The Pathway to Lung Invasion: RELN Is Upregulated in Invasive Patterns of Lung Adenocarcinoma as Compared to Preinvasive Lesions

Context: 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. Biomarkers of lung invasion in this setting are limited. Design: Previously published gene expression data from nonmucinous AIS and invasive AdCa (containing nonmucinous lepidic pattern) of various subtypes identified 2 predominant clusters of 340 differentially expressed genes localizing to 4 major regions on 7q. Comparative genomic hybridization and Affy 6.0 SNP array data showed copy number (CN) increase in these regions in invasive AdCa. CN data from an annotated Cancer Genome Atlas data set (total of 664 LADC samples) were combined with 43 AIS/MIA and 26 LPA. The RELN gene at 7q22 was selected for correlative immunohistochemistry (IHC) with its protein product reelin. IHC using Clone G10 (Novus USA) was performed on 478 LADC samples and read independently by 2 pathologists. Cytoplasmic positivity was scored for intensity (0-3) and percentage; an H-score was calculated for each (0-300). Results: Combined CN data showed 8% to 26% gains in RELN in invasive patterns of AdCa when compared with 28% loss in AIS/MIA. Increased reelin IHC scores were seen for most LADC invasive patterns including acinar, mucinous, lepidic, and papillary subtypes (median scores 100, 100, 200, and 100, respectively) when compared to AIS/MIA (median score, 50). No association with survival was seen. Conclusions: Reelin is a candidate biomarker of invasion in LADC. Potential diagnostic applications include the use of IHC/CN in small biopsy and cytology specimens where there is morphologic overlap among lepidic pattern lesions.