea.
Abstract:
In pheochromocytoma and paraganglioma (PPGL), germline or somatic mutations in one of the known susceptibility genes are identified in up to 60% patients. However, the peculiar genetic events that drive the aggressive behavior including metastasis in PPGL are poorly understood. We performed targeted next-generation sequencing analysis to characterize the mutation profile in fifteen aggressive PPGL patients and compared accessible data of aggressive PPGLs from The Cancer Genome Atlas (TCGA) with findings of our cohort. A total of 115 germline and 34 somatic variants were identified with a median 0.58 per megabase tumor mutation burden in our cohort. The most frequent mutation was SDHB germline mutation (27%) and the second frequent mutations were somatic mutations for SETD2, NF1, and HRAS (13%, respectively). Patients were subtyped into three categories based on the kind of mutated genes: pseudohypoxia (n = 5), kinase (n = 5), and unknown (n = 5) group. In copy number variation analysis, deletion of chromosome arm 1p harboring SDHB gene was the most frequently observed. In our cohort, SDHB mutation and pseudohypoxia subtype were significantly associated with poor overall survival. In conclusion, subtyping of mutation profile can be helpful in aggressive PPGL patients with heterogeneous prognosis to make relevant follow-up plan and achieve proper treatment.
Insights
Aggressive pheochromocytoma and paraganglioma (PPGL) genetics were analyzed. SDHB mutations and pseudohypoxia subtypes indicate poorer survival, aiding treatment planning for these rare tumors.
Area of Science:
- Endocrinology
- Oncology
- Genetics
Background:
- Pheochromocytoma and paraganglioma (PPGL) are rare tumors, with up to 60% exhibiting known genetic mutations.
- The genetic drivers of aggressive behavior and metastasis in PPGL remain poorly understood.
Purpose of the Study:
- To characterize the mutation profile of aggressive PPGL.
- To identify genetic events associated with aggressive PPGL behavior and metastasis.
- To subtype aggressive PPGL based on mutation profiles for prognostic insights.
Main Methods:
- Targeted next-generation sequencing was performed on fifteen aggressive PPGL patient samples.
- Data from aggressive PPGLs in The Cancer Genome Atlas (TCGA) were compared with the study cohort.
- Mutation profiles, including germline and somatic variants, and copy number variations were analyzed.
Main Results:
- A total of 115 germline and 34 somatic variants were identified, with a median tumor mutation burden of 0.58 per megabase.
- The most frequent mutation was SDHB germline mutation (27%), followed by somatic mutations in SETD2, NF1, and HRAS (13% each).
- Patients were subtyped into pseudohypoxia, kinase, and unknown groups; deletion of chromosome arm 1p was frequent.
- SDHB mutation and pseudohypoxia subtype were significantly linked to poor overall survival.
Conclusions:
- Mutation subtyping in aggressive PPGL patients can reveal heterogeneous prognoses.
- This approach can guide personalized follow-up plans and treatment strategies for aggressive PPGL.
- Further research into the genetic underpinnings of PPGL aggressiveness is warranted.
