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J. Zhu
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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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P3.04-069 - Exportin-5 (XPO5) in Lung Adenocarcinoma: A New Biomarker of Invasion in Pathology Specimens (ID 1283)
09:30 - 09:30 | Author(s): J. Zhu
- Abstract
Background:
The WHO/IASLC classification of lung adenocarcinoma (LADC) emphasizes the distinction of adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA) from their invasive counterparts. The distinction between lepidic-pattern lesions, in particular AIS/MIA and lepidic-predominant adenocarcinoma (LPA), is difficult in small biopsies and cytology specimens. Currently, there are no biomarkers of lung invasion in this setting.
Methods:
The WHO/IASLC classification of LADC was used for all components of this study. Gene expression (GE) data from 58 LADC samples including 33 samples of AIS/MIA and LPA identified two predominant clusters of 553 differentially expressed genes (p<0.01, FDR<0.06). The 317 genes upregulated in LPA localized to 6 regions on chromosomes 1, 2, 6 and 17 (Gene Set Enrichment Analysis). Expression data was compared to copy number (CN) data of AIS/MIA and LPA pooled from a re-annotated Cancer Genome Atlas data set along with prior annotated Affy 6.0 SNP array data (total 1086 LADC samples including 43 AIS/MIA and 26 LPA). Two regions (6p and 17q) contained genes with increased expression and CN increase in LPA. The XPO5 gene at 6p21 was selected for further study. Immunohistochemistry (IHC) for the XPO5 protein product Exportin-5 (XPO5, Sigma-Aldrich, St. Louis, USA) was performed on 686 lung cancers (NSCLC), on tissue microarrays and read independently by two pathologists. Nuclear (N) and cytoplasmic (C) positivity was scored for intensity (0-3) and percentage; an H-score was calculated for each (0-300, N-score and C-score). A total score (T-score) was calculated from the sum of the N-and C-scores (0 to 600). Statistical analysis was performed using the independent-samples Kruskal-Wallis test and pairwise analysis. Cox regression was used for survival analysis (continuous variable and quartile regressions), as well as Kaplan-Meier curves, logrank statistic.
Results:
XPO5 at 6p21 showed upregulation in LPAs by CN, GE and IHC. High XPO5 IHC T-scores correlated with CN, with a median T-score of 300 in tumors with CN gain vs. 50 in tumors without gain. High T-scores were seen in the following invasive patterns of NSCLCs as compared to AIS/MIA: acinar-ADC, solid-ADC, papillary-ADC, large cell carcinoma and squamous cell carcinoma; mean T-scores ranged from 144.7-251.4 in these groups vs. 48.3 and 72.1 in AIS and MIA, respectively. Importantly, T-scores correlated with overall survival for all-stage (n=686) and stage I (n=307) analyses, with higher scores predicting inferior survival. While IHC scores did not show statistically significant staining in LPA as compared to AIS/MIA, a qualitative difference was noted in some cases with acquisition of cytoplasmic positivity in the invasive component of LPAs.
Conclusion:
XPO5 is a candidate biomarker of invasion in LADC. GE and CN data along with IHC staining patterns in 686 NSCLC samples show upregulation of XPO5 in invasive tumors and in tumors with poor survival. In addition to its application in small biopsies, this marker may be of particular use in cytology specimens, where there is significant morphologic overlap between lepidic-pattern tumors and well-differentiated invasive patterns of LADC.
