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M. Lund-Iversen
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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): M. Lund-Iversen
- 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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P1.07 - Poster Session/ Small Cell Lung Cancer (ID 221)
- Event: WCLC 2015
- Type: Poster
- Track: Small Cell Lung Cancer
- Presentations: 1
- Moderators:
- Coordinates: 9/07/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P1.07-001 - Preoperative Serum proGRP as a Predictor for Lung Tumor Histology (ID 2561)
09:30 - 09:30 | Author(s): M. Lund-Iversen
- Abstract
Background:
Progastrin-releasing peptide (proGRP) is the stable precursor of gastrin-releasing peptide, a hormone secreted by neuroendocrine cells. Serum measurements of proGRP are helpful to detect relapses of small cell carcinoma during follow up, but its usefulness as a preoperative marker to distinguish between different lung tumors is unclear.
Methods:
Preoperative serum proGRP was determined in 116 patients with primary pulmonary tumors. 31% of the tumors displayed endocrine features (19 carcinoids, 8 small cell carcinoma, 9 large cell carcinomas) whilst the remainder were non-small cell carcinomas (40 adenocarcinomas and 40 squamous cell carcinomas). The presence of proGRP in tumors with possible endocrine features was evaluated by immunohistochemistry using two in-house anti-proGRP monoclonal antibodies (mAb M16 and mAb E149]. Tumors with less than 2 % positive cells were considered negative for proGRP expression. Serum levels of proGRP above 70 ng/L were considered elevated.
Results:
Mean serum proGRP (s-proGRP) was 267 ng/L (median: 96.5 ng/L, [range 25 – 2080 ng/L] for the neuroendocrine tumors, while adenocarcinomas and squamous cell carcinomas had mean values of 50 and 60 ng/L respectively [19,137] and median values 53.5 ng/L and 59.6 ng/L respectively (table 1). Among the tumors with possible endocrine features, serum levels of proGRP reflected the IHC score (Wilcoxon rank-sum test, p<0.0005). We did not find any relationship between tumor size and s-proGRP levels, but values >70 ng/L were predictive of either carcinoid tumor or small cell carcinoma. Table 1: Tumor characteristicsHistology ProGRP IHC positives (n/total) S-proGRP (median) S-proGRP (mean) Mean tumor size (mm) Carcinoid 9/19 127 424 26.1 Small cell carcinoma 5/8 75.5 145 30.2 Large cell carcinoma 3/9 46 72.8 42.2 Squamous cell carcinoma NA 59.6 60 NA Adenocarcinma NA 53.5 50 NA
Conclusion:
The correlation between s-proGRP and IHC scores suggest that the elevated s-proGRP results from proGRP produced by the tumor. The lack of correlation between s-proGRP and tumor size might be explained by variations in number of proGRP producing cells within the different tumors and/or to the amount proGRP secreted by different tumors. For lung tumors with unclear preoperative histology or cytology, s-proGRP-levels can be helpful as an adjuvant diagnostic marker to differentiate between tumors with and without endocrine features, but the test is not robust enough for final decision making.
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P3.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 235)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P3.04-087 - NUT Expression in Surgically Treated Small Cell, Non-Small Cell and Carcinoid Tumors of the Lung (ID 451)
09:30 - 09:30 | Author(s): M. Lund-Iversen
- Abstract
Background:
NUT midline carcinoma (NMT) is a rare, highly aggressive carcinoma defined by rearrangement of nuclear protein gene in testis (NUT) on chromosome 15; in most cases to bromodomain-containing protein 4 (BRD4) on chromosome 19. Although the majority of cases occur in midline structures above the diaphragm there are reports regarding cases in non-midline solid organs. There is an increased need to identify tumors with targetable mutations, and NUT-BRD4 translocations are potential goals for bromodomain and extra terminal (BET) inhibitors. The putative incidence among lung carcinomas low, but the true incidence is unknown.
Methods:
In a tissue micro array (TMA) set we investigated samples from 483 surgically resected lung tumors for the expression of the NUT protein using immunohistochemistry with monoclonal anti-NUT antibody (clone C52B1, Cell Signaling). 278 were adenocarcinomas, 140 squamous cell carcinomas, 30 large cell carcinomas, 7 small cell carcinoma, 18 carcinoid tumours and 10 carcinoma not otherwise specified. The median age were 66.3 [33.9 – 87.0], 247 were males and 236 were females. Testis and two previously confirmed NMT served as positive controls. Lymph nodes and normal lung tissue served as negative controls.
Results:
The positive controls had distinct nuclear staining without any unspecific background. The negative controls and all tumours were completely negative for the anti-NUT staining.
Conclusion:
We did not find any NUT expression in the investigated set of tumors. The golden standard for showing NUT rearrangement are fluorescence in situ hybridization (FISH), but the sensitivity and specificity for immunohistochemistry are high, 87% and 100% respectively (Haack et al. Am J Surg Pathol 2010). Although we cannot exclude a minority to be false negative, NUT translocations does not seem to be a relevant differential diagnostic issue in unselected early stage lung carcinomas.
