ECEESPE2025 Poster Presentations Endocrine Related Cancer (76 abstracts)
Exploring SDHA variants: navigating predisposition and incidental findings
Henriett Butz 1 , Balint Antal 2 , János Papp 1 , Aniko Bozsik 1 , Vince Kornel Grolmusz 1 , Petra Nagy 1 , Timea Pocza 1 , Julie Sanceau 3 , Judith Favier 3 & Attila Patócs 1
1National Institute of Oncology, Budapest, Hungary; 2Semmelweis University, Budapest, Hungary; 3Inserm, Centre de Recherche des Cordeliers, Université Paris-Cité, Sorbonne Université, Paris, France
JOINT1083
Background: Multigene panel testing (MGPT) is increasingly employed in oncology, leading to identification of numerous pathogenic/likely pathogenic (P/lP) variants in the SDHA gene. This includes incidental findings in patients with non-SDHA-associated tumours, creating challenges for clinical interpretation.
Aim: This study aimed to determine the prevalence and potential role of SDHA P/lP variants in the development of both SDHA-associated and non-SDHA-associated tumours.
Methods: A cohort of 1699 cancer patients who underwent MGPT from 2021 to 2023 was screened for suspected heritability. Tumours were categorized into SDHA-associated types (gastrointestinal stromal tumour, phaeochromocytoma-paraganglioma, renal cancer, neuroblastoma, pituitary adenoma; n = 62) and non-SDHA-associated types (endocrine tumours, hereditary breast-ovarian cancer syndrome, and other tumours; n = 1637). Controls were drawn from the gnomAD non-cancer database (n = 134, 187). Comprehensive analyses included next-generation sequencing, RNA characterization, and loss of heterozygosity (LOH) studies by immunohistochemistry. Additionally, somatic SDHA sequence and copy number variations in 10, 463 pan-cancer and 7988 breast tumour samples were examined through The Cancer Genome Atlas datasets.
Results: Germline SDHA P/lP variants were significantly enriched in SDHA-associated tumour group compared to controls (5. 41x, P = 0. 05), but their prevalence in patients with other tumour types was low (0. 23–1. 57x, p>0. 05). LOH was absent in non-SDHA-associated tumours with germline variants. Somatic SDHA alterations, including heterozygous and homozygous deletions, were identified in 1–4% of non-SDHA-associated tumours. In breast cancer, heterozygous SDHA copy number loss was linked to worse overall and relapse-free survival (hazard ratio=1. 55 and 1. 48, respectively; P < 0. 05).
Conclusion: Germline SDHA P/lP variants predispose to SDHA-associated tumours, supporting their role in these cancers. While SDHA rarely contributes to non-SDHA-associated tumours, somatic SDHA deletions in breast cancer may act as disease modifiers, influencing progression and prognosis.
Funding: TKP2021-EGA/TKP2021-NVA/TKP2021-NKTA, MOLORKIV to A. P., NRDI NKFI-FK135065, ÚNKP-23-5-SE-4, Bolyai Research Fellowship of the Hungarian Academy of Sciences
Volume 110
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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