Comprehensive germline genomic profiles of children, adolescents and young adults with solid tumors

Area of Science:

• Genomics
• Pediatric Oncology
• Cancer Genetics

Background:

• Targeted treatments for solid tumors in children, adolescents, and young adults (C-AYA) are limited compared to adult cancers.
• The role of germline genomic signatures in C-AYA targeted therapy is not fully understood.
• Germline variants can have implications for heritability and familial cancer risk.

Purpose of the Study:

• To investigate the prevalence and therapeutic implications of germline genomic alterations in C-AYA patients with solid tumors.
• To identify known cancer-predisposing genes (KCPG) and novel candidate genes associated with germline variants in this population.
• To assess the potential for targeted therapy based on identified germline alterations.

Main Methods:

• Variant-prioritization analysis was performed on germline DNA from 1,507 C-AYA patients.
• Germline pathogenic and/or likely pathogenic (P/LP) variants were identified in KCPG and candidate genes.
• Pathway and drug-target analyses were conducted to evaluate therapeutic opportunities.

Main Results:

• 12% of C-AYA patients carried germline P/LP variants in KCPG.
• An additional 61% had germline P/LP variants in candidate genes (e.g., PRKN, SMARCAL1, SMAD7).
• Drug-target analysis revealed that one-third of patients with germline P/LP variants have druggable alterations, with over half originating from candidate genes.

Conclusions:

• Germline variants are prevalent across a broad spectrum of genes in C-AYA solid tumors.
• A significant proportion of these patients harbor potentially targetable alterations, including those in novel candidate genes.
• Identifying these germline variants is crucial for expanding targeted therapy options in pediatric oncology.