Open AccessTherapeutic Implication of Genomic Landscape of Adult Metastatic Sarcoma
Author(s) -
Xiaolan Feng,
Erin Pleasance,
Eric Y. Zhao,
Tony Ng,
Jasleen Grewal,
Nissreen Mohammad,
Sara Taylor,
Christine Simmons,
Amirrtha Srikanthan,
Shahrad R. Rassekh,
Rebecca Deyell,
Jennifer Rauw,
M. Knowling,
Kei Siong Khoo,
Ursula Lee,
Krista Noonan,
Janace Hart,
R. Petter Tonseth,
Yaoqing Shen,
Emma Titmuss,
Martin Jones,
Melika Bonakdar,
Caralyn Reisle,
Greg Taylor,
Simon K. Chan,
Andrew J. Mungall,
Eric Chuah,
Yongjun Zhao,
Richard A. Moore,
Howard John Lim,
Daniel J. Renouf,
Karen A. Gelmon,
Stephen Yip,
Steven Jones,
Marco A. Marra,
Janessa Laskin
Publication year - 2019
Publication title -
jco precision oncology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.405
H-Index - 22
ISSN - 2473-4284
DOI - 10.1200/po.18.00325
Subject(s) - sarcoma , biology , copy number variation , cancer research , transcriptome , cancer , carcinogenesis , trabectedin , genome , gene , medicine , genetics , pathology , soft tissue sarcoma , gene expression
PURPOSE This study investigated therapeutic potential of integrated genome and transcriptome profiling of metastatic sarcoma, a rare but extremely heterogeneous group of aggressive mesenchymal malignancies with few systemic therapeutic options.METHODS Forty-three adult patients with advanced or metastatic non-GI stromal tumor sarcomas of various histology subtypes who were enrolled in the Personalized OncoGenomics program at BC Cancer were included in this study. Fresh tumor tissues along with blood samples underwent whole-genome and transcriptome sequencing.RESULTS The most frequent genomic alterations in this cohort are large-scale structural variation and somatic copy number variation. Outlier RNA expression as well as somatic copy number variations, structural variations, and small mutations together suggest the presence of one or more potential therapeutic targets in the majority of patients in our cohort. Point mutations or deletions in known targetable cancer genes are rare; for example, tuberous sclerosis complex 2 provides a rationale for targeting the mammalian target of rapamycin pathway, resulting in a few patients with exceptional clinical benefit from everolimus. In addition, we observed recurrent 17p11-12 amplifications, which seem to be a sarcoma-specific event. This may suggest that this region harbors an oncogene(s) that is significant for sarcoma tumorigenesis. Furthermore, some sarcoma tumors carrying a distinct mutational signature suggestive of homologous recombination deficiency seem to demonstrate sensitivity to double-strand DNA–damaging agents.CONCLUSION Integrated large-scale genomic analysis may provide insights into potential therapeutic targets as well as novel biologic features of metastatic sarcomas that could fuel future experimental and clinical research and help design biomarker-driven basket clinical trials for novel therapeutic strategies.