Carl M Thielmann1, Eleftheria Chorti1, Johanna Matull1, Rajmohan Murali2, Anne Zaremba1, Georg Lodde1, Philipp Jansen1, Luisa Richter1, Julia Kretz1, Inga Möller1, Antje Sucker1, Rudolf Herbst3, Patrick Terheyden4, Jochen Utikal5, Claudia Pföhler6, Jens Ulrich7, Alexander Kreuter8, Peter Mohr9, Ralf Gutzmer10, Friedegund Meier11, Edgar Dippel12, Michael Weichenthal13, Annette Paschen1, Elisabeth Livingstone1, Lisa Zimmer1, Dirk Schadendorf1, Eva Hadaschik1, Selma Ugurel1, Klaus G Griewank14. 1. Department of Dermatology, University Hospital Essen, University of Duisburg, Germany; German Cancer Consortium (DKTK), Partner Site Essen, Germany. 2. Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, USA. 3. Hauttumorzentrum, Helios Klinikum Erfurt, Erfurt, Germany. 4. Department of Dermatology, UKSH Campus Lübeck, Lübeck, Germany. 5. Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Heidelberg, Germany. 6. Department of Dermatology, Saarland University Medical School, Homburg, Saar, Germany. 7. Department of Dermatology and Venereology, Harzklinikum Dorothea Christiane Erxleben, Quedlinburg, Germany. 8. Department of Dermatology, Venereology and Allergology, HELIOS St. Elisabeth Klinik Oberhausen, University Witten/Herdecke, Oberhausen, Germany. 9. Dermatological Center Buxtehude, Elbe Kliniken Buxtehude, Buxtehude, Germany. 10. Skin Cancer Center, Hannover Medical School, Hannover, Germany; Department of Dermatology, Mühlenkreiskliniken Minden, Minden, Germany. 11. Department of Dermatology, Dermatooncology, University Hospital Carl Gustav Carus, TU Dresden, Dresden, Germany. 12. Department of Dermatology Ludwigshafen, Klinikum der Stadt Ludwigshafen am Rhein gGmbH, Ludwigshafen, Germany. 13. University Hospital Schleswig-Holstein (UKSH), Campus Kiel, Kiel, Germany. 14. Department of Dermatology, University Hospital Essen, University of Duisburg, Germany; German Cancer Consortium (DKTK), Partner Site Essen, Germany. Electronic address: klaus.griewank@uk-essen.de.
Abstract
BACKGROUND: NF1-mutated tumours represent a small subset (10-15%) of melanomas, not sufficiently analysed in large clinical cohorts. This study investigated the largest multicentre collection of NF1-mutated melanomas to date. METHODS: This study analysed a multicentre tumour tissue sample cohort from 266 patients with NF1-mutated melanoma. Targeted next-generation sequencing of the TERT promoter and 29 relevant melanoma genes was performed. Survival was compared with NF1 wild-type cohorts from the Tissue Registry in Melanoma project (n = 432). RESULTS: Most NF1-mutated melanoma arose in the head-and-neck region of patients >60 years. NF1 alterations were frequently inactivating, primarily non-sense, less frequently truncating mutations. Non-inactivating NF1 mutations more frequently co-occurred with activating BRAF and RAS mutations. NF1-mutated tumours had higher numbers of gene mutations and UV signature C>T and CC>TT transitions than BRAF, RAS and triple wild-type melanomas. NF1-mutated acral and mucosal melanomas harboured a different mutation signature and were frequent in women (69% and 83%, respectively), differing from non-acral cutaneous NF1-mutated melanomas (men 73%, women 27%). Overall survival in stage IV disease was comparable for patients with NF1-mutated or wild-type melanoma. However, in patients receiving first-line immune checkpoint inhibitor treatment, better median overall survival (mOS) was observed for NF1-mutated than wild-type tumours (mOS = not reached vs mOS = 25.82, p = 0.0154, n = 80 and 432, respectively). CONCLUSIONS: Cutaneous, acral and mucosal NF1-mutated melanomas vary in clinical and genetic characteristics and demonstrate a favourable outcome on immune checkpoint inhibition therapy.
BACKGROUND: NF1-mutated tumours represent a small subset (10-15%) of melanomas, not sufficiently analysed in large clinical cohorts. This study investigated the largest multicentre collection of NF1-mutated melanomas to date. METHODS: This study analysed a multicentre tumour tissue sample cohort from 266 patients with NF1-mutated melanoma. Targeted next-generation sequencing of the TERT promoter and 29 relevant melanoma genes was performed. Survival was compared with NF1 wild-type cohorts from the Tissue Registry in Melanoma project (n = 432). RESULTS: Most NF1-mutated melanoma arose in the head-and-neck region of patients >60 years. NF1 alterations were frequently inactivating, primarily non-sense, less frequently truncating mutations. Non-inactivating NF1 mutations more frequently co-occurred with activating BRAF and RAS mutations. NF1-mutated tumours had higher numbers of gene mutations and UV signature C>T and CC>TT transitions than BRAF, RAS and triple wild-type melanomas. NF1-mutated acral and mucosal melanomas harboured a different mutation signature and were frequent in women (69% and 83%, respectively), differing from non-acral cutaneous NF1-mutated melanomas (men 73%, women 27%). Overall survival in stage IV disease was comparable for patients with NF1-mutated or wild-type melanoma. However, in patients receiving first-line immune checkpoint inhibitor treatment, better median overall survival (mOS) was observed for NF1-mutated than wild-type tumours (mOS = not reached vs mOS = 25.82, p = 0.0154, n = 80 and 432, respectively). CONCLUSIONS: Cutaneous, acral and mucosal NF1-mutated melanomas vary in clinical and genetic characteristics and demonstrate a favourable outcome on immune checkpoint inhibition therapy.
