Novel mechanisms of gene disruption at the medulloblastoma isodicentric 17p11 breakpoint

McCabe, Martin G.; Ichimura, Koichi; Pearson, DM; Liu, L; Clifford, Steven C.; Ellison, DW; Collins, V. Peter

doi:10.1002/gcc.20625

Cited by 9 publications

(5 citation statements)

References 34 publications

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“…Gain of the long arm of chromosome 17 has been observed in various tumor entities, including neuroblastoma. The region harbors genes associated with tumor progression (Levin et al, ; Yu et al, ; McCabe et al, ). The proportion of tumors with partial 17q gain in our cohort of neuroblastoma patients was 46%, which is in the range found in other studies 38–65% (Caron, ; Lastowska et al, ; Plantaz et al, ; Abel et al, ; Bown et al, ; Brinkschmidt et al, ; Spitz et al, ; Vandesompele et al, ; Spitz et al, ).…”

Section: Discussionmentioning

confidence: 99%

Chromosome 17/17q gain and unaltered profiles in high resolution array‐CGH are prognostically informative in neuroblastoma

Theißen

Oberthuer

Hombach

et al. 2014

Genes Chromosomes & Cancer

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The prognostic relevance of chromosome 17 gain in neuroblastoma is still discussed. This investigation specifies the frequency, type, size, and transcriptional relevance in a large patient cohort. Primary tumor material of 202 patients was analyzed using high-resolution oligonucleotide array-based comparative genomic hybridization (aCGH) and correlated with clinical and survival data. A subset (n = 145) was correlated for differentially expressed genes (DEG) by microarray analysis. Chromosome 17 aCGH analysis showed numerical gain in 94/202 patients (47%), partial gain in 93/202 patients (46%), and no gain in 15/202 patients (7%). The frequency of partial gain was higher in stage 4 neuroblastoma (stage 1 15%; stage 2 12%; stage 3 16%; stage 4S 7%; and stage 4 50%). Overall survival (OS) was superior in patients with numerical gain compared with patients with partial gain or no gain (5-y-OS: 0.95 ± 0.02 vs. 0.63 ± 0.05 vs. 0.60 ± 0.13; P < 0.001). Gene expression analysis demonstrated 95/130 DEGs between tumors with numerical or partial chromosome/no gain. Only one DEG (CCKBR) was detected comparing tumors with partial gain and those with no gain. In patients with partial gain, the distribution of breakpoints did not correlate with stage and 11q status, but with MYCN amplification and 1p status. The "best" breakpoints in cases with partial 17q gain were at 42.5 Mb for event-free and 26.6 Mb for OS. Numerical gain of chromosome 17 is associated with a better prognosis than partial and no gain. The group of tumors with partial gain was similar to the group without gain with respect to stage distribution, outcome, and gene expression profile.

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Section: Discussionmentioning

confidence: 99%

Chromosome 17/17q gain and unaltered profiles in high resolution array‐CGH are prognostically informative in neuroblastoma

Theißen

Oberthuer

Hombach

et al. 2014

Genes Chromosomes & Cancer

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“…Current thinking is that non-allelic homologous recombination between these repeat sequences leads to the formation of an i17q [9, 72]. More recent fine mapping of the 17p breakpoint has identified a small number of poorly characterized genes whose disruption could play a role in the pathogenesis of medulloblastoma [70]. Intriguingly, recurrent medulloblastomas show increased levels of 17q gain as compared to the initial tumor, suggesting an important role for i17q in the progression of medulloblastoma [62].…”

