Integrative Genome Comparison of Primary and Metastatic Melanomas
ABSTRACT A cardinal feature of malignant melanoma is its metastatic propensity. An incomplete view of the genetic events driving metastatic progression has been a major barrier to rational development of effective therapeutics and prognostic diagnostics for melanoma patients. In this study, we conducted global genomic characterization of primary and metastatic melanomas to examine the genomic landscape associated with metastatic progression. In addition to uncovering three genomic subclasses of metastastic melanomas, we delineated 39 focal and recurrent regions of amplification and deletions, many of which encompassed resident genes that have not been implicated in cancer or metastasis. To identify progression-associated metastasis gene candidates, we applied a statistical approach, Integrative Genome Comparison (IGC), to define 32 genomic regions of interest that were significantly altered in metastatic relative to primary melanomas, encompassing 30 resident genes with statistically significant expression deregulation. Functional assays on a subset of these candidates, including MET, ASPM, AKAP9, IMP3, PRKCA, RPA3, and SCAP2, validated their pro-invasion activities in human melanoma cells. Validity of the IGC approach was further reinforced by tissue microarray analysis of Survivin showing significant increased protein expression in thick versus thin primary cutaneous melanomas, and a progression correlation with lymph node metastases. Together, these functional validation results and correlative analysis of human tissues support the thesis that integrated genomic and pathological analyses of staged melanomas provide a productive entry point for discovery of melanoma metastases genes.
Full-textDOI: · Available from: Stephan N Wagner, May 17, 2015
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ABSTRACT: Down syndrome (DS), one of the most common birth defects and the most widespread genetic cause of intellectual disabilities, is caused by extra genetic material on chromosome 21 (HSA21). The increased genomic dosage of trisomy 21 is thought to be responsible for the distinct DS phenotypes, including an increased risk of developing some types of childhood leukemia and germ cell tumors. Patients with DS, however, have a strikingly lower incidence of many other solid tumors. We hypothesized that the third copy of genes located in HSA21 may have an important role on the protective effect that DS patients show against most types of solid tumors. Focusing on Copy Number Variation (CNV) array data, we have generated frequencies of deleted regions in HSA21 in four different tumor types from which DS patients have been reported to be protected. We describe three different regions of deletion pointing to a set of candidate genes that could explain the inverse comorbidity phenomenon between DS and solid tumors. In particular we found RCAN1 gene in Wilms tumors and a miRNA cluster containing miR-99A, miR-125B2 and miR-LET7C in lung, breast, and melanoma tumors as the main candidates for explaining the inverse comorbidity observed between solid tumors and DS.
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ABSTRACT: Heat-shock factor 1 (HSF1) orchestrates the heat-shock response in eukaryotes. Although this pathway has evolved to help cells adapt in the presence of challenging conditions, it is co-opted in cancer to support malignancy. However, the mechanisms that regulate HSF1 and thus cellular stress response are poorly understood. Here we show that the ubiquitin ligase FBXW7α interacts with HSF1 through a conserved motif phosphorylated by GSK3β and ERK1. FBXW7α ubiquitylates HSF1 and loss of FBXW7α results in impaired degradation of nuclear HSF1 and defective heat-shock response attenuation. FBXW7α is either mutated or transcriptionally downregulated in melanoma and HSF1 nuclear stabilization correlates with increased metastatic potential and disease progression. FBXW7α deficiency and subsequent HSF1 accumulation activates an invasion-supportive transcriptional program and enhances the metastatic potential of human melanoma cells. These findings identify a post-translational mechanism of regulation of the HSF1 transcriptional program both in the presence of exogenous stress and in cancer.
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ABSTRACT: The post-transcriptional control of gene expression mediated by RNA-binding proteins (RBPs), long non-coding RNAs (lncRNAs) as well as miRNAs is essential to determine tumor cell fate and thus is a major determinant in cancerogenesis. The IGF2 mRNA binding protein family (IGF2BPs) comprises three RBPs. Two members of the family, IGF2BP1 and IGF2BP3, are bona fide oncofetal proteins, which are de novo synthesized in various human cancers. In vitro studies revealed that IGF2BPs serve as post-transcriptional fine-tuners modulating the expression of genes implicated in the control of tumor cell proliferation, survival, chemo-resistance and metastasis. Consistently, the expression of both IGF2BP family members was reported to correlate with an overall poor prognosis and metastasis in various human cancers. Due to the fact that most reports used a pan-IGF2BP antibody for studying IGF2BP expression in cancer, paralogue-specific functions can barely be evaluated at present. Nonetheless, the accordance of IGF2BPs’ role in promoting an aggressive phenotype of tumor-derived cells in vitro and their upregulated expression in aggressive malignancies provides strong evidence that IGF2BPs are powerful post-transcriptional oncogenes enhancing tumor growth, drug-resistance and metastasis. This suggests IGF2BPs as powerful biomarkers and candidate targets for cancer therapy.Seminars in Cancer Biology 12/2014; 29. DOI:10.1016/j.semcancer.2014.07.006 · 9.14 Impact Factor