학술논문
The clinical utility of integrative genomics in childhood cancer extends beyond targetable mutations
Document Type
Original Paper
Author
Villani, Anita; Davidson, Scott; Kanwar, Nisha; Lo, Winnie W.; Li, Yisu; Cohen-Gogo, Sarah; Fuligni, Fabio; Edward, Lisa-Monique; Light, Nicholas; Layeghifard, Mehdi; Harripaul, Ricardo; Waldman, Larissa; Gallinger, Bailey; Comitani, Federico; Brunga, Ledia; Hayes, Reid; Anderson, Nathaniel D.; Ramani, Arun K.; Yuki, Kyoko E.; Blay, Sasha; Johnstone, Brittney; Inglese, Cara; Hammad, Rawan; Goudie, Catherine; Shuen, Andrew; Wasserman, Jonathan D.; Venier, Rosemarie E.; Eliou, Marianne; Lorenti, Miranda; Ryan, Carol Ann; Braga, Michael; Gloven-Brown, Meagan; Han, Jianan; Montero, Maria; Spatare, Famida; Whitlock, James A.; Scherer, Stephen W.; Chun, Kathy; Somerville, Martin J.; Hawkins, Cynthia; Abdelhaleem, Mohamed; Ramaswamy, Vijay; Somers, Gino R.; Kyriakopoulou, Lianna; Hitzler, Johann; Shago, Mary; Morgenstern, Daniel A.; Tabori, Uri; Meyn, Stephen; Irwin, Meredith S.; Malkin, David; Shlien, Adam
Source
Nature Cancer. 4(2):203-221
Subject
Language
English
ISSN
2662-1347
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.
Shlien and colleagues report on 300 patients from the SickKids Cancer Sequencing program and identify clinically actionable variants in 56% of the patients by profiling somatic and germline data at multiple clinical time points.
Shlien and colleagues report on 300 patients from the SickKids Cancer Sequencing program and identify clinically actionable variants in 56% of the patients by profiling somatic and germline data at multiple clinical time points.