Section: Medulloblastomamentioning

confidence: 99%

Molecular diagnostics of CNS embryonal tumors

et al. 2010

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Tremendous progress has recently been made in both molecular subgrouping, and the establishment of prognostic biomarkers for embryonal brain tumors, particularly medulloblastoma. Several prognostic biomarkers that were initially identified in retrospective cohorts of medulloblastoma, including MYC and MYCN amplification, nuclear β-catenin accumulation, and chromosome 17 aberrations have now been validated in clinical trials. Moreover, molecular subgroups based on distinct transcriptome profiles have been consistently reported from various groups on different platforms demonstrating that the concept of distinct medulloblastoma subgroups is very robust. Well-described subgroups of medulloblastomas include tumors showing wingless signaling pathway (Wnt) activation, and another characterized by sonic hedgehog pathway activity. Two or more additional subgroups were consistently reported to contain the vast majority of high-risk tumors, including most tumors with metastatic disease at diagnosis and/or large cell/anaplastic histology. Several years ago, atypical teratoid rhabdoid tumor (AT/RT) was recognized as a separate entity based on its distinct biology and particularly aggressive clinical behavior. These tumors may occur supra or infratentorially and are usually found to have genetic alterations of SMARCB1 (INI1/hSNF5), a tumor suppressor gene located on chromosome 22q. Subsequent loss of SMARCB1 protein expression comprises a relatively specific and sensitive diagnostic marker for AT/RT. For CNS primitive neuroectodermal tumors (CNS PNETs), a consistent finding has been that they are molecularly distinct from medulloblastoma. Furthermore, a distinct fraction of CNS PNETs with particularly poor prognosis only occurring in young children was delineated, which was previously labeled ependymoblastoma or embryonal tumor with abundant neuropil and true rosettes (ETANTR) and which is morphologically characterized by the presence of multilayered “ependymoblastic” rosettes. This group of tumors shows a unique cytogenetic abnormality not seen in other brain tumors: focal amplification of a micro-RNA cluster at chromosome 19q13.42, which has never been found to be amplified in other CNS PNETs, medulloblastoma or AT/RT. In summary, these consistent findings have significantly contributed to our ability to sub-classify embryonal brain tumors into clinically and biologically meaningful strata and, for some of the subgroups, have led to the identification of specific targets for future development of molecularly targeted therapies.

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“…We sought to identify the prognostic impact of these chromosomal changes in a larger dataset. By combining our previously reported series of 41 medulloblastomas 20 with other series with explicit survival data related to chromosomal copy number abnormalities, we generated a combined dataset representing 227 patients. We report here our results from correlating alterations in chromosomes 1q, 6, and 17 with survival in the combined dataset.…”

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confidence: 99%

Chromosome 17 alterations identify good-risk and poor-risk tumors independently of clinical factors in medulloblastoma

et al. 2011

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Current risk stratification schemas for medulloblastoma, based on combinations of clinical variables and histotype, fail to accurately identify particularly good- and poor-risk tumors. Attempts have been made to improve discriminatory power by combining clinical variables with cytogenetic data. We report here a pooled analysis of all previous reports of chromosomal copy number related to survival data in medulloblastoma. We collated data from previous reports that explicitly quoted survival data and chromosomal copy number in medulloblastoma. We analyzed the relative prognostic significance of currently used clinical risk stratifiers and the chromosomal aberrations previously reported to correlate with survival. In the pooled dataset metastatic disease, incomplete tumor resection and severe anaplasia were associated with poor outcome, while young age at presentation was not prognostically significant. Of the chromosomal variables studied, isolated 17p loss and gain of 1q correlated with poor survival. Gain of 17q without associated loss of 17p showed a trend to improved outcome. The most commonly reported alteration, isodicentric chromosome 17, was not prognostically significant. Sequential multivariate models identified isolated 17p loss, isolated 17q gain, and 1q gain as independent prognostic factors. In a historical dataset, we have identified isolated 17p loss as a marker of poor outcome and 17q gain as a novel putative marker of good prognosis. Biological markers of poor-risk and good-risk tumors will be critical in stratifying treatment in future trials. Our findings should be prospectively validated independently in future clinical studies.

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Novel mechanisms of gene disruption at the medulloblastoma isodicentric 17p11 breakpoint

Cited by 9 publications

References 34 publications

Chromosome 17/17q gain and unaltered profiles in high resolution array‐CGH are prognostically informative in neuroblastoma

Chromosome 17/17q gain and unaltered profiles in high resolution array‐CGH are prognostically informative in neuroblastoma

Molecular diagnostics of CNS embryonal tumors

Chromosome 17 alterations identify good-risk and poor-risk tumors independently of clinical factors in medulloblastoma

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