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S. Solberg
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ORAL 06 - Next Generation Sequencing and Testing Implications (ID 90)
- Event: WCLC 2015
- Type: Oral Session
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:G. De Lima Lopes, V. Miller
- Coordinates: 9/07/2015, 10:45 - 12:15, Mile High Ballroom 1a-1f
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ORAL06.01 - Genomic Characterization of Large-Cell Neuroendocrine Lung Tumors (ID 1667)
11:05 - 11:16 | Author(s): S. Solberg
- Abstract
Background:
Neuroendocrine lung tumours account for 25% of all lung cancer cases, and they range from low-aggressive pulmonary carcinoids (PCA) to highly malignant small-cell lung cancer (SCLC) and large-cell neuroendocrine lung carcinoma (LCNEC). The last two are strongly associated with heavy smoking and are typically detected at a clinically advanced stage, having a poor survival. Comprehensive genomic analyses in lung neuroendocrine tumours are difficult because of limited availability of tissue. While more effort has been done in the context of SCLC, the detailed molecular features of LCNEC remain largely unknown.
Methods:
We conducted 6.0 SNP array analyses of 60 LCNEC tumours, exome sequencing of 55 tumor-normal pairs, genome sequencing of 11 tumour-normal pairs, transcriptome sequencing of 69 tumours, and expression arrays on 60 tumors. Data analyses were performed using in house developed and published pipelines.
Results:
Analyses of chromosomal gene copy number revealed amplifications of MYCL1, FGFR1, MYC, IRS2 and TTF1. We also observed deletions of CDKN2A and PTPRD. TTF1 amplifications are characteristic of lung adenocarcinoma (AD); CDKN2A deletions are frequent alterations in both AD and squamous-cell lung carcinoma (SQ); FGFR1 amplifications are found in SQ and, less frequently, in SCLC; and MYCL1 and IRS2 amplifications are frequent events in SCLC. Similar to the copy number data, we found patterns of mutations characteristic of other lung cancer subtypes: TP53 was the most frequently mutated gene (75%) followed by RB1 (27%), and inactivation of both TP53 and RB1, which is the hallmark of SCLC, occurred in 20% of the cases. Mutations in STK11 and KEAP1-NFE2L2 (frequently seen in AD and SQ) were found in 23% and 22% of the specimens, respectively. Interestingly, mutations in RB1 and STK11/KEAP1 occurred in a mutually exclusive fashion (p-value=0.016). Despite the heterogeneity observed at the mutation level, analysis of the pattern of expression of LCNEC in comparison with the other lung cancer subtypes (AD, SQ, SCLC, and PCA) points to LCNEC as being an independent entity. An average mutation rate of 10.7 mutations per megabase was detected in LCNEC, which is in line with the rate observed in other lung tumours associated with smoking. We found that, similar to SCLC, the mutation signatures associated with APOBEC family of cytidine deaminases, smoking, and age (based on Alexandrov et al 2013) were the predominant ones in LCNEC. However, the contribution of the individual SCLC and LCNEC samples to these three signatures was quite different, and we are currently exploring it.
Conclusion:
Taking into account somatic copy number and mutation data, we distinguished two well-defined groups of LCNEC: an SCLC-like group, carrying alterations in MYCL1, ISR2, and in both RB1 and TP53; and a group resembling AD and SQ, with alterations in CDKN2A, TTF1, KEAP1-NFE2L2, and STK11. Although these results suggest that LCNEC might be a mix of different lung cancer subtypes, mutation clonality and expression analyses show that they are likely to be a separate entity, sharing molecular characteristics with the other lung cancer subtypes. Their heterogeneity suggests that LCNEC might represent an evolutionary trunk that can branch to SCLC or AD/SQ.
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P1.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 233)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:
- Coordinates: 9/07/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P1.04-060 - Pathways Involved in Lung Adenocarcinomas, - Integrated Analyses on Methylation and mRNA Data (ID 2699)
09:30 - 09:30 | Author(s): S. Solberg
- Abstract
Background:
Lung cancer is one of the biggest cancer killers in the world. Despite certain recent advances, mortality is still high. Targeted therapy has increased the time to death for metastastic lung cancer, but such therapy is not available for all lung cancer patients. Targeted therapy is more often available for never smokers, due to presence of druggable driver mutations. In order to search for new putative targets of therapy, we seek to identify pathways involved different subgroups of patients and in patients with early relapse.
