Mutational Analysis Reveals the Origin and Therapy-Driven Evolution of Recurrent Glioma
Top Cited Papers
- 10 January 2014
- journal article
- other
- Published by American Association for the Advancement of Science (AAAS) in Science
- Vol. 343 (6167), 189-193
- https://doi.org/10.1126/science.1239947
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.Keywords
This publication has 60 references indexed in Scilit:
- The Life History of 21 Breast CancersCell, 2012
- The genomic complexity of primary human prostate cancerNature, 2011
- A map of human genome variation from population-scale sequencingNature, 2010
- Distant metastasis occurs late during the genetic evolution of pancreatic cancerNature, 2010
- Conserved role of intragenic DNA methylation in regulating alternative promotersNature, 2010
- Transcript assembly and quantification by RNA-Seq reveals unannotated transcripts and isoform switching during cell differentiationNature Biotechnology, 2010
- Frequent BRG1/SMARCA4-inactivating mutations in human lung cancer cell linesHuman Mutation, 2008
- The Catalogue of Somatic Mutations in Cancer (COSMIC)Current Protocols in Human Genetics, 2008
- Patterns of somatic mutation in human cancer genomesNature, 2007
- Tumour-derived p16 alleles encoding proteins defective in cell-cycle inhibitionNature, 1995