PURPOSE: Dabrafenib and trametinib are approved for the management of advanced non-small-cell lung cancers (NSCLCs) that harbor BRAF V600E mutations. Small series and pan-cancer analyses have identified non-V600 alterations as therapeutic targets. We sought to examine a large genomic data set to comprehensively characterize non-V600 BRAF alterations in lung cancer. PATIENTS AND METHODS: A total of 23,396 patients with lung cancer provided data to assay with comprehensive genomic profiling. Data were reviewed for predicted pathogenic BRAF base substitutions, short insertions and deletions, copy number changes, and rearrangements. RESULTS: Adenocarcinomas represented 65% of the occurrences; NSCLC not otherwise specified (NOS), 15%; squamous cell carcinoma, 12%; and small-cell lung carcinoma, 5%. BRAF was altered in 4.5% (1,048 of 23,396) of all tumors; 37.4% (n = 397) were BRAF V600E, 38% were BRAF non-V600E activating mutations, and 18% were BRAF inactivating. Rearrangements were observed at a frequency of 4.3% and consisted of N-terminal deletions (NTDs; 0.75%), kinase domain duplications (KDDs; 0.75%), and BRAF fusions (2.8%). The fusions involved three recurrent fusion partners: ARMC10, DOCK4, and TRIM24. BRAF V600E was associated with co-occurrence of SETD2 alterations, but other BRAF alterations were not and were instead associated with CDKN2A, TP53, and STK11 alterations (P < .05). Potential mechanisms of acquired resistance to BRAF V600E inhibition are demonstrated. CONCLUSION: This series characterized the frequent occurrence (4.4%) of BRAF alterations in lung cancers. Recurrent BRAF alterations in NSCLC adenocarcinoma are comparable to the frequency of other NSCLC oncogenic drivers, such as ALK, and exceed that of ROS1 or RET. This work supports a broad profiling approach in lung cancers and suggests that non-V600E BRAF alterations represent a subgroup of lung cancers in which targeted therapy should be considered.
PURPOSE: Dabrafenib and trametinib are approved for the management of advanced non-small-cell lung cancers (NSCLCs) that harbor BRAF V600E mutations. Small series and pan-cancer analyses have identified non-V600 alterations as therapeutic targets. We sought to examine a large genomic data set to comprehensively characterize non-V600 BRAF alterations in lung cancer. PATIENTS AND METHODS: A total of 23,396 patients with lung cancer provided data to assay with comprehensive genomic profiling. Data were reviewed for predicted pathogenic BRAF base substitutions, short insertions and deletions, copy number changes, and rearrangements. RESULTS: Adenocarcinomas represented 65% of the occurrences; NSCLC not otherwise specified (NOS), 15%; squamous cell carcinoma, 12%; and small-cell lung carcinoma, 5%. BRAF was altered in 4.5% (1,048 of 23,396) of all tumors; 37.4% (n = 397) were BRAF V600E, 38% were BRAF non-V600E activating mutations, and 18% were BRAF inactivating. Rearrangements were observed at a frequency of 4.3% and consisted of N-terminal deletions (NTDs; 0.75%), kinase domain duplications (KDDs; 0.75%), and BRAF fusions (2.8%). The fusions involved three recurrent fusion partners: ARMC10, DOCK4, and TRIM24. BRAF V600E was associated with co-occurrence of SETD2 alterations, but other BRAF alterations were not and were instead associated with CDKN2A, TP53, and STK11 alterations (P < .05). Potential mechanisms of acquired resistance to BRAF V600E inhibition are demonstrated. CONCLUSION: This series characterized the frequent occurrence (4.4%) of BRAF alterations in lung cancers. Recurrent BRAF alterations in NSCLC adenocarcinoma are comparable to the frequency of other NSCLC oncogenic drivers, such as ALK, and exceed that of ROS1 or RET. This work supports a broad profiling approach in lung cancers and suggests that non-V600E BRAF alterations represent a subgroup of lung cancers in which targeted therapy should be considered.
