Clinical significance of next generation sequencing (NGS) in Chinese patients with relapsed/refractory Wilm’s tumor.

Abstract

e22014 Background: Medical advances have been greatly improved in the five-year survival rate for Wilms’ tumor, but the survival is still dismal for relapsed/refractory (R/R) patients. In the present study, we aimed to investigate the genomic profiling and the incidence of germline cancer susceptibility mutationsof Chinese patients with R/R WT. Methods: Next-generation sequencing (NGS) of tumor specimens with matched blood samples obtained from R/R pediatric WT in Sun Yat-Sen University Cancer Center were used in a CAP-certified laboratory (Simcere Diagnostic Co, Ltd). Clinical information including age, gender and tumor histology were collected. Somatic and germline mutations including single nucleotide variants (SNV), insertion-deletion variants (Indels), copy number variations (CNVs) and fusion, as well as tumor mutational burden (TMB) were analyzed. Results: Nineteen patients with R/R WT were enrolled in this study, including 10 males and 9 females, with a median age of 4 years old (range, 0-14). All of the pathology was identified as favorable histology WT (FHWT). Somatic mutations were detected in 84.21% (16/19) of patients, and CNVs accounted for the majority of the total somatic aberrations, followed by SNVs. The most common somatic mutations were identified in the following genes, CTNNB1 , ERBB2, MCL1 , CDK2 and MDM4. Of the top 3 frequently mutated genes, the mutation frequency and their most common mutation type were CTNNB1, 26%, in-frame deletion, missense mutation; ERBB2 21%, missense mutation, amplification; MCL1 21%, amplification. It is worth noting that MCL1 mutation has never been reported in Chinese R/R WT patients before, which may be a potential valuable mechanism. Germline mutations were detected in 89.47% (17/19) of patients, and CNVs accounted for the majority of the total germline aberrations, followed by SNVs. The most common germline mutations were identified in the following genes, MCL1, RET, ALK, EPCAM, and FANCA. Of the top frequently mutated genes frequency and most common mutation type were MCL1 21%, amplification; RET 21% missense mutation, multiple mutations. There are also some suspected clinically pathogenic germline mutation of genes CDK4 , ERBB2, and MDM4 . All the mutation type were amplification. Notable cancer driver mutations were also characterized, such as the amplifications of ERBB2 / MET/EGFR / FGFR1, and the point mutations of CHEK2/FBXW7/NF1. The median TMB was 1.47 (range, 0-7.8). Conclusions: Overall, clinical and new results were detected in 14 (73.68%) in Chinese R/R WT patients. We discovered some driver genes mutations which potentially sensitive to the corresponding targeted drugs in Chinese R/R WT patients. Large sample size was needed to provide a better understanding of molecular features in R/R WT patients to achieve precision medicine.