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

University of California, San Francisco researchers recently reported in Science the mutational profiling of 23 initially low-grade gliomas (LGGs) and associated recurrent tumors and profiled a subset of recurrent tumors in temozolomide-treated patients. Three key findings with potentially important clinical implications for LGG management were demonstrated: (1) LGGs and paired recurrent tumors are highly divergent and often only share a few early mutations, thus partly explaining their differential therapeutic responses; (2) mutant isocitrate dehydrogenase-1 (IDH1) may be critical for LGG formation and is a potential therapeutic target; and (3) temozolomide therapy may contribute to malignant transformation and affect clinical outcome. Johnson et al1 determined the genetic profiles of LGGs and associated recurrences. Mutations that are shared or exclusive to the initial tumor or recurrences were characterized for each of 23 initial tumors and recurrences found up to 11 years later, and tumor phylogenies were mapped via evolutionary analyses. Overall, the paired tumors shared a significant percentage of mutations exclusive to the initial tumors in 43% of cases. These findings suggest that gliomas and recurrent tumors share early tumorigenic mutational origins but diverge afterward in tumorigenesis. LGG sequencing also revealed that an IDH1 mutation was present and remained unchanged in all paired tumors, highlighting IDH1 as a potentially critical LGG driver mutation. IDH1 mutants produce 2-hydroxyglutarate R-enantiomer, an interesting tumor metabolism product that inhibits histone enzymes and alters gene expression. Recent work highlights a possible LGG-selective therapeutic opportunity because inhibitors of IDH-1 mutant activity selectively reduce tumor growth rate and stimulate glioma differentiation.2 This work also reported the effects of temozolomide therapy on mutational profiles of recurrent gliomas, especially given that temozolomide use in LGG therapy is controversial. Mutational profiles of paired tumors in 10 temozolomide-treated patients were determined. Recurrent tumors from 6 of the 10 patients exhibited hypermutated phenotypes after temozolomide therapy, carrying many more mutations per million base pairs compared with their initial tumors. The hypermutated state is likely caused by the propensity of temozolomide to mutate and compromise DNA mismatch repair pathways. Additionally, the authors characterized the unique hypermutated signature and found significant association with high-grade glioma signaling pathways such as retinoblastoma and protein kinase B–mammalian target of rapamycin signaling (Figure, B). These results suggest that temozolomide therapy may contribute to malignant transformation of LGGs, and further studies are needed to determine whether this alters clinical outcomes.Figure: Recurrent tumors from patients treated with temozolomide (TMZ) harbor genetic alterations in the retinoblastoma (RB) and protein kinase B--mammalian target of rapamycin (AKT/mTOR) signaling pathways. A, the number of temozolomide-associated mutations and other mutations identified in the 6 patients with hypermutated recurrent tumors. B, somatic mutations and CNAs acquired upon recurrence in key genes of pathways associated with glioblastoma multiforme. C, expression level of RB1 at each exon and exon-exon junction in the initial and recurrent tumor of patient 01 showing aberrant splicing of the RB1 transcript in the recurrent tumor harboring the RB1 c.2520+1G>A splice-site mutation. The RB1 exon and exon junctions with significant differential use (red) and the location of the splice-site mutation are shown. D, gene set enrichment analysis shows significant enrichment of genes downregulated by RB1 and upregulated by E2F in the recurrent tumors of patients 01 (blue) and 10 (green), coincident with the acquisition of temozolomide-associated mutations in the retinoblastoma pathway. E, hematoxylin and eosin--stained tumor sample from the first recurrent tumor of patient 01. A dotted line separates the 2 morphologically distinct regions. Immunohistochemistry for phospho-RPS6, phospho-4E-BP1 and Ki-67 show differential activation of mTORC1 targets and proliferation rates in the 2 adjacent regions. Bars represent 100 μm. From Mutational analysis reveals the origin and therapy-driven evolution of recurrent glioma. Science. 2014;343(6167):189-193. Reprinted with permission from AAAS.