Authors: Dirk Schadendorf; F Stephen Hodi; Caroline Robert; Jeffrey S Weber; Kim Margolin; Omid Hamid; Debra Patt; Tai-Tsang Chen; David M Berman; Jedd D Wolchok Journal: J Clin Oncol Date: 2015-02-09 Impact factor: 44.544
Authors: Cameron W Brennan; Roel G W Verhaak; Aaron McKenna; Benito Campos; Houtan Noushmehr; Sofie R Salama; Siyuan Zheng; Debyani Chakravarty; J Zachary Sanborn; Samuel H Berman; Rameen Beroukhim; Brady Bernard; Chang-Jiun Wu; Giannicola Genovese; Ilya Shmulevich; Jill Barnholtz-Sloan; Lihua Zou; Rahulsimham Vegesna; Sachet A Shukla; Giovanni Ciriello; W K Yung; Wei Zhang; Carrie Sougnez; Tom Mikkelsen; Kenneth Aldape; Darell D Bigner; Erwin G Van Meir; Michael Prados; Andrew Sloan; Keith L Black; Jennifer Eschbacher; Gaetano Finocchiaro; William Friedman; David W Andrews; Abhijit Guha; Mary Iacocca; Brian P O'Neill; Greg Foltz; Jerome Myers; Daniel J Weisenberger; Robert Penny; Raju Kucherlapati; Charles M Perou; D Neil Hayes; Richard Gibbs; Marco Marra; Gordon B Mills; Eric Lander; Paul Spellman; Richard Wilson; Chris Sander; John Weinstein; Matthew Meyerson; Stacey Gabriel; Peter W Laird; David Haussler; Gad Getz; Lynda Chin Journal: Cell Date: 2013-10-10 Impact factor: 41.582
Authors: Selma Ugurel; Joachim Röhmel; Paolo A Ascierto; Keith T Flaherty; Jean Jacques Grob; Axel Hauschild; James Larkin; Georgina V Long; Paul Lorigan; Grant A McArthur; Antoni Ribas; Caroline Robert; Dirk Schadendorf; Claus Garbe Journal: Eur J Cancer Date: 2017-08-23 Impact factor: 9.162
Authors: Dirk Schadendorf; Alexander C J van Akkooi; Carola Berking; Klaus G Griewank; Ralf Gutzmer; Axel Hauschild; Andreas Stang; Alexander Roesch; Selma Ugurel Journal: Lancet Date: 2018-09-15 Impact factor: 79.321
Authors: Marco Donia; Eva Ellebaek; Trine Heide Øllegaard; Lone Duval; Jens Bull Aaby; Lise Hoejberg; Ulrich Heide Køhler; Henrik Schmidt; Lars Bastholt; Inge Marie Svane Journal: Eur J Cancer Date: 2018-12-31 Impact factor: 9.162
Authors: Lauren T McGillicuddy; Jody A Fromm; Pablo E Hollstein; Sara Kubek; Rameen Beroukhim; Thomas De Raedt; Bryan W Johnson; Sybil M G Williams; Phioanh Nghiemphu; Linda M Liau; Tim F Cloughesy; Paul S Mischel; Annabel Parret; Jeanette Seiler; Gerd Moldenhauer; Klaus Scheffzek; Anat O Stemmer-Rachamimov; Charles L Sawyers; Cameron Brennan; Ludwine Messiaen; Ingo K Mellinghoff; Karen Cichowski Journal: Cancer Cell Date: 2009-07-07 Impact factor: 31.743
Authors: Michael Krauthammer; Yong Kong; Byung Hak Ha; Perry Evans; Antonella Bacchiocchi; James P McCusker; Elaine Cheng; Matthew J Davis; Gerald Goh; Murim Choi; Stephan Ariyan; Deepak Narayan; Ken Dutton-Regester; Ana Capatana; Edna C Holman; Marcus Bosenberg; Mario Sznol; Harriet M Kluger; Douglas E Brash; David F Stern; Miguel A Materin; Roger S Lo; Shrikant Mane; Shuangge Ma; Kenneth K Kidd; Nicholas K Hayward; Richard P Lifton; Joseph Schlessinger; Titus J Boggon; Ruth Halaban Journal: Nat Genet Date: 2012-07-29 Impact factor: 38.330
Authors: Carl Maximilian Thielmann; Johanna Matull; Sebastian Roth; Jan-Malte Placke; Eleftheria Chorti; Anne Zaremba; Georg Lodde; Philipp Jansen; Frederik Krefting; Julia Kretz; Inga Möller; Antje Sucker; Annette Paschen; Elisabeth Livingstone; Lisa Zimmer; Selma Ugurel; Dirk Schadendorf; Eva Hadaschik; Klaus G Griewank Journal: Cancers (Basel) Date: 2022-04-22 Impact factor: 6.575