Genetic changes of non-small cell lung cancer under neoadjuvant therapy.
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).


CONCLUSIONS
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.
Institute of Pathology, Heidelberg University, Heidelberg, Germany.
Arne
A
Warth
Institute of Pathology, Heidelberg University, Heidelberg, Germany.
Volker
V
Endris
Institute of Pathology, Heidelberg University, Heidelberg, Germany.
Albrecht
A
Stenzinger
Institute of Pathology, Heidelberg University, Heidelberg, Germany.
Roland
R
Penzel
Institute of Pathology, Heidelberg University, Heidelberg, Germany.
Alexander
A
Harms
Department of Pneumology and Thoracic Oncology, Asklepios Hospital, Munich-Gauting, Germany.
Thomas
T
Duell
Department of Radiation Oncology, Heidelberg University, Heidelberg, Germany.
Amir
A
Abdollahi
Department of Thoracic Surgery, Asklepios Hospital, Munich-Gauting, Germany.
Michael
M
Lindner
Institute of Pathology, Heidelberg University, Heidelberg, Germany.
Peter
P
Schirmacher
Translational Research Unit, Thoraxklinik at Heidelberg University, Heidelberg, Germany.
Thomas
T
Muley
Department of Thoracic Surgery, Thoraxklinik at Heidelberg University, Heidelberg, Germany.
Hendrik
H
Dienemann
Institute of Pathology, Wetzlar, Germany.
Ludger
L
Fink
Institute of Pathology, Asklepios Hospital, Munich-Gauting, Germany.
Alicia
A
Morresi-Hauf
Institute of Pathology, Heidelberg University, Heidelberg, Germany.|Institute of Pathology, Technical University (TUM), Munich, Germany.
Nicole
N
Pfarr
Institute of Pathology, Heidelberg University, Heidelberg, Germany.|National Center for Tumor Diseases (NCT), Heidelberg, Germany.|Institute of Pathology, Technical University (TUM), Munich, Germany.
Wilko
W
Weichert
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics*; D056915:DNA Copy Number Variations / Q000187:drug effects*; D004252:DNA Mutational Analysis; D005260:Female; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics*; D008297:Male; D009154:Mutation / Q000187:drug effects*; D020360:Neoadjuvant Therapy
D000970:Antineoplastic Agents
driver mutations; lung cancer; molecular evolution; therapy