Robin Guo1, Lynne D Berry2, Dara L Aisner3, Jamie Sheren3, Theresa Boyle4, Paul A Bunn5, Bruce E Johnson6, David J Kwiatkowski7, Alexander Drilon8, Lynette M Sholl9, Mark G Kris8. 1. Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. Electronic address: guor@mskcc.org. 2. Center for Quantitative Sciences, Vanderbilt University, Nashville, Tennessee. 3. Department of Pathology, University of Colorado, Aurora, Colorado. 4. Department of Molecular Pathology, Moffitt Cancer Center, Tampa, Florida. 5. Division of Medical Oncology, University of Colorado Cancer Center, Aurora, Colorado. 6. Department of Medical Oncology, Brigham and Women's Hospital, Dana-Farber Cancer Institute, Boston, Massachusetts. 7. Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts. 8. Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York; Weill Cornell Medical College, New York, New York. 9. Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
Abstract
INTRODUCTION: MNNG HOS Transforming gene (MET) amplification and MET exon 14 (METex14) alterations in lung cancers affect sensitivity to MET proto-oncogene, receptor tyrosine kinase (MET [also known by the alias hepatocyte growth factor receptor]) inhibitors. Fluorescence in situ hybridization (FISH), next-generation sequencing (NGS), and immunohistochemistry (IHC) have been used to evaluate MET dependency. Here, we have determined the association of MET IHC with METex14 mutations and MET amplification. METHODS: We collected data on a tri-institutional cohort from the Lung Cancer Mutation Consortium. All patients had metastatic lung adenocarcinomas and no prior targeted therapies. MET IHC positivity was defined by an H-score of 200 or higher using SP44 antibody. MET amplification was defined by copy number fold change of 1.8x or more with use of NGS or a MET-to-centromere of chromosome 7 ratio greater than 2.2 with use of FISH. RESULTS: We tested tissue from 181 patients for MET IHC, MET amplification, and METex14 mutations. Overall, 71 of 181 patients (39%) were MET IHC-positive, three of 181 (2%) were MET-amplified, and two of 181 (1%) harbored METex14 mutations. Of the MET-amplified cases, two were FISH positive with MET-to-centromere of chromosome 7 ratios of 3.1 and 3.3, one case was NGS positive with a fold change of 4.4x, and one of the three cases was MET IHC-positive. Of the 71 IHC-positive cases, one (1%) was MET-amplified and two (3%) were METex14-mutated. Of the MET IHC-negative cases, two of 110 (2%) were MET-amplified. CONCLUSIONS: In this study, nearly all MET IHC-positive cases were negative for MET amplification or METex14 mutations. MET IHC can also miss patients with MET amplification. The limited number of MET-amplified cases in this cohort makes it challenging to demonstrate an association between MET IHC and MET amplification. Nevertheless, IHC appears to be an inefficient screen for these genomic changes. MET amplification or METex14 mutations can best be detected by FISH and a multiplex NGS panel.
INTRODUCTION: MNNG HOS Transforming gene (MET) amplification and MET exon 14 (METex14) alterations in lung cancers affect sensitivity to MET proto-oncogene, receptor tyrosine kinase (MET [also known by the alias hepatocyte growth factor receptor]) inhibitors. Fluorescence in situ hybridization (FISH), next-generation sequencing (NGS), and immunohistochemistry (IHC) have been used to evaluate MET dependency. Here, we have determined the association of MET IHC with METex14 mutations and MET amplification. METHODS: We collected data on a tri-institutional cohort from the Lung Cancer Mutation Consortium. All patients had metastatic lung adenocarcinomas and no prior targeted therapies. MET IHC positivity was defined by an H-score of 200 or higher using SP44 antibody. MET amplification was defined by copy number fold change of 1.8x or more with use of NGS or a MET-to-centromere of chromosome 7 ratio greater than 2.2 with use of FISH. RESULTS: We tested tissue from 181 patients for MET IHC, MET amplification, and METex14 mutations. Overall, 71 of 181 patients (39%) were MET IHC-positive, three of 181 (2%) were MET-amplified, and two of 181 (1%) harbored METex14 mutations. Of the MET-amplified cases, two were FISH positive with MET-to-centromere of chromosome 7 ratios of 3.1 and 3.3, one case was NGS positive with a fold change of 4.4x, and one of the three cases was MET IHC-positive. Of the 71 IHC-positive cases, one (1%) was MET-amplified and two (3%) were METex14-mutated. Of the MET IHC-negative cases, two of 110 (2%) were MET-amplified. CONCLUSIONS: In this study, nearly all MET IHC-positive cases were negative for MET amplification or METex14 mutations. MET IHC can also miss patients with MET amplification. The limited number of MET-amplified cases in this cohort makes it challenging to demonstrate an association between MET IHC and MET amplification. Nevertheless, IHC appears to be an inefficient screen for these genomic changes. MET amplification or METex14 mutations can best be detected by FISH and a multiplex NGS panel.
