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

Science. 2014 Jan 10;343(6167):189-193. doi: 10.1126/science.1239947. Epub 2013 Dec 12.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents, Alkylating / adverse effects*
  • Antineoplastic Agents, Alkylating / therapeutic use
  • Brain / drug effects
  • Brain / pathology
  • Brain Neoplasms / drug therapy*
  • Brain Neoplasms / genetics
  • Brain Neoplasms / pathology*
  • DNA Helicases / genetics
  • DNA Mutational Analysis
  • Dacarbazine / adverse effects
  • Dacarbazine / analogs & derivatives*
  • Dacarbazine / therapeutic use
  • Glioma / drug therapy*
  • Glioma / genetics
  • Glioma / pathology*
  • Humans
  • Mutagenesis / drug effects
  • Neoplasm Grading
  • Neoplasm Recurrence, Local / chemically induced*
  • Neoplasm Recurrence, Local / drug therapy
  • Neoplasm Recurrence, Local / genetics*
  • Nuclear Proteins / genetics
  • Proto-Oncogene Proteins B-raf / genetics
  • Proto-Oncogene Proteins c-akt / genetics
  • TOR Serine-Threonine Kinases / genetics
  • Temozolomide
  • Transcription Factors / genetics
  • Tumor Suppressor Protein p53 / genetics
  • X-linked Nuclear Protein

Substances

  • Antineoplastic Agents, Alkylating
  • Nuclear Proteins
  • TP53 protein, human
  • Transcription Factors
  • Tumor Suppressor Protein p53
  • Dacarbazine
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf
  • Proto-Oncogene Proteins c-akt
  • SMARCA4 protein, human
  • DNA Helicases
  • ATRX protein, human
  • X-linked Nuclear Protein
  • Temozolomide