Author：Zhenghang Wang, Xue Zheng, Jian Li, Xicheng Wang, Jing Gao, Zhongwu Li, Jianing Yu, Wanning Yang, Beibei Mao, Henghui Zhang, Lin Shen

Background: Metastases from colorectal cancer (CRC) are common and develop in 40 to 60% of the patients. The liver and lung are the most frequently metastatic sites. Although lung metastasis (LuM) is characterized with slower growth rate and longer survival duration compared to liver metastasis (LiM). Little is known about the genetic differences between LuM and LiM CRC patients. 

Methods: The LuM cohort was composed of 18 patients with isolated lung metastasis and LiM cohorts was composed of 18 patients with liver metastasis. All the 36 patients were left-sided CRC and all lesions were microsatellite stability (MSS). The two cohorts were matched case by case according to age, gender, primary location, T stage and N stage. The Control cohort involved 10 patients who had locally advanced tumors, received R0 resection and suffered no relapse in at least five years. Based on a 1408 cancer-related gene panel (covering 967010 bases), the next-generation sequencing (NGS) of primary tumors and metastases was performed on the primary and metastatic lesions of these patients. 

Results: For primary tumors, results showed that the frequency of BRD4 amplification in the LuM cohort (n = 16 ) was 50%, which was much higher than that in the LiM (n = 16) and Control cohorts (n = 10) (p< 0.05). U2AF1 amplification in the LuM (30%) was more common than that in LiM (0%) patients (p= 0.043). For metastatic lesions, amplification of MET and SDHC and Hippo pathway activation were more frequently observed in LuM cohort (n = 15) than that in LiM (n = 18). Median TMB of the primary tumors and metastases in the LuM cohort were 9.518 and 6.022 mutations/Mb, respectively, which were both much higher than that in the LiM and Control cohorts (p< 0.05). 

Conclusions: Amplification of BRD4 and U2AF1 was the characteristic feature of primary tumors which metastasized to the lungs, indicating this genetic alteration might be used in identifying patients at risk of developing LuM. MET amplification and Hippo pathway activation were promising therapeutic targets of left-sided CRC-LuM with MSS. Patients with LuM might respond well to immunotherapies due to relatively high level of TMB. Expanded prospective cohorts are warranted to further elucidate these findings.