Frank, Rieke, Scheffler, Matthias ORCID: 0000-0002-9031-1368, Merkelbach-Bruse, Sabine, Ihle, Michaela A., Kron, Anna, Rauer, Michael, Ueckeroth, Frank, Koenig, Katharina, Michels, Sebastian, Fischer, Rieke, Eisert, Anna, Fassunke, Jana, Heydt, Carina, Serke, Monika, Ko, Yon-Dschun, Gerigk, Ulrich, Geist, Thomas, Kaminsky, Britta, Heukamp, Lukas C., Clement-Ziza, Mathieu, Buettner, Reinhard and Wolf, Juergen (2018). ClinicalandPathological Characteristics of KEAP1- and NFE2L2-Mutated Non-Small Cell Lung Carcinoma (NSCLC). Clin. Cancer Res., 24 (13). S. 3087 - 3097. PHILADELPHIA: AMER ASSOC CANCER RESEARCH. ISSN 1557-3265

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Abstract

Purpose: KEAP1 and NFE2L2 mutations are associated with impaired prognosis in a variety of cancers and with squamous cell carcinoma formation in non-small cell lung cancer (NSCLC). However, little is known about frequency, histology dependence, molecular and clinical presentation as well as response to systemic treatment in NSCLC. Experimental Design: Tumor tissue of 1,391 patients with NSCLC was analyzed using next-generation sequencing (NGS). Clinical and pathologic characteristics, survival, and treatment outcome of patients with KEAP1 or NFE2L2 mutations were assessed. Results: KEAP1 mutations occurred with a frequency of 11.3% (n = 157) and NFE2L2 mutations with a frequency of 3.5% (n = 49) in NSCLC patients. In the vast majority of patients, both mutations did not occur simultaneously. KEAP1 mutations were found mainly in adenocarcinoma (AD; 72%), while NFE2L2 mutations were more common in squamous cell carcinoma (LSCC; 59%). KEAP1 mutations were spread over the whole protein, whereas NFE2L2 mutations were clustered in specific hotspot regions. In over 80% of the patients both mutations co-occurred with other cancer-related mutations, among them also targetable aberrations like activating EGFR mutations or MET amplification. Both patient groups showed different patterns of metastases, stage distribution and performance state. No patient with KEAP1 mutation had a response on systemic treatment in first-, second-, or third-line setting. Of NFE2L2-mutated patients, none responded to second-or third-line therapy. Conclusions: KEAP1- and NFE2L2-mutated NSCLC patients represent a highly heterogeneous patient cohort. Both are associated with different histologies and usually are found together with other cancer-related, partly targetable, genetic aberrations. In addition, both markers seem to be predictive for chemotherapy resistance. (C) 2018 AACR.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Frank, RiekeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Scheffler, MatthiasUNSPECIFIEDorcid.org/0000-0002-9031-1368UNSPECIFIED
Merkelbach-Bruse, SabineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ihle, Michaela A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kron, AnnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rauer, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ueckeroth, FrankUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Koenig, KatharinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Michels, SebastianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fischer, RiekeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Eisert, AnnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fassunke, JanaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heydt, CarinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Serke, MonikaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ko, Yon-DschunUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gerigk, UlrichUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Geist, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kaminsky, BrittaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heukamp, Lukas C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Clement-Ziza, MathieuUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Buettner, ReinhardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wolf, JuergenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-181822
DOI: 10.1158/1078-0432.CCR-17-3416
Journal or Publication Title: Clin. Cancer Res.
Volume: 24
Number: 13
Page Range: S. 3087 - 3097
Date: 2018
Publisher: AMER ASSOC CANCER RESEARCH
Place of Publication: PHILADELPHIA
ISSN: 1557-3265
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
TRANSCRIPTION FACTOR NRF2; PROTEASOMAL DEGRADATION; MUTATIONAL LANDSCAPE; CANCER-CELLS; E3 LIGASE; ACTIVATION; RESISTANCE; INDUCTION; CHEMORESISTANCE; ADENOCARCINOMAMultiple languages
OncologyMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/18182

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