A Cohort Study of Tumoral LINE-1 Hypomethylation and Prognosis in Colon Cancer

Ogino, Shuji; Nosho, Katsuhiko; Kirkner, Gregory J.; Kawasaki, Takako; Chan, Andrew T.; Schernhammer, Eva; Giovannucci, Edward; Fuchs, Charles S.

doi:10.1093/jnci/djn359

Cited by 339 publications

(302 citation statements)

References 46 publications

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“…These results are consistent with earlier observations that a reduction in global methylcytosine content is associated with malignant potential in cancer, and that it is especially prevalent in metastatic tumors (34). LINE-1 hypomethylation is also reportedly associated with poor prognosis in prostate (17), colon (35), and ovarian (36) cancers and in chronic myeloid leukemia (11). In normal cells, DNA methylation plays important roles in X-chromosome inactivation, genomic imprinting, and repression of repetitive elements, such as retrotransposons and endogenous retroviruses.…”

Section: Discussionsupporting

confidence: 92%

A Novel Correlation between LINE-1 Hypomethylation and the Malignancy of Gastrointestinal Stromal Tumors

Igarashi

Suzuki

Niinuma

et al. 2010

Clinical Cancer Research

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Purpose: Gastrointestinal stromal tumors (GIST) are the most important mesenchymal tumors of the gastrointestinal tract. The vast majority of GISTs exhibit activating mutations of KIT or PDGFRA, but epigenetic alteration of GISTs is largely unknown. In this study, we aimed to clarify the involvement of DNA methylation in GIST malignancy.Experimental Design: A total of 106 GIST specimens were studied. Levels of LINE-1 methylation were analyzed using bisulfite pyrosequencing. In addition, methylation of three other repetitive sequences (Alu Yb8, Satellite-α, and NBL2) was similarly analyzed, and CpG island hypermethylation was analyzed using MethyLight. Array-based comparative genomic hybridization (array CGH) was carried out in 25 GIST specimens.Results: LINE-1 hypomethylation was significantly correlated with risk, and high-risk GISTs exhibited significantly lower levels of LINE-1 methylation than low-risk (61.3% versus 53.2%; P = 0.001) or intermediate-risk GISTs (60.8% versus 53.2%; P = 0.002). Hypomethylation of Satellite-α and NBL2 was also observed in high-risk GISTs. By contrast, promoter hypermethylation was relatively infrequent (CDH1, 11.2%; MLH1, 9.8%; SFRP1, 1.2%; SFRP2, 11.0%; CHFR, 9.8%; APC, 6.1%; CDKN2A, 0%; RASSF1A, 0%; RASSF2, 0%) and did not correlate with LINE-1 methylation or risk. Array CGH analysis revealed a significant correlation between LINE-1 hypomethylation and chromosomal aberrations.Conclusions: Our data suggest that LINE-1 hypomethylation correlates significantly with the aggressiveness of GISTs and that LINE-1 methylation could be a useful marker for risk assessment. Hypomethylation may increase the malignant potential of GISTs by inducing accumulation of chromosomal aberrations. Clin Cancer Res; 16(21); 5114-23. ©2010 AACR.

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Section: Discussionsupporting

confidence: 92%

A Novel Correlation between LINE-1 Hypomethylation and the Malignancy of Gastrointestinal Stromal Tumors

Igarashi

Suzuki

Niinuma

et al. 2010

Clinical Cancer Research

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“…92 In addition to young onset (consistent with familial predisposition), colorectal cancers characterized by long interspersed element-1 hypomethylation consistently exhibited a poor prognosis. 93,94 Taken together, these findings further suggest molecular heterogeneity of familial colorectal cancer type X, with several possible molecular subtypes.…”

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

confidence: 52%

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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“…The L1 methylation level has been shown to decrease in gastric epithelial cells with the progression of the lesion along the multistep gastric carcinogenesis, although there are wide variations in L1 methylation levels in gastric cancers (GCs) [7,8]. Low L1 methylation status has been demonstrated to be closely associated with shorter survival of the cancer patient, not only for GCs [7,8] but also for colon cancers [9], rectal cancers [10], esophageal squamous cell carcinomas [11], and lung adenocarcinomas [12,13].…”

Section: Introductionmentioning

confidence: 99%

Methylation status of long interspersed element-1 in advanced gastric cancer and its prognostic implication

et al. 2015

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Backgrounds Reportedly, the pyrosequencing methylation assay can produce inconsistent results between paired snap-frozen and formalin-fixed paraffin-embedded archival tissue samples. In this study, we assayed the methylation levels at four individual CpG sites of L1 using pyrosequencing and found that the methylation levels at individual CpG sites were different but were closely correlated between paired snap-frozen and formalin-fixed paraffinembedded tissue samples. We aimed to determine whether low methylation status of L1 is associated with gastric cancer patient prognosis. Methods We analyzed 434 formalin-fixed paraffinembedded tissue samples of advanced gastric cancer for their methylation status at four CpG sites of L1 [nucleotide positions 328, 321, 318, and 306 of X58075 (Genbank)] using pyrosequencing, and correlated the L1 methylation level with clinicopathological features.Results Older age at onset, males, tumor location at antrum or lower body, intestinal type, and lymphatic or venous invasion were associated with a low average methylation level of L1 at the two CpG sites 1 and 4 combined. The average methylation level of L1 at CpG sites 1 and 4 combined was significantly lower in microsatellite-stable and EBV-negative gastric cancers than in EBV-positive or microsatellite-unstable gastric cancers. Low methylation status of L1 was independently correlated with shorter overall survival and disease-free survival time. Conclusion Our findings indicate that the discrepancy in the methylation level of L1 between fresh tissue and formalin-fixed paraffin-embedded tissue samples depends on the CpG sites considered, and that the methylation status of L1 at CpG sites 1 and 4 combined could be utilized as a prognostic parameter for advanced gastric cancers.

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A Cohort Study of Tumoral LINE-1 Hypomethylation and Prognosis in Colon Cancer

Cited by 339 publications

References 46 publications

A Novel Correlation between LINE-1 Hypomethylation and the Malignancy of Gastrointestinal Stromal Tumors

A Novel Correlation between LINE-1 Hypomethylation and the Malignancy of Gastrointestinal Stromal Tumors

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

Methylation status of long interspersed element-1 in advanced gastric cancer and its prognostic implication

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