A Hypermutation Phenotype and Somatic MSH6 Mutations in Recurrent Human Malignant Gliomas after Alkylator Chemotherapy

Abstract

Malignant gliomas have a very poor prognosis. The current standard of care for these cancers consists of extended adjuvant treatment with the alkylating agent temozolomide after surgical resection and radiotherapy. Although a statistically significant increase in survival has been reported with this regimen, nearly all gliomas recur and become insensitive to further treatment with this class of agents. We sequenced 500 kb of genomic DNA corresponding to the kinase domains of 518 protein kinases in each of nine gliomas. Large numbers of somatic mutations were observed in two gliomas recurrent after alkylating agent treatment. The pattern of mutations in these cases showed strong similarity to that induced by alkylating agents in experimental systems. Further investigation revealed inactivating somatic mutations of the mismatch repair gene MSH6 in each case. We propose that inactivating somatic mutations of MSH6 confer resistance to alkylating agents in gliomas in vivo and concurrently unleash accelerated mutagenesis in resistant clones as a consequence of continued exposure to alkylating agents in the presence of defective mismatch repair. The evidence therefore suggests that when MSH6 is inactivated in gliomas, alkylating agents convert from induction of tumor cell death to promotion of neoplastic progression. These observations highlight the potential of large scale sequencing for revealing and elucidating mutagenic processes operative in individual human cancers. (Cancer Res 2006; 66(8): 3987-91)

NEO212, Temozolomide Conjugated to Perillyl Alcohol, Is a Novel Drug for Effective Treatment of a Broad Range of Temozolomide-Resistant Gliomas

“…MGMT expression in GBM occurs in approximately 40% to 50% of patients with GBM, yet temozolomide resistance is almost universal, demonstrating that other mechanisms of temozolomide resistance are operating (17,45,46). MMR deficiencies are also documented in recurrent patients with GBM (19,20,47). As much as 25% of recurrent GBMs exhibit MMR deficiencies (48).…”

Breast Tumor Heterogeneity: Cancer Stem Cells or Clonal Evolution?

“…13 Clonal evolution is also supported by findings that various drug-resistant clones are observed after some cancer therapies, such as treatment with the alkylating agent temozolomide or the tyrosine kinase inhibitor imatinib. [57][58] Finally, several studies of various cancers have shown that the patterns of genetic alterations seen between primary tumors, metastases, and recurrences match what is expected from clonal evolution. Within individual patients, most mutations in primary tumors and metastases are identical, but some are unique to each; increasing degree of tumor cell chromosomal aberration correlates with more malignant properties; and recurrences contain the mutations seen before in primary tumors along with additional ones.…”

PTEN signaling in brain: neuropathology and tumorigenesis

“…Although elevation of AKT activity is seen more frequently than PTEN mutation in gliomas and medulloblastomas (Schlegel et al, 2002;Hartmann et al, 2006), mutations causing increased activity of any AKT isoform have not been observed frequently. AKT1 amplification has been reported in various human cancers, including a single case of gliosarcoma (Knobbe and Reifenberger, 2003) and AKT3 mutation has been reported in a single case of glioma (Hunter et al, 2006); however, the consequence of this missense mutation (G171R) on the activity of the enzyme is unknown. While AKT2 amplification has been observed frequently in head and neck tumors, as well as pancreatic, ovarian and breast cancers (Bellacosa et al, 1995;Cheng et al, 1996;Pedrero et al, 2005;Nakayama et al, 2006), it has not yet been described in primary human brain tumors, although studies indicate it may be overexpressed and drive tumorigenicity in some glioma cell lines (Pu et al, 2006).…”