Low-level copy number changes of MYC genes have a prognostic impact in medulloblastoma

Abstract

High-level amplifications of MYC genes are associated with poor outcomes in childhood medulloblastoma (MB). However, the occurrence of MYCN and MYCC copy number increases below the intense amplification pattern is rarely reported, and its clinical impact has not yet been determined. Here, we describe this phenomenon and its prognostic significance in a cohort of 29 MB patients. Using interphase fluorescence in situ hybridization (I-FISH), low-level copy number alterations, i.e. gain of MYCN, were shown in 5/27 (19%) samples, whereas amplification was revealed in only 1/27 (4%) samples. MYCC gain was revealed in 6/29 (21%) MB, while amplification was disclosed in only 2/29 (7%). Hyperploidy and co-incidence of gains in both MYC loci were frequently observed in samples with copy number aberrations. Survival analysis has clearly shown that MYC copy number increases are associated with lowered event-free survival and overall survival in MB. In the case of MYCN, this negative correlation was statistically significant. We conclude that limited numerical alterations in loci 2p24 (MYCN) and 8q24 (MYCC), as assessed by I-FISH, are present in MB with a higher frequency than high-level amplifications. Poor prognoses were observed in patients with copy number increases in MYC genes. Our data illustrate the importance of further investigations in multicenter trials to better refine the emerging genomic-based prognostic stratification in MB.

MYC family amplification and clinical risk-factors interact to predict an extremely poor prognosis in childhood medulloblastoma

“…5%) within individual tumours highlights potential sampling limitations and the requirement for assessment of sufficient tumour nuclei ([200 in this study) to avoid false-negative results. Haploid copy numbers \5 were more commonly associated with chromosomal gains, which have been suggested elsewhere to confer a poor prognosis [4,28]; however, these did not show prognostic significance in multivariate survival analysis in the present study. Although significant in univariate survival analysis, the limited numbers of MYCN 'gained' cases (n = 2) dictate the requirement of extended studies to definitively assess their relationships to survival.…”

“…Studies by us and others have associated MYC family amplification with a poor prognosis; however, findings are not consistent between studies and suggest heterogeneous biological and clinical behaviour of the MYC genes [2,7,11,14,15,21,23,28]. Specifically, while some studies have combined MYCC and MYCN together for analysis and demonstrated prognostic significance [14,21], others have indicated their individual roles as prognostic biomarkers may differ; our most recent study found prognostic significance for MYCC but not MYCN [7].…”

“…Specifically, while some studies have combined MYCC and MYCN together for analysis and demonstrated prognostic significance [14,21], others have indicated their individual roles as prognostic biomarkers may differ; our most recent study found prognostic significance for MYCC but not MYCN [7]. Additional studies have suggested that MYC family copy number gain may also impact [28]. Initial reports further indicate MYC family copy number heterogeneity at the cellular level within tumours may impact on their clinical significance, although consensus findings have been hindered by the use of different analytical methodologies and amplification detection cut-offs to assess prognostic relationships [2,7,11,14,15,21,23,28].…”

“…Additional studies have suggested that MYC family copy number gain may also impact [28]. Initial reports further indicate MYC family copy number heterogeneity at the cellular level within tumours may impact on their clinical significance, although consensus findings have been hindered by the use of different analytical methodologies and amplification detection cut-offs to assess prognostic relationships [2,7,11,14,15,21,23,28]. At the expression level, MYCC transcript levels have also been associated with poor prognosis, but these findings are similarly inconsistent [4,8,9,11].…”

Biological and clinical heterogeneity of MYCN-amplified medulloblastoma

“…Amplification of MYC family oncogenes appears to be pivotal for tumor biology and clinical behavior in up to 15% of pediatric cases [9,11,30,35,36]. It has been recognized that focal high-level amplification of the MYC (MYCC) locus at 8q24 was significantly associated with poor clinical outcome and this has been confirmed in various independent series [1,6,11,12,35,48].…”