Molecular mechanisms of genomic imprinting and clinical implications for cancer

Abstract

Genomic imprinting is an epigenetic marking of genes in the parental germline that ensures the stable transmission of monoallelic gene expression patterns in a parent-of-origin-specific manner. Epigenetic marking systems are thus able to regulate gene activity independently of the underlying DNA sequence. Several imprinted gene products regulate cell proliferation and fetal growth; loss of their imprinted state, which effectively alters their dosage, might promote or suppress tumourigenic processes. Conversely, global epigenetic changes that underlie tumourigenesis might affect imprinted gene expression. Here, we review imprinted genes with regard to their roles in epigenetic predisposition to cancer, and discuss acquired epigenetic changes (DNA methylation, histone modifications and chromatin conformation) either as a result of cancer or as an early event in neoplasia. We also address recent work showing the potential role of noncoding RNA in modifying chromatin and affecting imprinted gene expression, and summarise the effects of loss of imprinting in cancer with regard to the roles that imprinted genes play in regulating growth signalling cascades. Finally, we speculate on the clinical applications of epigenetic drugs in cancer.

TCEB3C a putative tumor suppressor gene of small intestinal neuroendocrine tumors

“…Imprinted genes are of particular interest in cancer because only one mutational hit is required to fulfill the Knudson's two-hit hypothesis of tumor suppressor genes. The imprinted allele is normally inactivated by epigenetic mechanisms, in a way that could be tissue specific (Ferguson-Smith 2011, Uribe-Lewis et al 2011. TCEB3C is currently the only known imprinted gene on chromosome 18 (http://www.geneimprint.com) and is located at 18q21.1.…”

“…Imprinted genes are of particular interest in cancer since only one mutational hit is required to fulfill the Knudson's two-hit hypothesis of tumor suppressor genes. Imprinted genes are epigenetically regulated and have a parental origin-specific differential expression of the two alleles and the epigenetic regulation is often tissue-specific (Ferguson-Smith 2011, Uribe-Lewis et al 2011. Presently, the only known imprinted gene on chromosome 18 (http://www.geneimprint.com) is TCEB3C (18q21.1), which is maternally imprinted in some tissues (Strichman-Almashanu et al 2002, Li et al 2010 and encompasses a CpG island.…”

Epigenetics: from the past to the present

“…The McCune-Albright, Angelman and Prader-Willi syndromes (MAS, AS and PWS, respectively) exhibit imprinting defects. In AS and PWS, defects can occur due to deletions in the active gene-containing chromosome, the inheritance of both gene copies from the same parent or the presence of mutations in the components responsible for imprinting during gametogenesis (Feinberg et al 2002;Uribe-Lewis et al 2011).…”

Methylomes

“…First, genomic demethylation causes a significant elevation in mutation rates] and aberrant activation of"normally"silenced tumor promoting genes [41][42][43]. Second, hypomethylation of DNA results in the loss of genomic imprinting (LOI), which is currently considered as one of the earliest and most frequent alterations in human tumors [44][45][46]. Third, demethylation of repetitive sequences, such as long interspersed nucleotide elements (LINE)-1, short interspersed nucleotide elements (SINE), and retroviral intracisternal.…”