Aristaless-like Homeobox-4 Gene Methylation Is a Potential Marker for Colorectal Adenocarcinomas

Ebert, Matthias; Model, Fabian; Mooney, Suzanne; Hale, Kari; Lograsso, Joe; Tonnes-Priddy, Lori; Hoffmann, Juliane; Csepregi, A.; Röcken, Christoph; Molnár, Béla; Schulz, H.-U.; Malfertheiner, Peter; Lofton–Day, Catherine

doi:10.1053/j.gastro.2006.08.034

Cited by 107 publications

(94 citation statements)

References 30 publications

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“…In the present study, neither BRAF nor K-ras mutations proved to be complementary to the most informative single methylation marker for tumor detection sensitivity. Recently, vimentin, ALX4, and BMP3 have been found to be methylated in colorectal cancer (9,15,19,54), and the present study extends and corroborates these findings. Vimentin has been evaluated as a candidate stool marker, alone (9) and in combination with other markers (14), and has proved to be informative for colorectal neoplasia.…”

Section: Discussionsupporting

confidence: 88%

“…Methylated genes have been detected in the blood and stool of patients with colorectal cancer and proposed as candidate screening markers (8,9,11,(14)(15)(16)(17)(18)(19)(20). In this study, we found four genes, BMP3, EYA2, ALX4, and vimentin, to be methylated in the majority of both colorectal cancers and premalignant adenomas.…”

Section: Discussionmentioning

confidence: 58%

“…Several methylated genes have been detected in the stool and serum/plasma samples from colorectal cancer patients (8,9,11,14,(16)(17)(18)(19)(20). Whereas some methylated genes have been found in a majority of colorectal cancers, the yield of bodily fluid -based assays remains suboptimal (8)(9)(10)(11)(13)(14)(15)(16)(17)(18)(19)(20).…”

Section: Introductionmentioning

confidence: 99%

“…Whereas some methylated genes have been found in a majority of colorectal cancers, the yield of bodily fluid -based assays remains suboptimal (8)(9)(10)(11)(13)(14)(15)(16)(17)(18)(19)(20). It is unclear as to what extent biological or technical factors account for such observations.…”

Section: Introductionmentioning

confidence: 99%

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Highly Methylated Genes in Colorectal Neoplasia: Implications for Screening

Zou

Harrington

Shire

et al. 2007

Cancer Epidemiology, Biomarkers &Amp; Prevention

113

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Discriminant markers are required for accurate cancer screening. We evaluated genes frequently methylated in colorectal neoplasia to identify the most discriminant ones. Four genes specifically methylated in colorectal cancer [bone morphogenetic protein 3 (BMP3), EYA2, aristaless-like homeobox-4 (ALX4), and vimentin] were selected from 41 candidate genes and evaluated on 74 cancers, 62 adenomas, and 70 normal epithelia. Methylation status was analyzed qualitatively and quantitatively and confirmed by bisulfite genomic sequencing. Effect of methylation on gene expression was evaluated in five colon cancer cell lines. K-ras and BRAF mutations were detected by sequencing. Methylation of BMP3, EYA2, ALX4, or vimentin was detected respectively in 66%, 66%, 68%, and 72% of cancers; 74%, 48%, 89%, and 84% of adenomas; and 7%, 5%, 11%, and 11% of normal epithelia (P < 0.01, cancer or adenoma versus normal). Based on area under the curve analyses, discrimination was not significantly improved by combining markers. Comethylation was frequent (two genes or more in 72% of cancers and 84% of adenomas), associated with proximal neoplasm site (P < 0.001), and linked with both BRAF and K-ras mutations (P < 0.01). Cell line experiments supported silencing of expression by methylation in all four study genes. This study shows BMP3, EYA2, ALX4, and vimentin genes are methylated in most colorectal neoplasms but rarely in normal epithelia. Comethylation of these genes is common, and pursuit of complementary markers for methylation-negative neoplasms is a rational strategy to optimize screening sensitivity. (Cancer Epidemiol Biomarkers Prev 2007;16(12):2686 -96)

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Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 58%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Highly Methylated Genes in Colorectal Neoplasia: Implications for Screening

Zou

Harrington

Shire

et al. 2007

Cancer Epidemiology, Biomarkers &Amp; Prevention

113

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“…Bisulfite treatment and methylation specific polymerase chain reaction (PCR) are the two most commonly used techniques. A blood biomarker with a high sensitivity and specificity for CRC can not only be used to segregate high-risk patients for further clinical tests but also be an excellent tool for monitoring CRC recurrence in patients who have undergone tumor resection (Table 1) [20][21][22][23][24][25][26][27][28][29][30] .…”

