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The clinical utility of integrative genomics in childhood cancer extends beyond targetable mutations.

ABSTRACT: We conducted integrative somatic-germline analyses by deeply sequencing 864 cancer-associated genes, complete genomes and transcriptomes for 300 mostly previously treated children and adolescents/young adults with cancer of poor prognosis or with rare tumors enrolled in the SickKids Cancer Sequencing (KiCS) program. Clinically actionable variants were identified in 56% of patients. Improved diagnostic accuracy led to modified management in a subset. Therapeutically targetable variants (54% of patients) were of unanticipated timing and type, with over 20% derived from the germline. Corroborating mutational signatures (SBS3/BRCAness) in patients with germline homologous recombination defects demonstrates the potential utility of PARP inhibitors. Mutational burden was significantly elevated in 9% of patients. Sequential sampling identified changes in therapeutically targetable drivers in over one-third of patients, suggesting benefit from rebiopsy for genomic analysis at the time of relapse. Comprehensive cancer genomic profiling is useful at multiple points in the care trajectory for children and adolescents/young adults with cancer, supporting its integration into early clinical management.

SUBMITTER: Villani A

PROVIDER: S-EPMC9970873 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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The clinical utility of integrative genomics in childhood cancer extends beyond targetable mutations.

Villani Anita A Davidson Scott S Kanwar Nisha N Lo Winnie W WW Li Yisu Y Cohen-Gogo Sarah S Fuligni Fabio F Edward Lisa-Monique LM Light Nicholas N Layeghifard Mehdi M Harripaul Ricardo R Waldman Larissa L Gallinger Bailey B Comitani Federico F Brunga Ledia L Hayes Reid R Anderson Nathaniel D ND Ramani Arun K AK Yuki Kyoko E KE Blay Sasha S Johnstone Brittney B Inglese Cara C Hammad Rawan R Goudie Catherine C Shuen Andrew A Wasserman Jonathan D JD Venier Rosemarie E RE Eliou Marianne M Lorenti Miranda M Ryan Carol Ann CA Braga Michael M Gloven-Brown Meagan M Han Jianan J Montero Maria M Spatare Famida F Whitlock James A JA Scherer Stephen W SW Chun Kathy K Somerville Martin J MJ Hawkins Cynthia C Abdelhaleem Mohamed M Ramaswamy Vijay V Somers Gino R GR Kyriakopoulou Lianna L Hitzler Johann J Shago Mary M Morgenstern Daniel A DA Tabori Uri U Meyn Stephen S Irwin Meredith S MS Malkin David D Shlien Adam A

Nature cancer 20221230 2

We conducted integrative somatic-germline analyses by deeply sequencing 864 cancer-associated genes, complete genomes and transcriptomes for 300 mostly previously treated children and adolescents/young adults with cancer of poor prognosis or with rare tumors enrolled in the SickKids Cancer Sequencing (KiCS) program. Clinically actionable variants were identified in 56% of patients. Improved diagnostic accuracy led to modified management in a subset. Therapeutically targetable variants (54% of pa ...[more]

PMID: 36585449

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Project description:Survival of children with relapsed cancer remains unacceptably low. Cancer genomic profiling may identify new therapeutic options, enhance diagnostic accuracy, and improve understanding of tumorsÃ¢Â€Â™ origins and continued evolution. We deeply sequenced 864 cancer-associated genes and the complete genomes and transcriptomes for 300 pediatric and adolescent/young adult (AYA) patients with poor prognosis or rare tumors. Using integrative somatic-germline analyses, we assessed the clinical utility of cancer genomics in this population. We analyzed tumor mutational signatures and burden to interrogate the relevance of germline variants in DNA repair genes and the impact of therapeutic exposures on tumor evolution. We also evaluated the frequency of changes to tumor drivers and therapeutic targets at relapse in those with serial samples. Integrative analysis yielded clinically actionable variants in a majority of patients. Improved diagnostic accuracy led to modified management in a subset. Therapeutically targetable variants were of unanticipated timing and type, with many of these derived from the germline. Enrichment in corroborating mutational signature 3 (Ã¢Â€Â˜BRCAnessÃ¢Â€Â™) in patients with germline homologous recombination defects suggests they are drivers of pediatric cancers and potential targets for PARP inhibition. We show that mutation burden, which may in part be driven by prior therapeutic exposures, was significantly elevated in a minority of patients. Over one-third of patients with sequential samples analyzed showed a change in therapeutically-targetable drivers. Comprehensive somatic-germline cancer genomic profiling is useful at multiple points in the care trajectory for pediatric/AYA patients, supporting its integration into early clinical management. Re-biopsy at the time of relapse should be considered, and specific attention to mutational burden is indicated. Defective DNA repair genes in the germline may represent important targetable drivers.

Dataset Information

The clinical utility of integrative genomics in childhood cancer extends beyond targetable mutations.

Publications

The clinical utility of integrative genomics in childhood cancer extends beyond targetable mutations.

Similar Datasets

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