Genetic changes of non-small cell lung cancer under neoadjuvant therapy
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Arne Warth1,#, Volker Endris1, Albrecht Stenzinger1, Roland Penzel1, Alexander Harms1, Thomas Duell2, Amir Abdollahi3,+, Michael Lindner4, Peter Schirmacher1, Thomas Muley5,#, Hendrik Dienemann6,#, Ludger Fink7,#, Alicia Morresi-Hauf8, Nicole Pfarr1,10,§, Wilko Weichert1,9,10,+,§
1Institute of Pathology, Heidelberg University, Heidelberg, Germany
2Department of Pneumology and Thoracic Oncology, Asklepios Hospital, Munich-Gauting, Germany
3Department of Radiation Oncology, Heidelberg University, Heidelberg, Germany
4Department of Thoracic Surgery, Asklepios Hospital, Munich-Gauting, Germany
5Translational Research Unit, Thoraxklinik at Heidelberg University, Heidelberg, Germany
6Department of Thoracic Surgery, Thoraxklinik at Heidelberg University, Heidelberg, Germany
7Institute of Pathology, Wetzlar, Germany
8Institute of Pathology, Asklepios Hospital, Munich-Gauting, Germany
9National Center for Tumor Diseases (NCT), Heidelberg, Germany
10Institute of Pathology, Technical University (TUM), Munich, Germany
#Translational Lung Research Centre Heidelberg, Member of the German Center for Lung Research (DZL-TLRC)
+Member of the German Cancer Consortium (DKTK)
§shared senior authorship
Arne Warth, email: [email protected]
Wilko Weichert, email: [email protected]
Keywords: lung cancer, molecular evolution, driver mutations, therapy
Received: November 06, 2015 Accepted: March 28, 2016 Published: April 20, 2016
Background: Large scale sequencing efforts defined common molecular alterations in non-small cell lung cancer (NSCLC) and revealed potentially druggable mutations. Yet, systematic data on the changes of the respective molecular profiles under standard therapy in NSCLC are limited.
Results: 14 out of 68 observed coding mutations (21%) and 6 out of 33 (18%) copy number variations (CNV) were lost or gained during therapy. Mutational and CNV changes clustered in 6/37 (16%) and 3/37 (8%) patients. Changes in clinically relevant mutations were rare but present in single cases for genes such as BRAF and PIK3CA. The type of radiochemotherapy but not the duration of therapy impacted on the frequency of mutational changes.
Methods: We established a lung cancer specific next-generation sequencing panel covering ~7500 hotspots of 41 genes frequently mutated in NSCLC and performed ultradeep multigene sequencing of 37 corresponding pre- and post-therapeutic formalin fixed paraffin-embedded specimens to discover mutational changes and copy number variations under neo-adjuvant radio- (RTX) and/or chemotherapy (CTX).
Conclusion: We unraveled changes in common driver gene candidates in NSCLC under neo-adjuvant therapy. Our data shed first light on the genetic changes of NSCLC under conventional therapy and might be taken into account when the relevance of sequential biopsy approaches is discussed.
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