Pathologic subtype-defined prognosis is dependent on both tumor stage and status of oncogenic driver mutations in lung adenocarcinoma

// Yu Dong 1, * , Ying Li 1, * , Bo Jin 1 , Jie Zhang 2 , Jinchen Shao 2 , Hong Peng 3 , Shichun Tu 4, 5, 6 and Baohui Han 1 1 Department of Pulmonary Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, China 2 Department of Pathology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, China 3 Department of Advocacy Section, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, China 4 Scintillon Institute for Biomedical and Bioenergy Research, San Diego, CA 92121, USA 5 Allele Biotechnology & Pharmaceuticals, Inc., San Diego, CA 92121, USA 6 Shanghai Righton Biotechnology Co., Ltd, Shanghai 201403, China * These authors have contributed equally to this work Correspondence to: Baohui Han, email: 18930858216@163.com Keywords: lung adenocarcinoma, overall survival, pathologic subtype, tumor stage, oncogenic driver mutation Received: March 31, 2017      Accepted: June 19, 2017      Published: July 17, 2017 ABSTRACT Previous studies have shown that the prognosis of lung adenocarcinoma is associated with pathological characterization. In this study, we investigated whether pathology-based prognosis was further influenced by both tumor stage and oncogenic driver mutations. To this end, we recruited a cohort of 465 lung adenocarcinoma patients in China. These patients were classified into 6 pathology-defined subtypes i.e., lepidic-predominant adenocarcinoma (LPA), acinar-predominant adenocarcinoma (APA), papillary-predominant adenocarcinoma (PPA), micropapillary-predominant adenocarcinoma (MPA), solid-predominant adenocarcinoma (SPA), and invasive mucinous adenocarcinoma (IMA). Oncogenic mutations in EGFR , KRAS , ALK , RET , and BRAF genes were determined using fluorescent real-time RT-PCR. The associations of pathogenic subtype or oncogenic mutation with clinical characteristics were analyzed using Fisher’s exact tests. The interactive effects on overall survival (OS) by pathologic subtype, oncogenic mutations, and tumor stage were also determined. We have found that pathogenic subtype of lung adenocarcinoma correlated with smoking habit and tumor cell differentiation. These pathology-defined subtypes can be regrouped into 3 pathology-based prognostic groups: PPG1 (LPA), PPG2 (IMA+APA+PPA), and PPG3 (MPA+SPA) with a favorable, intermediate, and poor OS, respectively. We further demonstrated that this pathology-determined OS can be affected by both tumor stage and status of oncogenic mutations in EGFR , KRAS , ALK , RET , and BRAF genes. Interestingly, the presence of genetic mutations related to ALK , RET and BRAF had an opposite effect on OS between PPG2 (worsen) and PPG3 (improved) patients, reversing the prognostic favorability for patients within these two groups. In conclusion, prognosis of lung adenocarcinoma was defined interactively by pathologic subtype, tumor stage and oncogenic mutation.