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F. Kwong
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MA12 - Miscellaneous Biology/Pathology (ID 476)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: Biology/Pathology
- Presentations: 1
- Moderators:B. Dome, W.D. Travis
- Coordinates: 12/06/2016, 14:20 - 15:50, Schubert 1
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MA12.04 - Mitochondrial-Related Proteins, PGAM5 and FUNDC1, in COPD-Associated Non-Small Cell Lung Carcinoma (ID 5646)
14:44 - 14:50 | Author(s): F. Kwong
- Abstract
- Presentation
Background:
Patients with COPD and/or emphysema have an increased risk of non-small cell lung cancer (NSCLC). COPD and lung cancer are both characterised by increased oxidative stress associated with mitochondrial dysfunction. We hypothesise that mitochondrial dysfunction is a driving mechanism for the increased risk of NSCLC in COPD. We determined whether there is dysregulated expression of mitochondrial-related proteins in NSCLC arising in COPD, and if so, their clinical significance.
Methods:
To determine the clinical relevance of mitochondrial related gene expression, we examined a database containing transcriptomic data of more than 1, 000 human NSCLC samples and with survival outcomes (https://precog.stanford.edu/). Immunohistochemistry for PGAM5 and FUNDC1 was performed on cancer and background (‘normal’) tissue from lung cancer resections from non-smokers, healthy smokers (without COPD) and COPD/ emphysema patients. Protein expression was assessed using a semi-quantitative immunohistochemical scoring system (H score). Specific gene expression was further correlated with outcome in dataset GSE 72194, containing transcriptomic data of NSCLC cases and patient survival.
Results:
25 mitochondrial-related genes were linked to survival in NSCLC. Of those 25, we chose to study further the expression of PGAM5 and FUNDC1, which are regulators of mitochondrial degradation (mitophagy). In background lung tissue, PGAM5 and FUNDC1, only expressed in alveolar macrophages, were most highly expressed in COPD (H score: 180 ± 58 and 23 ± 9, respectively) compared to healthy smokers (146 ± 58 and 20 ± 8) and non-smokers (68 ± 48 and 3.3 ± 1.4) (p<0.05). In cancerous tissue, only the malignant epithelial cells and associated macrophages, at the periphery of the cancer, expressed PGAM5 and FUNDC1. PGAM5 was also expressed in pre-neoplastic epithelium (squamous dysplasia and carcinoma in situ). There was no difference in expression across the 3 groups, although the macrophages, at the edge of cancer, from COPD patients tended to show higher expression of PGAM5 and FUNDC1, compared to those from the other groups. When the expression of PGAM5 was compared with that of 50 known macrophage transcriptomic signatures within NSCLC samples, there was a positive correlation between PGAM5 and 9 macrophage signatures (r= 0.27 - 0.44, p<0.05), with one a determinant of patient survival.
Conclusion:
PGAM5 expression in pre-neoplastic tissue and NSCLC, but not in normal epithelium, suggests it plays a role in the transformation of malignant epithelial cells. PGAM5 and FUNDC1 may contribute to the pathogenesis of both COPD and NSCLC, possibly through mitophagic processes.
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P2.03b - Poster Session with Presenters Present (ID 465)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.03b-086 - High Expression of PDL-1 Correlates with Pleomorphic Features in Non-Small Cell Lung Carcinomas (ID 5761)
14:30 - 14:30 | Author(s): F. Kwong
- Abstract
Background:
With immunomodulatory therapy being integrated into treatment regimes for non-small cell carcinoma (NSCLC), we have reviewed our initial experience within the UK in relation to potential access to treatment with pembrolizumab, in order to assess correlation between tumour morphology and staining patterns.
Methods:
Immunohistochemistry for PD-L1 (IHC/PD-L1) was performed with the PD-L1 IHC 22C3 pharmDxTM assay (Dako) on cases being considered for treatment. The test was considered adequate when more than 100 tumour cells were seen microscopically. When adequate, PD-L1 staining was scored as 0%, <1%, ≥ 1-49% or ≥ 50% positive membrane staining within tumour cells only. PD-L1 staining was considered positive when the score was >50%. In initial cases, it was noticed that there was increased staining in cases with pleomorphic features, so a separate cohort of 9 resections of pleomorphic carcinomas was additionally assessed.
Results:
PD-L1 expression was assessed in 72 NSCLC test cases which comprised 19 lung resections, 31 lung biopsies, 11 lymph node biopsies (5 of which were TBNAs), 4 pleural/pericardial tissue (2 from effusions), and 7 other metastatic sites (cores). There were 52 ADC (8 of which were NSCLC-ADC on IHC and 3 of which were invasive mucinous ADC), 7 SQCC (2 of which were NSCLC-SQCC on IHC), one LCC, 2 NSCLC-NE and 4 NSCLC-NOS. 6 cases were inadequate. Of the 65 cases with adequate tissue, 9 cases had pleomorphic features. A score of >50% was found in 78% (7/9) of cases with pleomorphic features with the remainder being 1-49%, compared to 27% (15/56) in those without pleomorphic features (p<0.05) (1-49% = 22 ,<1% = 19). 8 of 9 (89%) additional resected pleomorphic carcinomas showed >50% positivity with one case showing 10% positive staining concentrated in the pleomorphic area.
Conclusion:
Initial data show a correlation between PD-L1 staining and pleomorphic features in non-small cell lung carcinomas. Assessment on cell blocks obtained from TBNAs and effusions also provide assessable material.
