Identification of RET fusions in a Chinese multicancer retrospective analysis by next-generation sequencing

Abstract

Fusion of RET with different partner genes has been detected in papillary thyroid, lung, colorectal, pancreatic, and breast cancer. Approval of selpercatinib for treatment of lung and thyroid cancer with RET gene mutations or fusions calls for studies to explore RET fusion partners and their eligibility for RET-based targeted therapy. In this study, RET fusion patterns in a large group of Chinese cancer patients covering several cancer types were identified using next-generation sequencing. A total of 44 fusion patterns were identified in the study cohort with KIF5B, CCDC6, and ERC1 being the most common RET fusion partners. Notably, 17 novel fusions were first reported in this study. Prevalence of functional RET fusions was 1.05% in lung cancer, 6.03% in thyroid cancer, 0.39% in colorectal cancer, and less than 0.1% in gastric cancer and hepatocellular carcinoma. Analysis showed a preference for fusion partners in different tumor types, with KIF5B being the common type in lung cancer, CCDC6 in thyroid cancer, and NCOA4 in colorectal cancer. Co-occurrence of EGFR mutations and RET fusions with rare partner genes (rather than KIF5B) in lung cancer patients was correlated with epidermal growth factor receptor-tyrosine kinase inhibitor resistance and could predict response to targeted therapies. Findings from this study provide a guide to clinicians in determining tumors with specific fusion patterns as candidates for RET targeted therapies.

Keywords: EGFR-TKI resistance; NGS; RET fusion; lung cancer; multicancer.

FIGURE 1

RET fusions identified in different cancers. A, Counts of functional and nonfunctional RET fusions identified in different cancer types. B, Proportion of functional RET fusions identified in different cancer types. CRC, colorectal cancer; GC, gastric cancer; HCC, hepatocellular carcinoma; LC, lung cancer; PTC, papillary thyroid cancer

FIGURE 2

Distribution of fusion partners identified in cancer patients with RET fusions. A, In 135 lung cancer patients with RET fusions, 137 fusion events were identified with two patients carrying two different RET fusions. B, C, Fusion events identified in 11 colorectal cancer patients (B) and 14 papillary thyroid cancer patients (C). Each patient carried only one functional RET fusion. Different colors and sizes indicate the frequency of each RET fusion partner in all RET fusion events identified

FIGURE 3

Breakpoint positions in RET. Different colors represent different cancer types: purple, colorectal cancer; red, lung cancer; orange, hepatocellular carcinoma; cyan, gastric cancer; green, papillary thyroid cancer. Numbers beyond circles represent the counts of functional RET fusions detected in different cancer type

FIGURE 4

Ligand‐independent activation of the RET fusion protein. RET fusions maintain the tyrosine kinase domain of the 3′ RET gene. A variety of fusion partners contribute different domains, such as coiled‑coil, to RET fusion proteins. These motifs mediate ligand‑independent dimerization of the RET fusion protein. Identification and annotation of genetically mobile domains and analysis of domain architectures (http://smart.embl‐heidelberg.de/)

FIGURE 5

Heatmap of the average per‐base coverage for RET exons 2‐19 (Z‐score). Data for each sample was log2‐transformed and then Z‐score standardized using scale function

FIGURE 6

Coexistence status of actionable genes with RET fusions in 135 lung cancer patients. Driver mutations EGFR/L858R, EGFR/19DeL, and ALK fusion in nine individuals with RET fusions were exclusive to each other. The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor resistance mutation, EGFR T790M, was present in six of eight EGFR‐driven patient tumors. The oncoprint of RET fusion and other driver mutations was identified using next‐generation sequencing. Different colors represent different categories of mutations