Genetic differences between lung metastases and liver metastases from left-sided microsatellite stable colorectal cancer: next generation sequencing and clinical implications

Zhenghang Wang; Xue Zheng; Xicheng Wang; Yawei Chen; Zhongwu Li; Jianing Yu; Wanning Yang; Beibei Mao; Henghui Zhang; Jian Li; Lin Shen

doi:10.21037/atm-21-2221

Genetic differences between lung metastases and liver metastases from left-sided microsatellite stable colorectal cancer: next generation sequencing and clinical implications

Ann Transl Med. 2021 Jun;9(12):967. doi: 10.21037/atm-21-2221.

Authors

Zhenghang Wang¹, Xue Zheng², Xicheng Wang¹, Yawei Chen², Zhongwu Li³, Jianing Yu², Wanning Yang², Beibei Mao², Henghui Zhang^{2

4}, Jian Li¹, Lin Shen¹

Affiliations

¹ Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China.
² Genecast Biotechnology Co., Ltd., Wuxi, China.
³ Department of Pathology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China.
⁴ Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing Key Laboratory of Emerging Infectious Diseases, Beijing, China.

Abstract

Background: Data regarding the clinical characteristics and outcomes of lung metastases (LuM) from colorectal cancer (CRC) are different from those of liver metastases (LiM) from CRC. However, little is known about the genetic features of LuM. This study aimed to identify the different genetic characteristics of LuM and LiM from left-sided microsatellite stable CRC.

Methods: Tissue samples of the primary tumors and paired metastases from 18 CRC patients with isolated LuM (LuM cohort), 18 patients with isolated LiM (LiM cohort), and 10 locally advanced CRC patients without metastases (control cohort) were selected for next-generation sequencing. Patients in the LiM cohort had matched clinicopathological characteristics with the LuM cohort. The single-nucleotide variations (SNVs), copy number variations (CNVs), pathway alterations, and tumor mutation burdens (TMBs) were also calculated and analyzed.

Results: The CNV results showed that ZFHX4, GATA2, and FAM131B amplifications were more common in the metastatic cohorts than in the control cohort, while RECQL4 and FLCN amplifications were common in the controls. The LuM cohort had significantly higher proportions of HNF4A, BRD4, and U2AF1 amplification. The LuM, LiM, and control cohorts were successfully separated using pathway alteration analysis. The LuM cohort had more frequent alterations in the RTK/RAS pathway, HIPPO pathway, KRAS, and MET than the LiM group. The LuM cohort also had relatively higher TMBs than the LiM cohort.

Conclusions: CNVs in primary tumors could identify patients with LuM. Targeting the HIPPO pathway or MET and immune checkpoint inhibitors (ICIs) combined with other agents might be novel therapies for LuM.

Keywords: colorectal cancer (CRC); copy number variation (CNV); liver metastasis; lung metastasis; tumor mutation burden (TMB).