Genomic profiling of esophageal squamous cell carcinoma to reveal actionable genetic alterations.
Authors: Liu Fang , Li Xiaomo , Liu Si , Ma Tonghui , Cai Boning , Liang Lanqing , Qu Baolin , Zhang Pei , Du Lehui , Huang Xiang , Yu Wei 
Published: June 2021

e16042 Background: Esophageal cancer is the eighth most common cancer in the world and more than half of global cases occur in China. Studies demonstrated that esophageal squamous cell carcinomas (ESCC) and esophageal adenocarcinomas (EAC) are two distinct disease entities. Due to the lack of effective therapies, the five-year survival rates of ESCC patients remain dismal. Therefore, there is an urgent need to establish a framework through genomic profiling to facilitate the development of precision therapies for ESCC. Methods: To characterize therapeutic targets in 118 Chinese ESCC patients, deep panel sequencing of 831 cancer genes (OncoPanscan, Genetronhealth) was performed on their tumor tissues and paired genomic DNA samples. Results: The most frequently mutated genes in our ESCC cohort were TP53 (97%), PIK3CA (19%), CDKN2A (18%), NOTCH1 (17%), KMT2D (15%), LRP1B (15%) NOTCH3 (15%) NFE2L2 (13%), and EP300 (12%). Consistent with previous reports, we found significantly elevated mutations in cancer-related genes including NOTCH1 (16.9%), NOTCH2 (3.2%), NOTCH3 (15.3%) and RB1 (9.3%). Importantly, 17.8% (21/118) patients in our cohort harbored the 11q13 amplicon ( CCND1, FGF3, FGF4 and FGF19). The median copy number was 8.19 (range 6.07-42.3). These patients can participate in clinical trials with FGFR inhibitor alone or in combination with CDK4/6 inhibitors. Additionally, we also observed frequent genetic alterations in the KEAP1 (Kelch-like ECH-associated protein 1)-NFE2L2 (nuclear factor erythroid 2 like 2)-CUL3 (cullin 3) pathway. 80% (12/15) of missense mutations in NFE2L2 were located at the KEAP1 binding domain of NRF2 protein. These mutations were either around the ETGE motif (D77G, E79Q, G81V/D and E82D) or the DLG motif (D27V, I28T, D29G, L30F, G31E, V32E, R34G). We also identified four missense mutations of KEAP1 and one alternation of CUL3 in splicing site. Taken together, 17% (20/118) of ESCC patients harbored mutations in the NFE2L2/KEAP1/CUL3 pathway, which may be eligible for clinical trials of glutaminase inhibitor telaglenastat. Two patients had high level of ERBB2 amplification which can be targeted with anti-HER2 therapy. Furthermore, 11.9% (14/118) patients carried activating PIK3CA mutations including N345K, E542K, E545K, M1043I and H1047R which may be targeted by PIK3CA inhibitor alpelisib. Lastly, patients with loss-of-function mutation in NF1 (n = 4), STK11 (n = 1) and PTEN (n = 3) can be respectively targeted with MEK inhibitor and mTOR inhibitor. Overall, 43% of patients in our ESCC cohort had actionable genetic mutations with corresponding precision therapy options. Conclusions: Our findings indicated that amplification of the 11q13 amplicon and dysfunction of the KEAP1-NRF2-CUL3 axis are the major driving events of ESCC. The results of genomic profiling can guide physicians to enroll a significant portion of ESCC patients into genomically matched clinical trials.