A Study Of Clinicopathological And Molecular Features Associated With The Prognosis Of Lung Adenocarcinoma

To meet the needs of assessment for clinical outcomes and individualized treatment, looking for pathological and molecular prognostic factors of lung adenocarcinoma based on TNM staging and morphology is a critical problem to be solved. In this study, a total of263cases who were underwent surgical resection and followed-up at least5years were re-classified according to UICC/AJCC7th edition of TNM staging system and2011IASLC/ATS/ERS international multidisciplinary classification; Immunohistochemistry were performed on tissue microarray platform to detect expression of Napsin A, TTF-1, ERCC1, RRM1, total EGFR, EGFR special for exon21and exonl9mutant, ERα, ERβ1,PR, HER2, Bcl-2protein in lung adenocarcinoma;31cases of stage I were analyzed by array comparative genomic hybridization (array CGH). In the current study, morphological characteristics and expression of immune markers were analyzed to evaluate the relationship with prognosis in lung adenocarcinoma. We also attempt to pick up a cluster of gene/chromosome fragment with amplification or deletion from the "DNA copy number variation (CNV) profiles" as molecular markers specialized in predicting.The first part was analysis of the clinicopathology features related to prognosis. The results showed that5-year overall survival (OS) rate of263cases was73.2%, according to the7th edition TNM classification,5-year OS rates for Ⅰ-Ⅳ stages were89.2%,63.4%,37.0%and0respectively, as to the6th edition, they were86.9%,47.4%,40.5%and9.1%respectively. Difference between the two editions was statistically significant, P<0.001; According to univariate survival analysis, tumor size, degree of differentiation, the new IASLC/ATS/ERS classification, mitotic count, necrosis, pleural invasion, and vascular invasion were associated with overall survival. Tumor size, degree of differentiation, mitotic count and tumor embolus also related to disease-free survival, P<0.05; Cutoffs of5%and30%for lepidic growth pattern component can stratify patients into three groups with significantly different clinical outcom, P<0.05. Multivariate survival analysis showed that,6th and7th edition TNM staging, mitotic count, tumor embolus and lepidic growth pattern were independent prognostic factors for overall survival; The two editions TNM staging, mitotic count, vascular invasion and postoperative adjuvant therapy were independent prognostic factors related to disease-free survival. In the second part, we analysed expression of12immune markers in lung adenocarcinoma. The results showed that, efficiency of immunohistochemistry test on tissue microarray platform were91.2%-95.6%; By univariate survival analysis: Napsin A, TTF-1and ERCC1expression associated with longer overall survival (P<0.05), TTF-1expression related to longer disease-free survival, P<0.05. By multivariate survival analysis, all12markers were not independent prognostic factors for lung adenocarcinoma.Genomic DNA copy number variations were analysed on FFPE tissue of31stage Ⅰ cases using array CGH technology in the third part. The results showed that,5q22.3-q23.1,9p24.1,15q14-q15.1deletion and6p21.22-p21.32,7p14.1-p13,7q21.3-q22.1,8p11.21,8q22.2,11q22.1-q22.3,11q13.1,11q13.1-q13.2,17q12,17q12-q21.2and17q21.2-q21.31amplification were chromosome fragments associated with prognosis of stage Ⅰ lung adenocarcinoma. There were244known genes existed in the above fragments, gene functions concentrated in biological functions such as NFkB binding and metalloendopeptidase activity et al. Selection of genes of interest and validation work are in progress.In conclusion, compared with the6th edition, the7th TNM staging system was better in reflecting the different prognosis of patients with the same stage and could provide more accurate prognostic information;2011IASLC/ATS/ERS international multidisciplinary classification for lung adenocarcinoma showed an advantage in prognostic grouping, but not an independent prognostic factor; Cutoff of5%and30%for lepidic growth pattern was independent prognostic factor in the current patients; Napsin A, TTF-1and ERCC1expression prompted better prognosis, but none of them was not an independent prognostic factor, they could be viewed as assistant index to stratify patients of the same stage into different prognostic group. Chromosome fragments5q22.3-q23.1,9p24.1,15q14-q15.1deletion and6p21.22-p21.32,7p14.1-p13,7q21.3-q22.1,8p11.21,8q22.2,11q22.1-q22.3,11q13.1,11q13.1-q13.2,17q12,17q12-q21.2and17q21.2-q21.31amplification were associated with the poor prognosis of stage Ⅰ lung adenocarcinoma, chromosome fragment11q22.1-q22.3amplification and genes located in the section such as MMPs, BIRC family and YAP1were worth for more attention and further validation and study are needed.