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Mutational analysis reveals the origin and therapy-driven evolution of recurrent glioma.

ABSTRACT: Tumor recurrence is a leading cause of cancer mortality. Therapies for recurrent disease may fail, at least in part, because the genomic alterations driving the growth of recurrences are distinct from those in the initial tumor. To explore this hypothesis, we sequenced the exomes of 23 initial low-grade gliomas and recurrent tumors resected from the same patients. In 43% of cases, at least half of the mutations in the initial tumor were undetected at recurrence, including driver mutations in TP53, ATRX, SMARCA4, and BRAF; this suggests that recurrent tumors are often seeded by cells derived from the initial tumor at a very early stage of their evolution. Notably, tumors from 6 of 10 patients treated with the chemotherapeutic drug temozolomide (TMZ) followed an alternative evolutionary path to high-grade glioma. At recurrence, these tumors were hypermutated and harbored driver mutations in the RB (retinoblastoma) and Akt-mTOR (mammalian target of rapamycin) pathways that bore the signature of TMZ-induced mutagenesis.

SUBMITTER: Johnson BE

PROVIDER: S-EPMC3998672 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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Mutational analysis reveals the origin and therapy-driven evolution of recurrent glioma.

Johnson Brett E BE Mazor Tali T Hong Chibo C Barnes Michael M Aihara Koki K McLean Cory Y CY Fouse Shaun D SD Yamamoto Shogo S Ueda Hiroki H Tatsuno Kenji K Asthana Saurabh S Jalbert Llewellyn E LE Nelson Sarah J SJ Bollen Andrew W AW Gustafson W Clay WC Charron Elise E Weiss William A WA Smirnov Ivan V IV Song Jun S JS Olshen Adam B AB Cha Soonmee S Zhao Yongjun Y Moore Richard A RA Mungall Andrew J AJ Jones Steven J M SJM Hirst Martin M Marra Marco A MA Saito Nobuhito N Aburatani Hiroyuki H Mukasa Akitake A Berger Mitchel S MS Chang Susan M SM Taylor Barry S BS Costello Joseph F JF

Science (New York, N.Y.) 20131212 6167

Tumor recurrence is a leading cause of cancer mortality. Therapies for recurrent disease may fail, at least in part, because the genomic alterations driving the growth of recurrences are distinct from those in the initial tumor. To explore this hypothesis, we sequenced the exomes of 23 initial low-grade gliomas and recurrent tumors resected from the same patients. In 43% of cases, at least half of the mutations in the initial tumor were undetected at recurrence, including driver mutations in TP5 ...[more]

PMID: 24336570

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Project description:Cancer results from molecular mutations occurring in specific cell types, thus determining the cell-of-origin is critical for effective cancer treatment. Inferring such information from terminal tumors can be misleading because malignant tumor cells tend to acquire aberrant properties. Animal models are widely used because one can initiate mutations in specific cell types. However, cell-of-mutation that harbors initial molecular changes may not directly transform, rather merely passes along mutations to its progeny cell lineage, which then serves as cell-of-origin and finally transforms into malignancy. Such a problem is exemplified in the glioma field: glioma can be induced either by mutating tumor suppressor genes in neural stem cells (NSCs) or by over-expressing oncogenes in restricted progenitor cells such as oligodendrocyte precursor cells (OPCs). However, for the NSC glioma model, it remains unknown whether NSCs directly transform or simply pass along mutations to OPC lineage for malignancy. Here we use a genetic system termed Mosaic Analysis with Double Markers (MADM) to study the earliest stage of gliomagenesis from mutated NSCs. At an in vivo single-cell resolution, we unbiasedly analyzed tumorigenic potential of NSCs and all cell lineages derived from them. At pathologically undetectable pre-transforming phases, we found no significant aberrant growth of mutant NSCs and their derivatives except for the OPC lineage. We then tracked the tumor progression from earliest stage and confirmed the expansion of OPCs lead to gliomagenesis. Consistently, transcriptome profiling reveals that terminal-stage tumor cells display salient OPC features and resemble human proneural subtype of glioblastoma multiform (GBM). Most importantly, introducing the same mutations directly into OPCs was sufficient for malignant transformation and these tumor cells are indistinguishable in their gene expression profiles from those in which the first mutations were introduced into NSCs. Our findings strongly implicate OPCs as the transforming cell type for glioma even when initial mutations could occur in NSCs, and highlight the importance of analyzing early phases of tumorigenesis to distinguish cell-of-origin from cell-of-mutation.

Dataset Information

Mutational analysis reveals the origin and therapy-driven evolution of recurrent glioma.

Publications

Mutational analysis reveals the origin and therapy-driven evolution of recurrent glioma.

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