Succinate dehydrogenase (SDHB, SDHC, SDHD) gene variants significantly modify clinical outcomes in paraganglioma-pheochromocytoma but have a limited impact on head and neck paraganglioma.
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Bayley Jean-Pierre, Fishbein Lauren, Akker Scott, Rijken Johannes A, Robledo Mercedes, Cascon Alberto, Pęczkowska Mariola, Januszewicz Andrzej, Rapizzi Elena, Canu Letizia, Greenberg Samantha E, Buchmann Luke, Naumer Anne, Else Tobias, Chiara María-Dolores, Hamidi Oksana, Persu Alexandre, Vikkula Miikka, van Nesselrooij Bernadette P M, Niemeijer Nicolasine D, Kotecka-Blicharz Agnieszka, Oczko-Wojciechowska Malgorzata, Brock Pamela L, Kirschner Lawrence S, Donato Sara, Cavaco Branca Maria, Clifton-Bligh Roderick, Sen Indrani, Ferrara Alfonso Massimiliano, Elhassan Yasir S, Ayuk John, Rees D Aled, Bourdeau Isabelle, Parisien-La Salle Stefanie, Dahia Patricia L M, Rhee Yumie, Mitchell Anna L, Brennan Paul, Verga Uberta, Carosi Giulia, Mantovani Giovanna, Seong Moon-Woo, Lee Jee-Soo, Kim Jung Hee, Richter Susan, Pamporaki Christina, Kroiss Matthias, Remde Hanna, Fassnacht Martin, Hanzu Felicia Alexandra, Casey Ruth T, Brunaud Laurent, Nomine-Criqui Claire, Clabaut Delphine, Gauchotte Guillaume, Akerstrom Tobias, Crona Joakim, Chen Xiaohong, Navarro Elena, Disotuar Dueñas, Tous Maria Del Castillo, Ghayee Hans K, Perdomo Rodriguez Juan Pablo, Brown Lisa A, Llorente Jose Luis, Arístegui Miguel, Souviron Rosalia, Bower Thomas C, Young William F, Schiavi Francesca, Zovato Stefania, Lim Eugenie, Khatun Aklima, Hall Charlotte L, Benn Diana, Luxford Catherine, Richardson Tristan, Deutschbein Timo, Lluch Ana Romero, Lee Seung Hun, Escola Cristina Alvarez, Araujo-Castro Marta, Al-Mrayat Ma'en, Mullan Karen R, Darrat Milad, Myint Khin Swe, Ahluwalia Rupa, Sinclair Georgia, Tan Tricia, Yang Lisa, Vaidya Bijay, Benyon Sarah, Szatko Alicja, Glinicki Piotr, de Krijger Ronald R, Leemans C René, Petri Bart-Jeroen, Timmers Henri J L M, Bisschop Peter H, Feelders Richard R, Dreijerink Koen M A, Kerstens Michiel N, Zandee Wouter T, Hensen Erik F, Neumann Hartmut P H, Maher Eamonn R, Corssmit Eleonora P M, Jansen Jeroen C, Devilee Peter
Аннотация
METHODS: In this genotype-phenotype study of 2706 patients with PPGL-HNPGL and SDH variants from 57 centres worldwide, we analysed correlations of SDHB, SDHC and SDHD variants with tumour incidence, age of diagnosis, risk of metastasis and other clinical characteristics.
RESULTS: SDH variant types (missense variants vs. protein truncating variants (PTVs)) had a major differential impact on PPGLs, but little effect on HNPGLs. Combined PPGL and HNPGL (sPP&pHNPGL) was significantly more common in patients with SDHD variants, especially PTVs. Compared to PTVs, SDH missense variants showed broader clinical variability. Common vs. rare variants appeared to differentially impact clinical outcomes, including metastasis. Furthermore, specific SDH variants exhibited distinct clinical profiles. Regarding novel general findings, patients with SDHB (but not SDHC or SDHD) variants were diagnosed with PPGLs significantly earlier than HNPGLs, and paediatric cases with HNPGL showed elevated risk for metastasis and sPP&pHNPGL. We also observed an elevated risk for sPP&pHNPGL in males.
CONCLUSION: SDH variant types exhibit tissue-specific clinical differences, significantly influencing PPGL but not HNPGL clinical outcomes and underlining biological differences between precursor tissues.