One hit, two hits, three hits, more? Genomic changes in the development of retinoblastoma

Abstract

The childhood eye cancer retinoblastoma is initiated by the loss of both alleles of the prototypic tumor suppressor gene, RB1. However, a large number of cytogenetic and comparative genomic hybridization (CGH) studies have shown that these M1 and M2 mutational events--although necessary for initiation--are not the only genomic changes in retinoblastoma. Some of these subsequent changes, which we have termed M3 to Mn, are likely crucial for tumor progression not only in retinoblastoma but also in other cancers. Moreover, genes showing genomic change in cancer are more stable markers and, therefore, possible therapeutic targets than genes simply differentially expressed. In this review, we provide the first comprehensive summary of the genomic evidence implicating gain of 1q, 2p, 6p, and 13q, and loss of 16q in retinoblastoma oncogenesis, including karyotype, CGH, and microarray CGH data. We discuss the search for candidate oncogenes and tumor suppressor genes within these regions, including the candidates (KIF14, MDM4, MYCN, E2F3, DEK, CDH11, and others), plus associations between genomic changes and clinical parameters. We also review studies of other regions of the retinoblastoma genome, the epigenetic changes of aberrant methylation of MGMT, RASSF1A, CASP8, and MLH1, and the roles microRNAs might play in this cancer. Although many candidate genes have yet to be functionally validated in retinoblastoma, work in this field lays out a molecular cytogenetic pathway of retinoblastoma development. Candidate cancer genes carry diagnostic, prognostic, and therapeutic implications beyond retinoblastoma.

Consensus transcriptome signature of perineural invasion in pancreatic carcinoma

“…Expression of KIF14 is elevated in mitotic cells (21), and knockdown of this protein leads to multinucleation and apoptosis (21,22). KIF14 is overexpressed in various malignant diseases, including retinoblastoma and breast and lung cancer, and high expression of this protein correlates with poor outcome in these diseases (23)(24)(25). Here, we identified KIF14 as a suppressor of perineural invasion.…”

Array CGH demonstrates characteristic aberration signatures in human papillary thyroid carcinomas governed by RET/PTC

“…It is of note that 21 tumour-suppressor genes map within either the specific or the consistently altered regions. TIMP3 and PTEN have already been reported as tumour suppressors in thyroid tumours (Hu et al, 2006;Hou et al, 2007;Wang et al, 2007), while others are involved in a variety of different tumour types, for example, TGFBR3 and ANXA7 in prostate cancer (Torosyan et al, 2006;Dong et al, 2007), TNFSF15 and TUSC1 in lung cancer (Shan et al, 2004;Hou et al, 2005), SYK and Net1 in breast cancer (Repana et al, 2006;Huang et al, 2007), SLIT1, RSU1 and KLF6 in gliomas and glioblastosmas (Chunduru et al, 2002;Dickinson et al, 2004;Camacho-Vanegas et al, 2007), DBC1 in bladder cancer (Louhelainen et al, 2006), DEC1 in oesophageal squamous cell carcinomas (Yang et al, 2005), RB1 in retinoblastoma (Corson and Gallie, 2007) and LATS2 and DLEU7 in leukaemias (Hammarsund et al, 2004;Jimenez-Velasco et al, 2005). Some of these tumour suppressors have influence on the regulation of chromatin acetylation …”

AP2 transcription factor induces apoptosis in retinoblastoma cells

“…Karyotypic analysis of retinoblastoma tumors has revealed a number of common chromosome abnormalities, with the most distinctive and frequent abnormalities involving extra copies of chromosome arm 6p, usually in the form of an isochromosome 6p (Corson and Gallie, 2007). To date, no gene on 6p has been directly implicated in retinoblastoma tumor formation or progression.…”