Abstract
BackgroundThe current classification of human lung adenocarcinoma defines five different histological growth patterns within the group of conventional invasive adenocarcinomas. The five growth patterns are characterised by their typical architecture, but also by variable tumor biological behaviour.AimsThe aim of this study was to identify specific gene signatures of the five adenocarcinoma growth patterns defined by the joint IASLC/ATS/ERS working group.MethodsTotal RNA from microdissected adenocarcinoma tissue samples of ten lepidic, ten acinar, ten solid, nine papillary, and nine micropapillary tumor portions was isolated and prepared for gene expression analysis. Differential expression of genes was determined using the R package “LIMMA”. The overall significance of each signature was assessed via global test. Gene ontology statistics were analysed using GOstat. For immunohistochemical validation, tissue specimens from 20 tumors with solid and 20 tumors with lepidic growth pattern were used.ResultsMicroarray analyses between the growth patterns resulted in numerous differentially expressed genes between the solid architecture and other patterns. The comparison of transcriptomic activity in the solid and lepidic patterns revealed 705 up- and 110 downregulated non-redundant genes. The pattern-specific protein expression of Inositol-1,4,5-trisphosphate-kinase-A (ITPKA) and angiogenin by immunohistochemistry confirmed the RNA levels. The strongest differences in protein expression between the two patterns were shown for ITPKA (p = 0.02) and angiogenin (p = 0.113).ConclusionsIn this study growth pattern-specific gene signatures in pulmonary adenocarcinoma were identified and distinct transcriptomic differences between lung adenocarcinoma growth patterns were defined. The study provides valuable new information about pulmonary adenocarcinoma and allows a better assessment of the five adenocarcinoma subgroups.
Highlights
In 2011, a joint IASLC/ATS/ERS working group introduced a new classification of human lung adenocarcinoma [1]
The five growth patterns should be characterised by their typical architecture, and by variable tumor biological behaviour
Whereas lepidic predominant adenocarcinoma seems to be the one with the best prognosis, the micropapillary and solid architectures are associated with a poor prognosis [3,4,5,6,7]
Summary
In 2011, a joint IASLC/ATS/ERS working group introduced a new classification of human lung adenocarcinoma [1] This new classification defined five different histological growth patterns within the group of conventional invasive adenocarcinomas: lepidic (corresponding to the former non-mucinous bronchioloalveolar pattern), acinar, papillary, micropapillary (newly added) and solid predominant adenocarcinoma. Three molecular subtypes (bronchoid/terminal respiratory, magnoid/proximal-proliferative and squamoid/proximal-inflammatory) were defined and successfully verified across several microarray and sequencing datasets [11,12,13]. Such molecular profiles are used to decipher prognostic/predictive biomarkers and therapeutic target sites specific for patient subgroups. The five growth patterns are characterised by their typical architecture, and by variable tumor biological behaviour
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