Authors: Lynette M Sholl; Khanh Do; Priyanka Shivdasani; Ethan Cerami; Adrian M Dubuc; Frank C Kuo; Elizabeth P Garcia; Yonghui Jia; Phani Davineni; Ryan P Abo; Trevor J Pugh; Paul van Hummelen; Aaron R Thorner; Matthew Ducar; Alice H Berger; Mizuki Nishino; Katherine A Janeway; Alanna Church; Marian Harris; Lauren L Ritterhouse; Joshua D Campbell; Vanesa Rojas-Rudilla; Azra H Ligon; Shakti Ramkissoon; James M Cleary; Ursula Matulonis; Geoffrey R Oxnard; Richard Chao; Vanessa Tassell; James Christensen; William C Hahn; Philip W Kantoff; David J Kwiatkowski; Bruce E Johnson; Matthew Meyerson; Levi A Garraway; Geoffrey I Shapiro; Barrett J Rollins; Neal I Lindeman; Laura E MacConaill Journal: JCI Insight Date: 2016-11-17
Authors: Mark M Awad; Geoffrey R Oxnard; David M Jackman; Daniel O Savukoski; Dimity Hall; Priyanka Shivdasani; Jennifer C Heng; Suzanne E Dahlberg; Pasi A Jänne; Suman Verma; James Christensen; Peter S Hammerman; Lynette M Sholl Journal: J Clin Oncol Date: 2016-01-04 Impact factor: 44.544
Authors: Lynette M Sholl; Dara L Aisner; Marileila Varella-Garcia; Lynne D Berry; Dora Dias-Santagata; Ignacio I Wistuba; Heidi Chen; Junya Fujimoto; Kelly Kugler; Wilbur A Franklin; A John Iafrate; Marc Ladanyi; Mark G Kris; Bruce E Johnson; Paul A Bunn; John D Minna; David J Kwiatkowski Journal: J Thorac Oncol Date: 2015-05 Impact factor: 15.609
Authors: David R Spigel; Martin J Edelman; Kenneth O'Byrne; Luis Paz-Ares; Simonetta Mocci; See Phan; David S Shames; Dustin Smith; Wei Yu; Virginia E Paton; Tony Mok Journal: J Clin Oncol Date: 2016-12-12 Impact factor: 44.544
Authors: Donavan T Cheng; Talia N Mitchell; Ahmet Zehir; Ronak H Shah; Ryma Benayed; Aijazuddin Syed; Raghu Chandramohan; Zhen Yu Liu; Helen H Won; Sasinya N Scott; A Rose Brannon; Catherine O'Reilly; Justyna Sadowska; Jacklyn Casanova; Angela Yannes; Jaclyn F Hechtman; Jinjuan Yao; Wei Song; Dara S Ross; Alifya Oultache; Snjezana Dogan; Laetitia Borsu; Meera Hameed; Khedoudja Nafa; Maria E Arcila; Marc Ladanyi; Michael F Berger Journal: J Mol Diagn Date: 2015-03-20 Impact factor: 5.568
Authors: Joanna H Tong; Sai F Yeung; Anthony W H Chan; Lau Y Chung; Shuk L Chau; Raymond Wai Ming Lung; Carol Y Tong; Chit Chow; Edith K Y Tin; Yau H Yu; Hui Li; Yi Pan; Wing P Chak; Calvin S H Ng; Tony S K Mok; Ka F To Journal: Clin Cancer Res Date: 2016-02-04 Impact factor: 12.531
Authors: Joel W Neal; Suzanne E Dahlberg; Heather A Wakelee; Seena C Aisner; Michaela Bowden; Ying Huang; David P Carbone; Gregory J Gerstner; Rachel E Lerner; Jerome L Rubin; Taofeek K Owonikoko; Philip J Stella; Preston D Steen; Ahmed Ali Khalid; Suresh S Ramalingam Journal: Lancet Oncol Date: 2016-11-04 Impact factor: 41.316
Authors: Na Wang; Yili Zhu; Ying Wu; Bo Huang; Junhua Wu; Ruiguang Zhang; Jun Fan; Xiu Nie Journal: J Cancer Res Clin Oncol Date: 2022-07-29 Impact factor: 4.322
Authors: Alessa Fischer; Lorenz Bankel; Stefanie Hiltbrunner; Markus Rechsteiner; Jan H Rüschoff; Elisabeth Jane Rushing; Christian Britschgi; Alessandra Curioni-Fontecedro Journal: Target Oncol Date: 2022-09-22 Impact factor: 4.864
Authors: Alessandro Russo; Ana Rita Lopes; Michael G McCusker; Sandra Gimenez Garrigues; Giuseppina R Ricciardi; Katherine E Arensmeyer; Katherine A Scilla; Ranee Mehra; Christian Rolfo Journal: Curr Oncol Rep Date: 2020-04-16 Impact factor: 5.075
Authors: Michael Offin; Jia Luo; Robin Guo; John K Lyo; Christina Falcon; Jordan Dienstag; Olivia Wilkins; Jason Chang; Charles M Rudin; Gregory Riely; Natasha Rekhtman; Maria E Arcila; Glenn Heller; Marc Ladanyi; Bob T Li; Mark G Kris; Paul Paik; Alexander Drilon Journal: JCO Precis Oncol Date: 2020-07-27
Authors: Saiama N Waqar; Mary W Redman; Susanne M Arnold; Fred R Hirsch; Philip C Mack; Lawrence H Schwartz; David R Gandara; Thomas E Stinchcombe; Natasha B Leighl; Suresh S Ramalingam; Saloni H Tanna; Ryan S Raddin; Katherine Minichiello; Jeffrey D Bradley; Karen Kelly; Roy S Herbst; Vassiliki A Papadimitrakopoulou Journal: Clin Lung Cancer Date: 2020-10-14 Impact factor: 4.785