Genetic and epigenetic stability of oligodendrogliomas at recurrence

Abstract

Among diffuse gliomas, oligodendrogliomas show relatively better prognosis, respond well to radiotherapy and chemotherapy, and seldom progress to very aggressive tumors. To elucidate the genetic and epigenetic background for such behavior and tumor evolution during tumor relapse, we comparatively analyzed 12 pairs of primary and recurrent oligodendrogliomas with 1p/19q-codeletion. Initial treatment for these patients was mostly chemotherapy alone. Temozolomide was used for 3, and procarbazine, nimustine and vincristine (PAV chemotherapy) were used for 7 patients. World Health Organization histological grade at recurrence was mostly stable; it was increased in 2, the same in 9, and decreased in 1 cases. Whole-exome sequencing demonstrated that the rate of shared mutation between the primary and recurrent tumors was relatively low, ranging from 3.2-57.9% (average, 33.3%), indicating a branched evolutionary pattern. The trunk alterations that existed throughout the course were restricted to IDH1 mutation, 1p/19q-codeletion, and TERT promoter mutation, and mutation of the known candidate tumor suppressor genes CIC and FUBP1 were not consistently observed between primary and recurrent tumors. Multiple sampling from different regions within a tumor showed marked intratumoral heterogeneity. Notably, in general, the number of mutations was not significantly different after recurrence, remaining under 100, and no hypermutator phenotype was observed. FUBP1 mutation, loss of chr. 9p21, and TCF12 mutation were among a few recurrent de novo alterations that were found at recurrence, indicating that these events were clonally selected at recurrence but were not enough to enhance malignancy. Genome-wide methylation status, measured by Illumina 450 K arrays, was stable between recurrence and the primary tumor. In summary, although oligodendroglioma displays marked mutational heterogeneity, histological malignant transformation accompanying events such as considerable increase in mutation number and epigenetic profile change were not observed at recurrence, indicating that noticeable temporal and spatial genetic heterogeneity in oligodendrogliomas does not result in rapid tumor progression.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-017-0422-z) contains supplementary material, which is available to authorized users.

IDH‐mutated astrocytomas with 19q‐loss constitute a subgroup that confers better prognosis

“…11 Whole exome sequencing identified FUBP1 on 1p31.1 and CIC on 19q13.2 as the most frequently mutated genes on 1p and 19q in oligodendrogliomas, but the mutation rates remain 50%-60% at most, 12 and meticulous studies on mutational landscape have shown that mutations of those two genes can be heterogeneous within a tumor, indicating mutations of those genes are later events following the translocation. 13,14 In Although the 19-loss-only astrocytomas appear to constitute only <10% of lower grade astrocytomas, and hence pose limitations to our study, the validation study on the independent TCGA dataset was in line with our notion.…”

The Capicua tumor suppressor: a gatekeeper of Ras signaling in development and cancer

“…More recent studies have identified distinct CIC missense mutations within a single tumor, suggesting that selective pressure to inactivate CIC function causes several subclones to acquire distinct mutations independently, thereby contributing to intratumoral heterogeneity [56]. These CIC mutations are not always maintained in recurrent oligodendrogliomas, adding further support to the concept that some of these mutations may be subclonal secondary events [57]. Finally, the presence of mutated CIC alleles correlates with a more aggressive phenotype when compared to tumors that only harbor the 1p/19q co-deletion, indicating that Embryonic or perinatal lethality with incomplete penetrance and hyperproliferation of neural stem cells in the SVZ [42] complete inactivation of CIC function actively contributes to tumor progression [58].…”

Mechanisms and clinical implications of tumor heterogeneity and convergence on recurrent phenotypes

“…Through profiling 4 to 5 regions of primary tumors from 11 patients with HC, Lin and colleagues determined that, on average, 39% of somatic mutations varied across the spatial samples studied from each patient’s tumor [27]. This is similar to the 36% seen across 3 to 4 samplings each from 13 patients with esophageal squamous cell carcinoma (ESCC) [10] and 43% seen in 4 patients with oligodendroglioma [28]. However, this difference in spatial somatic mutation varied widely per patient, ranging from 5–92% in HC, 8–61% in ESCC, and 10–64% in oligodendroglioma, demonstrating the unique evolutionary trajectory inherent to different cancer types and to each individual patient.…”

“…This study took findings one step further, however, by identifying recurrent molecular alterations seen in relapse, including reversion mutations in BRCA1 and BRCA2 and translocation of the ABCB1 gene such that it becomes fused to a strong promoter. Interestingly, Aihara and colleagues employed exome sequencing of 12 paired primary and recurrent oligodendrogliomas resected from patients as part of routine clinical care to demonstrate that approximately one-third of mutations from the primary tumor are retained in the recurrent tumor [28]. Thus, despite limited access to sequential samples, several groups identified temporal heterogeneity in various cancers as evidenced by changes in subclonal dynamics and in overall mutational burden over time.…”