WHO grading system for invasive pulmonary lung adenocarcinoma reveals distinct molecular signature: An analysis from the cancer genome atlas database.

Lung adenocarcinoma grading has gained interest in the past years. Recently a three-tier tumor grading was proposed showing that it is related to patients' prognosis. Nevertheless, the underlying molecular basis of this morphological grading remains partly unknown. The aim of our work is to take advantage of The Cancer Genome Atlas lung adenocarcinoma (TCGA_LUAD) cohort to describe the molecular data associated to tumor grading. We performed a study on publicly available data of the TCGA database first by assessing a tumor grade on downloadable tumor slides. Secondly we analyzed the molecular features of each tumor grade group. Our work was performed on a study group of 449 patients. We show that aneuploidy score was significantly different between grade 2 and grade 3 groups with different chromosomal imbalance (p < 0.001). SCGB1A1 mRNA expression was higher in grade 2 (p = 0.0179) whereas NUP155, CHFR, POLQ and CDC7 have a higher expression in grade 3 (p = 0.0189, 0.0427, 0.0427 and 0.427 respectively). GZMB and KRT80 have a higher methylation of DNA in grade 2 (p = 0.0201 and 0.0359 respectively). MT1G, CLEC12B and NDUFA7 have a higher methylation of DNA in grade 3 (p < 0.001, 0.0246 and 0.0359 respectively). We showed that the number of activated pathways is different between grade 2 and grade 3 patients (p = 0.004). We showed that differentially expressed genes by mRNA analysis and DNA methylation analysis involve several genes implied in chemoresistance. This could suggest that grade 3 lung adenocarcinoma might be more resistant to chemotherapy.