Universität zu Köln

Vollbrecht, Claudia ORCID: 0000-0002-0861-001X, Werner, Robert, Walter, Robert Fred Henry, Christoph, Daniel Christian, Heukamp, Lukas Carl, Peifer, Martin ORCID: 0000-0002-5243-5503, Hirsch, Burkhard, Burbat, Lina, Mairinger, Thomas, Schmid, Kurt Werner, Wohlschlaeger, Jeremias and Mairinger, Fabian Dominik (2015). Mutational analysis of pulmonary tumours with neuroendocrine features using targeted massive parallel sequencing: a comparison of a neglected tumour group. Br. J. Cancer, 113 (12). S. 1704 - 1712. LONDON: NATURE PUBLISHING GROUP. ISSN 1532-1827

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Abstract

Background: Lung cancer is the leading cause of cancer-related deaths worldwide. The typical and atypical carcinoid (TC and AC), the large-cell neuroendocrine carcinoma (LCNEC) and the small-cell lung cancers (SCLC) are subgroups of pulmonary tumours that show neuroendocrine differentiations. With the rising impact of molecular pathology in routine diagnostics the interest for reliable biomarkers, which can help to differentiate these subgroups and may enable a more personalised treatment of patients, grows. Methods: A collective of 70 formalin-fixed, paraffin-embedded (FFPE) pulmonary neuroendocrine tumours (17 TCs, 17 ACs, 19 LCNECs and 17 SCLCs) was used to identify biomarkers by high-throughput sequencing. Using the Illumina TruSeq Amplicon-Cancer Panel on the MiSeq instrument, the samples were screened for alterations in 221 mutation hot spots of 48 tumour-relevant genes. Results: After filtering >26 000 detected variants by applying strict algorithms, a total of 130 mutations were found in 29 genes and 49 patients. Mutations in JAK3, NRAS, RB1 and VHL1 were exclusively found in SCLCs, whereas the FGFR2 mutation was detected in LCNEC only. KIT, PTEN, HNF1A and SMO were altered in ACs. The SMAD4 mutation corresponded to the TC subtype. We prove that the frequency of mutations increased with the malignancy of tumour type. Interestingly, four out of five ATM-mutated patients showed an additional alteration in TP53, which was by far the most frequently altered gene (28 out of 130; 22%). We found correlations between tumour type and IASLC grade for ATM-(P = 0.022; P = 0.008) and TP53-mutated patients (P<0.001). Both mutated genes were also associated with lymph node invasion and distant metastasis (P <= 0.005). Furthermore, PIK3CA-mutated patients with high-grade tumours showed a reduced overall survival (P = 0.040) and the mutation frequency of APC and ATM in high-grade neuroendocrine lung cancer patients was associated with progression-free survival (PFS) (P = 0.020). Conclusions: The implementation of high-throughput sequencing for the analysis of the neuroendocrine lung tumours has revealed that, even if these tumours encompass several subtypes with varying clinical aggressiveness, they share a number of molecular features. An improved understanding of the biology of neuroendocrine tumours will offer the opportunity for novel approaches in clinical management, resulting in a better prognosis and prediction of therapeutic response.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Vollbrecht, Claudia UNSPECIFIED orcid.org/0000-0002-0861-001X UNSPECIFIED Werner, Robert UNSPECIFIED UNSPECIFIED UNSPECIFIED Walter, Robert Fred Henry UNSPECIFIED UNSPECIFIED UNSPECIFIED Christoph, Daniel Christian UNSPECIFIED UNSPECIFIED UNSPECIFIED Heukamp, Lukas Carl UNSPECIFIED UNSPECIFIED UNSPECIFIED Peifer, Martin UNSPECIFIED orcid.org/0000-0002-5243-5503 UNSPECIFIED Hirsch, Burkhard UNSPECIFIED UNSPECIFIED UNSPECIFIED Burbat, Lina UNSPECIFIED UNSPECIFIED UNSPECIFIED Mairinger, Thomas UNSPECIFIED UNSPECIFIED UNSPECIFIED Schmid, Kurt Werner UNSPECIFIED UNSPECIFIED UNSPECIFIED Wohlschlaeger, Jeremias UNSPECIFIED UNSPECIFIED UNSPECIFIED Mairinger, Fabian Dominik UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-383531
DOI:	10.1038/bjc.2015.397
Journal or Publication Title:	Br. J. Cancer
Volume:	113
Number:	12
Page Range:	S. 1704 - 1712
Date:	2015
Publisher:	NATURE PUBLISHING GROUP
Place of Publication:	LONDON
ISSN:	1532-1827
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language CELL LUNG-CANCER; MEDULLARY-THYROID CARCINOMA; RET MUTATION; GENE; P53; NEOPLASMS; VARIANTS; SURVIVAL; CLASSIFICATION; POLYMORPHISM Multiple languages Oncology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/38353