Increasing evidence has shown that micropapillary lung adenocarcinoma is positively associated with a higher percentage of driver gene mutations, a higher incidence of metastasis and a poorer prognosis, while lepidic lung adenocarcinoma has a relatively better prognosis. Although specific genetic alterations associated with poorer prognosis of patients with micropapillary lung adenocarcinoma were identified, novel gene mutations and their related key mechanisms are not fully understood. Therefore, three lepidic and three micropapillary lung adenocarcinoma tissue samples were carried out using whole-exome sequencing. Comprehensive analysis of genomic variations and the difference between lepidic and micropapillary lung adenocarcinoma was performed.