Abstract 3882: Clinical exome and transcriptome sequencing for identification of actionable cancer targets: A pilot study for children and young adults with relapsed or refractory solid tumors
Authors: Chang Wen-I , Brohl Andrew S. , Patidar Rajesh , Shern Jack F. , Wei Jun S. , Song Young K. , Liao Hongling , Lin Jimmy , Sindiri Sivasish , Chen Li , Gryder Berkley , Yohe Marielle E. , Zhang Shile , Merchant Melinda S. , Widemann Brigitte C. , Khan Javed 
Published: August 2015

Background. With technological advances such as next-generation sequencing, recent gains in understanding pediatric cancer can aid in treatment decisions, especially in the setting of relapse. To discover expressed, clinically significant mutations for pediatric patients with relapsed tumors, we performed a pilot trial using a combination of whole exome sequencing (WES) of tumor/normal DNA and whole transcriptome sequencing (WTS) of tumors, complemented by single nucleotide polymorphism (SNP) arrays.

Objectives. We identified 48 pediatric and young adult patients with relapsed or refractory solid tumors with matched tumor/normal samples. Our goals were to determine the feasibility of performing comprehensive genomic analyses in this population, to compare the genomic profile of relapsed tumors to prior reports of primary tumors, and to delineate the percentage of patients with actionable mutations. Actionable changes were defined as reportable germ line mutations determined by the American College of Medical Genetics (ACMG), a change in diagnosis, and somatic changes targetable by FDA approved medications or drugs undergoing clinical trials.

Methods. WES was performed on matched tumor and normal samples to identify germ line and somatic mutations. WTS was performed on tumor samples to identify fusion genes, gene expression profiling, and expressed variants. SNP arrays were performed to identify copy number changes. Sanger validation confirmed reportable mutations.

Results. In the exome, we noted a median of 33 somatic mutations per sample (range 1-375), a higher mutational burden compared to previously reported primary pediatric malignancies. Transcriptome data further refined results to a median of 7 expressed somatic mutations per sample (range 0-95). The majority of patients had one oncogenic driver. Sequencing relapsed tumors at multiple time points showed the continued presence of driver mutations but a shift in passenger mutations. Eleven of the 48 patients (23%) had a targetable mutation, such as ALK, BRAF, GNAQ, GNA11, IDH1, MTOR, PIK3CA, and SKP2. Two patients (4%) had a change in diagnosis due to the presence or absence of diagnostic fusion genes. In the germ line of 5 patients (10%) we discovered mutations in ACMG-reportable genes MUTYH, SCN5A, TP53, and MLH1. A total of 16 patients (33%) had actionable mutations.

Conclusions. Our study showed the feasibility of next-generation sequencing in relapsed pediatric solid tumors, with actionable mutations detected in a third of our patients. We demonstrated the utility in using exome and transcriptome sequencing with SNP arrays. Implementation of these techniques has the potential to change the practice of precision medicine. In summary, we have developed a prototype that will be utilized to design a national Pediatric Match trial in collaboration with the Children's Oncology Group. 

Citation Format: Wen-I Chang, Andrew S. Brohl, Rajesh Patidar, Jack F. Shern, Jun S. Wei, Young K. Song, Hongling Liao, Jimmy Lin, Sivasish Sindiri, Li Chen, Berkley Gryder, Marielle E. Yohe, Shile Zhang, Melinda S. Merchant, Brigitte C. Widemann, Javed Khan. Clinical exome and transcriptome sequencing for identification of actionable cancer targets: A pilot study for children and young adults with relapsed or refractory solid tumors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3882. doi:10.1158/1538-7445.AM2015-3882