胶质瘤治疗新进展

zp123456 · 发表于 2008-11-14 15:39

New Insights on Glioblastoma Via a Comprehensive Genomics Approach

   Two large-scale genomic investigations, the most comprehensive cancer genomics studies to date, have uncovered the mutational characteristics of core signaling pathways in glioblastoma.[1,2] The studies, one at The Cancer Genome Atlas (TCGA) Research Network[2] and the other at the Johns Hopkins Kimmel Cancer Center,[1] performed nucleotide sequencing of protein coding regions, whole genome gene expression, copy number, and methylation (TCGA only) analysis in order to paint a holistic picture of the genetic aberrations underlying glioblastoma.

   Most brain cancers arise from transformed glial cells called astrocytes. The highest-grade astrocytoma (World Health Organization grade IV) is known as a glioblastoma.[3] Glioblastoma is the most common malignant brain tumor.[4] It is treated aggressively by surgical resection followed by adjuvant radiation therapy and chemotherapy, resulting in a dismal median survival of only 15 months.[5] This grim outcome has improved only modestly after more than 25 years,[6] except for a subset of patients with genomic aberrations affecting the MGMT gene.[7] Patients with an inactivated MGMT gene, which removes alkyl groups from guanine DNA residues, present improved clinical response to DNA alkylating agents.[8] This targeted therapeutic strategy exemplifies the clinical benefit attainable with a more complete understanding of the molecular underpinnings of glioblastoma as well as any other type of cancer.

   The Cancer Genome Atlas Research Network was launched 3 years ago with the goal of accelerating our understanding of the molecular basis of cancer through the application of whole genome technologies. Although faced with harsh criticism[9] and plagued by biospecimen collection problems,[10] a 3-year, $100 million pilot project was launched focusing on glioblastoma and lung and ovarian cancers.[11] The initial results of the glioblastoma pilot project, which focuses on the comprehensive characterization of 601 genes, appeared in the September 2008 issue of Nature.[2]

   The results confirm the involvement of receptor tyrosine kinase/Ras/PI(3)K (RTK), p53, and RB signaling pathways in glioblastoma. However, the number of samples involved (91 with matching normal tissue or peripheral blood), and the extent of the characterization of each sample, allowed for a more integrative analysis of these pathways. Of the 206 samples, 66%, 70%, and 59% harbored copy number alterations in the RB, TP53, and RTK pathways, respectively. When somatic alterations from sequencing data are included (n = 91), these percentages increased to 87%, 78%, and 88%, respectively, highlighting the involvement of these pathways in nearly all glioblastomas. More intriguing is that there was a strong statistical tendency towards the mutual exclusivity of alterations of components within each pathway. That is, each pathway tended to contain only 1 somatic alteration per sample. Additionally, 74% of samples harbored an aberration in all 3 core pathways. Similar observations were made in a study performed by the Johns Hopkins Kimmel Cancer Center and published in the September 2008 issue of Science.[1] Taken together, these results point to one of many sources of variability in therapeutic response to future therapies that may be developed to target these core signaling pathways. The mutual exclusivity of somatic aberrations in core pathways, combined with the concomitant involvement of core pathways, results in a large number of combinations of somatic alterations that may contribute to tumorigenesis in any individual case.

   With the inclusion of samples from cases that had undergone treatment with temozolomide, somatic alterations that may underlie resistance to alkylating agents were observed.[2] Seven of 19 samples from patients previously treated with temozolomide displayed a large increase in the number of somatic mutations.[2] Of these hypermutated samples, 6 of 7 harbored mutations in at least 1 mismatch repair gene compared with only 1 sample among 84 non-hypermutated samples. Treatment by temozolomide, especially in cases where MGMT is silenced, leads to unrepaired alkylation of guanine and initiates a futile mismatch repair cycle.[12] This results in a strong selective pressure to lose mismatch repair in the tumor, and likely leads to the mismatch repair gene mutations observed in treated samples. This loss of mismatch repair function may increase the capability of tumors to evade treatment by other targeted therapies as a result of their overall elevated mutation rate and suggests that caution should be taken in combining temozolomide treatment with targeted therapies.

   The development of targeted therapies will benefit from the molecular insights provided by the comprehensive genomic characterization of tumors. However, much remains to be seen and learned from this massive amount of data. The Johns Hopkins Study[1] estimated that approximately 15% of missense mutations would have an impact on tumor progression. At an average of 47 mutations per tumor (not including hypermutated tumors), one would expect an average of 7 missense mutations with an impact on tumor progression per sample. Given the mutual exclusivity of mutations within core pathways -- ie, the tendency of only 1 mutation to occur in each of the 3 core pathways -- more than half of the mutations driving tumor progression per sample remain to be explained. These mutations are likely to affect a wider set of genes and pathways, given that they are not immediately evident by basic statistical analyses. Therefore, they are likely to account for a large proportion of mutations contributing to tumor progression and provide an additional layer of complexity in the variables that may affect clinical outcome. This complexity is enhanced further when copy number, methylation, and other genomic aberrations are added to the mix. A parallel study conducted in pancreatic cancer had many analogous findings.[13] These studies represent a first stab at understanding the enormous complexity of cancer. As our knowledge regarding the molecular mechanisms of cancer initiation and progression grows at an increasingly rapid pace, comprehensive genomic studies should lead to increasingly powerful therapeutic strategies in the war on cancer.