Authors: Rafael Rosell; Enric Carcereny; Radj Gervais; Alain Vergnenegre; Bartomeu Massuti; Enriqueta Felip; Ramon Palmero; Ramon Garcia-Gomez; Cinta Pallares; Jose Miguel Sanchez; Rut Porta; Manuel Cobo; Pilar Garrido; Flavia Longo; Teresa Moran; Amelia Insa; Filippo De Marinis; Romain Corre; Isabel Bover; Alfonso Illiano; Eric Dansin; Javier de Castro; Michele Milella; Noemi Reguart; Giuseppe Altavilla; Ulpiano Jimenez; Mariano Provencio; Miguel Angel Moreno; Josefa Terrasa; Jose Muñoz-Langa; Javier Valdivia; Dolores Isla; Manuel Domine; Olivier Molinier; Julien Mazieres; Nathalie Baize; Rosario Garcia-Campelo; Gilles Robinet; Delvys Rodriguez-Abreu; Guillermo Lopez-Vivanco; Vittorio Gebbia; Lioba Ferrera-Delgado; Pierre Bombaron; Reyes Bernabe; Alessandra Bearz; Angel Artal; Enrico Cortesi; Christian Rolfo; Maria Sanchez-Ronco; Ana Drozdowskyj; Cristina Queralt; Itziar de Aguirre; Jose Luis Ramirez; Jose Javier Sanchez; Miguel Angel Molina; Miquel Taron; Luis Paz-Ares Journal: Lancet Oncol Date: 2012-01-26 Impact factor: 41.316
Authors: Scott A Foster; Daniel M Whalen; Ayşegül Özen; Matthew J Wongchenko; JianPing Yin; Ivana Yen; Gabriele Schaefer; John D Mayfield; Juliann Chmielecki; Philip J Stephens; Lee A Albacker; Yibing Yan; Kyung Song; Georgia Hatzivassiliou; Charles Eigenbrot; Christine Yu; Andrey S Shaw; Gerard Manning; Nicholas J Skelton; Sarah G Hymowitz; Shiva Malek Journal: Cancer Cell Date: 2016-03-17 Impact factor: 31.743
Authors: Michael Röring; Ricarda Herr; Gina J Fiala; Katharina Heilmann; Sandra Braun; Anja E Eisenhardt; Sebastian Halbach; David Capper; Andreas von Deimling; Wolfgang W Schamel; Darren N Saunders; Tilman Brummer Journal: EMBO J Date: 2012-04-17 Impact factor: 11.598
Authors: Luping Lin; Saurabh Asthana; Elton Chan; Sourav Bandyopadhyay; Maria M Martins; Victor Olivas; Jenny Jiacheng Yan; Luu Pham; Mingxue Michelle Wang; Gideon Bollag; David B Solit; Eric A Collisson; Charles M Rudin; Barry S Taylor; Trever G Bivona Journal: Proc Natl Acad Sci U S A Date: 2014-02-03 Impact factor: 11.205
Authors: Shih-Hsun Chen; Youyan Zhang; Robert D Van Horn; Tinggui Yin; Sean Buchanan; Vipin Yadav; Igor Mochalkin; Swee Seong Wong; Yong Gang Yue; Lysiane Huber; Ilaria Conti; James R Henry; James J Starling; Gregory D Plowman; Sheng-Bin Peng Journal: Cancer Discov Date: 2016-01-05 Impact factor: 39.397
Authors: Katherine E Hutchinson; Doron Lipson; Philip J Stephens; Geoff Otto; Brian D Lehmann; Pamela L Lyle; Cindy L Vnencak-Jones; Jeffrey S Ross; Jennifer A Pietenpol; Jeffrey A Sosman; Igor Puzanov; Vincent A Miller; William Pao Journal: Clin Cancer Res Date: 2013-12-15 Impact factor: 12.531
Authors: Helen Davies; Graham R Bignell; Charles Cox; Philip Stephens; Sarah Edkins; Sheila Clegg; Jon Teague; Hayley Woffendin; Mathew J Garnett; William Bottomley; Neil Davis; Ed Dicks; Rebecca Ewing; Yvonne Floyd; Kristian Gray; Sarah Hall; Rachel Hawes; Jaime Hughes; Vivian Kosmidou; Andrew Menzies; Catherine Mould; Adrian Parker; Claire Stevens; Stephen Watt; Steven Hooper; Rebecca Wilson; Hiran Jayatilake; Barry A Gusterson; Colin Cooper; Janet Shipley; Darren Hargrave; Katherine Pritchard-Jones; Norman Maitland; Georgia Chenevix-Trench; Gregory J Riggins; Darell D Bigner; Giuseppe Palmieri; Antonio Cossu; Adrienne Flanagan; Andrew Nicholson; Judy W C Ho; Suet Y Leung; Siu T Yuen; Barbara L Weber; Hilliard F Seigler; Timothy L Darrow; Hugh Paterson; Richard Marais; Christopher J Marshall; Richard Wooster; Michael R Stratton; P Andrew Futreal Journal: Nature Date: 2002-06-09 Impact factor: 49.962
Authors: M Kordes; M Röring; C Heining; S Braun; B Hutter; D Richter; C Geörg; C Scholl; S Gröschel; W Roth; A Rosenwald; E Geissinger; C von Kalle; D Jäger; B Brors; W Weichert; C Grüllich; H Glimm; T Brummer; S Fröhling Journal: Leukemia Date: 2015-11-19 Impact factor: 11.528
Authors: Anna Michelotti; Marco de Scordilli; Elisa Bertoli; Elisa De Carlo; Alessandro Del Conte; Alessandra Bearz Journal: Int J Mol Sci Date: 2022-06-17 Impact factor: 6.208
Authors: Alessandro Di Federico; Andrea De Giglio; Francesco Gelsomino; Dario De Biase; Francesca Giunchi; Arianna Palladini; Francesca Sperandi; Barbara Melotti; Andrea Ardizzoni Journal: Cancers (Basel) Date: 2022-07-17 Impact factor: 6.575
Authors: Marcelo V Negrao; Victoria M Raymond; Richard B Lanman; Jacqulyne P Robichaux; Junqin He; Monique B Nilsson; Patrick K S Ng; Bianca E Amador; Emily B Roarty; Rebecca J Nagy; Kimberly C Banks; Viola W Zhu; Chun Ng; Young Kwang Chae; Jeffrey M Clarke; Jeffrey A Crawford; Funda Meric-Bernstam; Sai-Hong Ignatius Ou; David R Gandara; John V Heymach; Trever G Bivona; Caroline E McCoach Journal: J Thorac Oncol Date: 2020-06-13 Impact factor: 15.609