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Next-Generation Rapid Autopsies Enable Tumor Evolution Tracking and Generation of Preclinical Models.

TitleNext-Generation Rapid Autopsies Enable Tumor Evolution Tracking and Generation of Preclinical Models.
Publication TypeJournal Article
Year of Publication2017
AuthorsPisapia DJ, Salvatore S, Pauli C, Hissong E, Eng K, Prandi D, Sailer V-W, Robinson BD, Park K, Cyrta J, Tagawa ST, Kossai M, Fontugne J, Kim R, Sigaras A, Rao R, Pancirer D, Faltas B, Bareja R, Molina AM, Nanus DM, Rajappa P, Souweidane MM, Greenfield J, Emde A-K, Robine N, Elemento O, Sboner A, Demichelis F, Beltran H, Rubin MA, Mosquera JMiguel
JournalJCO Precis Oncol
Volume2017
Date Published2017
ISSN2473-4284
Abstract

Purpose: Patients with cancer who graciously consent for autopsy represent an invaluable resource for the study of cancer biology. To advance the study of tumor evolution, metastases, and resistance to treatment, we developed a next-generation rapid autopsy program integrated within a broader precision medicine clinical trial that interrogates pre- and postmortem tissue samples for patients of all ages and cancer types.

Materials and Methods: One hundred twenty-three (22%) of 554 patients who consented to the clinical trial also consented for rapid autopsy. This report comprises the first 15 autopsies, including patients with metastatic carcinoma (n = 10), melanoma (n = 1), and glioma (n = 4). Whole-exome sequencing (WES) was performed on frozen autopsy tumor samples from multiple anatomic sites and on non-neoplastic tissue. RNA sequencing (RNA-Seq) was performed on a subset of frozen samples. Tissue was also used for the development of preclinical models, including tumor organoids and patient-derived xenografts.

Results: Three hundred forty-six frozen samples were procured in total. WES was performed on 113 samples and RNA-Seq on 72 samples. Successful cell strain, tumor organoid, and/or patient-derived xenograft development was achieved in four samples, including an inoperable pediatric glioma. WES data were used to assess clonal evolution and molecular heterogeneity of tumors in individual patients. Mutational profiles of primary tumors and metastases yielded candidate mediators of metastatic spread and organotropism including CUL9 and PIGM in metastatic ependymoma and ANKRD52 in metastatic melanoma to the lung. RNA-Seq data identified novel gene fusion candidates.

Conclusion: A next-generation sequencing-based autopsy program in conjunction with a pre-mortem precision medicine pipeline for diverse tumors affords a valuable window into clonal evolution, metastasis, and alterations underlying treatment. Moreover, such an autopsy program yields robust preclinical models of disease.

DOI10.1200/PO.16.00038
Alternate JournalJCO Precis Oncol
PubMed ID29333526
PubMed Central IDPMC5761727
Grant ListKL2 TR000458 / TR / NCATS NIH HHS / United States
R01 CA116337 / CA / NCI NIH HHS / United States
U01 CA111275 / CA / NCI NIH HHS / United States