Abstract
AbstractCompared to adult carcinomas, there is a paucity of targeted treatments for solid tumors in children, adolescents, and young adults (C-AYA). The impact of germline genomic signatures has implications for heritability, but its impact on targeted therapies has not been fully appreciated. Performing variant-prioritization analysis on germline DNA of 1,507 C-AYA patients with solid tumors, we show 12% of these patients carrying germline pathogenic and/or likely pathogenic variants (P/LP) in known cancer-predisposing genes (KCPG). An additional 61% have germline pathogenic variants in non-KCPG genes, including PRKN, SMARCAL1, SMAD7, which we refer to as candidate genes. Despite germline variants in a broad gene spectrum, pathway analysis leads to top networks centering around p53. Our drug-target analysis shows 1/3 of patients with germline P/LP variants have at least one druggable alteration, while more than half of them are from our candidate gene group, which would otherwise go unidentified in routine clinical care.
Funder
American Cancer Society
Ambrose Monell Foundation
VeloSano Foundation
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry
Reference69 articles.
1. Grobner, S. N. et al. The landscape of genomic alterations across childhood cancers. Nature 555, 321–327 (2018).
2. Zhang, J. et al. Germline mutations in predisposition genes in pediatric cancer. N. Engl. J. Med. 373, 2336–2346 (2015).
3. Parsons, D. W. et al. Diagnostic yield of clinical tumor and germline whole-exome sequencing for children with solid tumors. JAMA Oncol. 2, 616–624 (2016).
4. Mody, R. J. et al. Integrative clinical sequencing in the management of refractory or relapsed cancer in youth. JAMA 314, 913–925 (2015).
5. McGee, R. B. & Nichols, K. E. Introduction to cancer genetic susceptibility syndromes. Hematol. Am. Soc. Hematol. Educ. Program 2016, 293–301 (2016).
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