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Review
. 2016 Oct 19;17(10):1744.
doi: 10.3390/ijms17101744.

A Proteogenomic Approach to Understanding MYC Function in Metastatic Medulloblastoma Tumors

Jerome A Staal  1   2 , Yanxin Pei  3 , Brian R Rood  4
Affiliations
Review

A Proteogenomic Approach to Understanding MYC Function in Metastatic Medulloblastoma Tumors

Jerome A Staal et al. Int J Mol Sci. .

Abstract

Brain tumors are the leading cause of cancer-related deaths in children, and medulloblastoma is the most prevalent malignant childhood/pediatric brain tumor. Providing effective treatment for these cancers, with minimal damage to the still-developing brain, remains one of the greatest challenges faced by clinicians. Understanding the diverse events driving tumor formation, maintenance, progression, and recurrence is necessary for identifying novel targeted therapeutics and improving survival of patients with this disease. Genomic copy number alteration data, together with clinical studies, identifies c-MYC amplification as an important risk factor associated with the most aggressive forms of medulloblastoma with marked metastatic potential. Yet despite this, very little is known regarding the impact of such genomic abnormalities upon the functional biology of the tumor cell. We discuss here how recent advances in quantitative proteomic techniques are now providing new insights into the functional biology of these aggressive tumors, as illustrated by the use of proteomics to bridge the gap between the genotype and phenotype in the case of c-MYC-amplified/associated medulloblastoma. These integrated proteogenomic approaches now provide a new platform for understanding cancer biology by providing a functional context to frame genomic abnormalities.

Keywords: MYC; medulloblastoma; quantitative proteomics.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
(A) Summary for the proposed risk stratification of MYC-amplified tumors in Group 3 medulloblastoma. Interestingly, although c-MYC genomic amplifications are almost exclusively found in Group 3 tumors and associated with poor survival (>50% survival), mRNA expression patterns are similar to that seen in the WNT subgroup (B) which has the best clinical outcome of all medulloblastoma subgroups. Increased gene transcripts are significantly associated with MYC-amplified Group 3 medulloblastomas when compared to nonamplified tumors from the same group (C); (Northcott et al., 2012 dataset under accession number GSE37385 [3]).
Figure 2
Figure 2
Schematic presentation of super-SILAC (stable isotopic labeling by amino acids in cell culture) methodology. All proteins within different medulloblastoma primary/cell lines are isotopically labeled, in vivo (using stable isotope labeling of amino acids in mammals: SILAM) or in vitro, through incorporation of 13C6-Arg (MB—medulloblastoma). This causes a known shift of 6 Da in the mass spectrometry spectra. The combined lysates of the isotopically labeled cultures are mixed (1:1 ratio) with tumor lysates from different medulloblastoma tumor/cell samples resulting in two spectra profiles per protein (separated by 6 Da). The protein of interest can now be quantified in the sample as a ratio of the isotopically labeled protein in the same sample.
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