Mutational Analysis Reveals the Origin and Therapy-driven Evolution of Recurrent Glioma

Overview

Journal Science

Specialty Science

Date 2013 Dec 17

PMID 24336570

Citations 754

Authors

Brett E Johnson

Tali Mazor

Chibo Hong

Michael Barnes

Koki Aihara

Cory Y McLean

Shaun D Fouse

Shogo Yamamoto

Hiroki Ueda

Kenji Tatsuno

Saurabh Asthana

Llewellyn E Jalbert

Sarah J Nelson

Andrew W Bollen

W Clay Gustafson

Elise Charron

William A Weiss

Ivan V Smirnov

Jun S Song

Adam B Olshen

Soonmee Cha

Yongjun Zhao

Richard A Moore

Andrew J Mungall

Steven J M Jones

Martin Hirst

Marco A Marra

Nobuhito Saito

Hiroyuki Aburatani

Akitake Mukasa

Mitchel S Berger

Susan M Chang

Barry S Taylor

Joseph F Costello

Affiliations

Soon will be listed here.

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.

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