Aberrant DNA Methylation in Hereditary Nonpolyposis Colorectal Cancer Without Mismatch Repair Deficiency

Goel, Ajay; Xicola, Rosa M.; Nguyen, Thuy–Phuong; Doyle, Brian J.; Sohn, Vanessa R.; Bandipalliam, Prathap; Rozek, Laura S.; Reyes, José Antonio Muñoz; Cordero, Carmen; Balaguer, Francesc; Castells, Antoni; Jover, Rodrigo; Andreu, Montserrat; Syngal, Sapna; Boland, C. Richard; Llor, Xavier

doi:10.1053/j.gastro.2010.01.035

Cited by 93 publications

(83 citation statements)

References 39 publications

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“…49,51,[53][54][55][56] Global DNA hypomethylation has been associated with poor prognosis, shorter survival, younger age of onset, and familial colorectal cancer risk. 39,51,[55][56][57][58][59] The predisposition to LINE-1 hypomethylation in FCCTX tumors gives an evidence for a link between distinct molecular signatures and phenotypes associated with specific epigenotypes. 59 In hereditary colorectal cancer, relatively less is known about the patterns of specific histone modifications that also regulate gene expression through controlling chromatin conformation.…”

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confidence: 99%

Familial colorectal cancer type X: genetic profiles and phenotypic features

Dominguez‐Valentin

Therkildsen²,

Silva³

et al. 2015

Modern Pathology

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Heredity is a major cause of colorectal cancer, but although several rare high-risk syndromes have been linked to disease-predisposing mutations, the genetic mechanisms are undetermined in the majority of families suspected of hereditary cancer. We review the clinical presentation, histopathologic features, and the genetic and epigenetic profiles of the familial colorectal cancer type X (FCCTX) syndrome with the aim to delineate tumor characteristics that may contribute to refined diagnostics and optimized tumor prevention.

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mentioning

confidence: 99%

Familial colorectal cancer type X: genetic profiles and phenotypic features

Dominguez‐Valentin

Therkildsen²,

Silva³

et al. 2015

Modern Pathology

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“…The importance of hypomethylation in this region has been highlighted in various types of human cancer, including HCC, chronic myeloid leukemia, bladder cancer, gastrointestinal stromal tumors, gastric cancer and ovarian cancer (12). Transcription of L1 induced by hypomethylation significantly correlates with the degree of malignancy, particularly in colorectal cancer (21)(22)(23). This suggests that L1 hypomethylation may serve a more important role in human cancer than the hypomethylation-induced inhibition of transcription of specific tumor suppressor genes.…”

Section: Discussionmentioning

confidence: 82%

Binding of LINE-1 RNA to PSF transcriptionally promotes GAGE6 and regulates cell proliferation and tumor formation in vitro

Zhao

2017

Experimental and Therapeutic Medicine

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Abstract. Hepatocellular carcinoma (HCC) has one of the highest mortality rates among numerous types of cancer. It has been demonstrated that in hepatitis B (HBV)-associated HCC, the expression of chimeric fusion transcript HBx-long interspersed nuclear element-1 (LINE-1) initiated by HBV integration is correlated with hepatocarcinogenesis and poor patient survival rates. Furthermore, increased rates of LINE-1 hypomethylation have been detected in HCC tissues compared with adjacent tissues. This suggests that individual LINE-1 RNA (L1 RNA) serves an important role in the processes of hepatocarcinogenesis. The present study assessed the epigenic interaction between L1 RNA and polypyrimidine tract-binding protein-associated splicing factor (PSF) in the A549 human alveolar epithelial and 16HBE human bronchial epithelial cell lines. In addition, changes in the transcriptional regulatory activity of PSF on its target gene, proto-oncogene G antigen 6 (GAGE6), were investigated following overexpression of L1 RNA, as well as its impact on cell-proliferative capacity, carried out by plotting cell growth curves and 5-ethynyl-2'-deoxyuridine assay. It was observed that L1 RNA specifically bound to the RNA binding domain of PSF and released the GAGE6 promoter region from the DNA-binding domain of PSF. This increased the transcription of GAGE6 and led to the promotion of cell proliferation as well as colony formation. Furthermore, at least two binding sites specific for PSF were identified on L1 RNA. In conclusion, the transcriptional regulatory activity of L1 RNA may partially result in cell transformation, and endogenous L1 RNA may function as an important regulatory factor in the process of tumorigenesis.

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“…91,92 More specifically, colorectal cancers with microsatellite stable (ie, lacking mismatch-repair deficiency) and Amsterdam Criteria positive were found to display a significantly lower degree of long interspersed element-1 methylation as compared with other patient groups, ie, Lynch syndrome with identified mismatch-repair mutations and sporadic colorectal cancers with or without microsatellite instability. Long interspersed element-1 comprises a substantial portion of the human genome and its methylation correlates with global methylation status.…”

Section: Familial Colorectal Cancer Type X Is Distinct From Lynch Synmentioning

confidence: 99%

“…Genomewide DNA hypomethylation has an important role in genomic instability and carcinogenesis. 91 Additionally, it was suggested that cancers characterized by long interspersed element-1 extreme hypomethylation constitute a previously unrecognized and distinct subtype of colorectal cancer. 92 In addition to young onset (consistent with familial predisposition), colorectal cancers characterized by long interspersed element-1 hypomethylation consistently exhibited a poor prognosis.…”

Section: Familial Colorectal Cancer Type X Is Distinct From Lynch Synmentioning

confidence: 99%

Gene discovery in familial cancer syndromes by exome sequencing: prospects for the elucidation of familial colorectal cancer type X

Cooper

et al. 2012

Modern Pathology

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Recent advances in genotyping and sequencing technologies have provided powerful tools with which to explore the genetic basis of both Mendelian (monogenic) and sporadic (polygenic) diseases. Several hundred genomewide association studies have so far been performed to explore the genetics of various polygenic or complex diseases including those cancers with a genetic predisposition. Exome sequencing has also proven very successful in elucidating the etiology of a range of hitherto poorly understood Mendelian disorders caused by high-penetrance mutations. Despite such progress, the genetic etiology of several familial cancers, such as familial colorectal cancer type X, has remained elusive. Familial colorectal cancer type X and Lynch syndrome are similar in terms of their fulfilling certain clinical criteria, but the former group is not characterized by germline mutations in DNA mismatch-repair genes. On the other hand, the genetics of sporadic colorectal cancer have been investigated by genome-wide association studies, leading to the identification of multiple new susceptibility loci. In addition, there is increasing evidence to suggest that familial and sporadic cancers exhibit similarities in terms of their genetic etiologies. In this review, we have summarized our current knowledge of familial colorectal cancer type X, discussed current approaches to probing its genetic etiology through the application of new sequencing technologies and the recruitment of the results of colorectal cancer genome-wide association studies, and explore the challenges that remain to be overcome given the uncertainty of the current genetic model (ie, monogenic vs polygenic) of familial colorectal cancer type X.

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Aberrant DNA Methylation in Hereditary Nonpolyposis Colorectal Cancer Without Mismatch Repair Deficiency

Cited by 93 publications

References 39 publications

Familial colorectal cancer type X: genetic profiles and phenotypic features

Familial colorectal cancer type X: genetic profiles and phenotypic features

Binding of LINE-1 RNA to PSF transcriptionally promotes GAGE6 and regulates cell proliferation and tumor formation in vitro

Gene discovery in familial cancer syndromes by exome sequencing: prospects for the elucidation of familial colorectal cancer type X

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