Methods:
A total of 190 patients undergoing surgery for lung cancer were included in the study (154 EGFR positive, 23 EGFR negative, 170 smokers and 20 non-smokers). Lung cancer tissue and clinical information was available for all patients and normal lung tissue was available for 30 of the patients. Whole genome expression array analysis (Agilent) was performed using mRNA isolated from all samples and DNA-methylation was analysed for 168 tumours and 21 matched normal lung tissue samples. R was used for statistical analyses; annHeatmap (from Heatplus) for hierarchical clustering, limma to identify differentially expressed genes, SPIA for pathway analysis and canonical correlation of methylation and mRNA-expression was performed with the CCA function from the PMA package. Pathways with an FDR<0.1 were considered significant. DAVID was used for gene ontology analysis.
Results:
Based on correlation of mRNA and methylation, different pathways were identified as predominant in specific subgroups of lung adenocarcinomas. Preliminary results indicate that genes involved in the KEGG-pathways cell cycle are more highly expressed in EGFR positive than in EGFR negative tumours in smokers. In the EGFR-negative tumours, several pathways are up-regulated: Oocyte meiosis, progesterone-mediated oocyte maturation, HTLV-1 infection, p53 signalling pathway and small cell lung cancer. For non-smoking patients, four pathways were up-regulated in EGFR-positive tumours: ECM-receptor interaction, TGF-beta signalling pathway, bile secretion and cocaine addiction. There were no pathways up-regulated in EGFR-negative compared with EGFR-positive never-smokers. This may partly be due to small numbers. Similarly, pathways dominating the tumours of patients with early relapse will be identified. Genes whose expression and methylation status were correlated were identified within smokers and non-smokers separately.
Conclusion:
Based on correlation between mRNA and methylation, specific pathways were identified activated in subgroups of lung adenocarcinomas. There are significant differences between ever-smokers and never-smokers. Survival analyses are ongoing.
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P2.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 234)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P2.04-011 - Whole-Genome Copy Number Analyses of NSCLC Tumors Reveal Aberrations Associated With EGFR Mutations and May Have Prognostic Impact (ID 1504)
09:30 - 09:30 | Author(s): S. Solberg
- Abstract
Background:
Knowledge about genetic alterations in Non-Small Cell Lung Cancer (NSCLC) has given us a significant insight in the biology of these tumors. It is of great clinical importance with consequences for the patients, and DNA mutations and translocations are currently targets for therapy. Aberrations in DNA copy number are frequent events in NSCLC tumors and important in tumorogenesis. In this present study we want to investigate how the copy number changes varies between different subgroups of NSCLC tumors based on the patients’ smoking status, histology or EGFR-, KRAS- and TP53 mutations. The DNA copy number data will be integrated with global mRNA expression to study the cis-associated mRNA expression changes. Last, we want to investigate whether genomic events, like specific copy number changes or the complex arm-wise aberration index (CAAI), have prognostic impact in patients with NSCLC.
Methods:
In this study we have included 200 patients with operable NSCLC tumors. Copy number data were obtained by using the Affimetrix Genome-wide human SNP array 6.0. Histopathological information, EGFR-, KRAS- and TP53 mutation status were determined and clinical information and follow-up data was obtained for all patients. The mRNA expression was determined by the Agilent 60K mRNA expression array on a subset of 117 patients. The data was analyzed by using bioinformatic tools like ASCAT and integration of the mRNA data and the survival analyses are on-going.
Results:
Preliminary results have shown that copy number aberrations are frequent events in NSCLC tumors, consistent with previous reports. We have identified that the copy number patterns differ between adenocarcinomas and squamous cell carcinomas, and between tumors from patients with different smoking history. However, the largest differences were found between the EGFR-mutated adenocarcinomas compared with EGFR wildtype tumors, where we identified a specific pattern of copy number changes in the tumors that harbour EGFR mutation. These changes were mainly located at chromosome arm 1p, 2p, 3q, 5q, 7, 12 and 13. Preliminary analyses have also identified specific copy number aberrations with prognostic significance.
Conclusion:
Copy number aberrations are frequent in NSCLC tumors and may have great impact on gene expression and give us valuable prognostic information. EGFR-mutated adenocarcinomas have a specific pattern of copy number changes, which provides new insight of the biology of these tumors.
