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Mutational analysis of pulmonary tumours with neuroendocrine features using targeted massive parallel sequencing: a comparison of a neglected tumour group
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Mutational analysis of pulmonary tumours with neuroendocrine features using targeted massive parallel sequencing: a comparison of a neglected tumour group
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Journal Article
Mutational analysis of pulmonary tumours with neuroendocrine features using targeted massive parallel sequencing: a comparison of a neglected tumour group
2015
Overview
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.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