Section: Biomarkers Of Dna Methylation In Bloodmentioning

confidence: 99%

Advances in epigenetic biomarker research in colorectal cancer

Kuang

2014

WJG

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Colorectal cancer (CRC) causes approximately 600000 deaths annually and is the third leading cause of cancer mortality worldwide. Despite significant advancements in treatment options, CRC patient survival is still poor owing to a lack of effective tools for early diagnosis and a limited capacity for optimal therapeutic decision making. Since there exists a need to find new biomarkers to improve diagnosis of CRC, the research on epigenetic biomarkers for molecular diagnostics encourages the translation of this field from the bench to clinical practice. Epigenetic alterations are thought to hold great promise as tumor biomarkers. In this review, we will primarily focus on recent advances in the study of epigenetic biomarkers for colorectal cancer and discuss epigenetic biomarkers, including DNA methylation, microRNA expression and histone modification, in cancer tissue, stool, plasma, serum, cell lines and xenografts. These studies have improved the chances that epigenetic biomarkers will find a place in the clinical practices of screening, early diagnosis, prognosis, therapy choice and recurrence surveillance for CRC patients. However, these studies have typically been small in size, and evaluation at a larger scale of well-controlled randomized clinical trials is the next step that is necessary to increase the quality of epigenetic biomarkers and ensure their widespread clinical use.

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Protein phosphorylation and kinome profiling reveal altered regulation of multiple signaling pathways in B lymphocytes from patients with systemic lupus erythematosus

Taher¹,

Parikh²,

Flores-Borja³

et al. 2010

Arthritis & Rheumatism

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Objective. The cause of B lymphocyte hyperactivity and autoantibody production in systemic lupus erythematosus (SLE) remains unclear. Previously, we identified abnormalities in the level and translocation of signaling molecules in B cells in SLE patients. The present study was undertaken to examine the extent of signaling abnormalities that relate to altered B cell responses in SLE.Methods. B lymphocytes from 88 SLE patients and 72 healthy controls were isolated from blood by negative selection. Protein tyrosine phosphorylation and cellular kinase levels were analyzed by Western blotting, flow cytometry, and a kinome array protocol. Changes in protein phosphorylation were determined in ex vivo B cells and following B cell receptor engagement.Results. Differences in tyrosine phosphorylation in B cells from patients with SLE, compared with matched controls, were demonstrated. Further, the kinome array analysis identified changes in the activation of key kinases, i.e., the activity of phosphatidylinositol 3-kinase, which regulates survival and differentiation, was up-regulated and the activity of Rac and Rho kinases, which regulate the cytoskeleton and migration, was increased. In contrast, the activity of ATR, which regulates the cell cycle, was down-regulated in SLE patients compared with controls. Differences in signaling pathways were seen in all SLE B lymphocyte subsets that manifested phenotypic features of immature, mature, and memory cells. Conclusion. This study revealed dysregulation in multiple signaling pathways that control key responses in B cells of SLE patients. Data generated in this study provide a molecular basis for further analysis of the altered B lymphocyte responses in SLE.Systemic lupus erythematosus (SLE) has many features of immunologic abnormality, including dysregulated T and B lymphocyte responses and production of autoantibodies (1,2). The etiology of SLE remains unknown, but the available evidence indicates that its pathogenesis involves genetic, hormonal, and environmental factors (3). SLE immunopathology involves almost all immune system compartments, but a major role of B lymphocytes in the disease process has been established (4). B cells produce pathogenic autoantibodies and disease-promoting cytokines and activate autoreactive T cells (4). The therapeutic use of B celltargeted anti-CD20 antibodies has proved to be effective (5), thus strengthening the rationale that B cells play a key role in SLE.How autoreactive B cell responses are triggered, however, remains unclear. It is not known whether the induction of autoreactive B cells is due to intrinsic factors, autoreactive T lymphocytes, or altered self antigens (6-8). Structural and genetic studies of antidouble-stranded DNA (anti-dsDNA) autoantibodies in SLE suggest that they are T lymphocyte driven (9). However, studies in murine lupus suggest that antidsDNA autoantibodies could be produced as a result of

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Aristaless-like Homeobox-4 Gene Methylation Is a Potential Marker for Colorectal Adenocarcinomas

Cited by 107 publications

References 30 publications

Highly Methylated Genes in Colorectal Neoplasia: Implications for Screening

Highly Methylated Genes in Colorectal Neoplasia: Implications for Screening

Advances in epigenetic biomarker research in colorectal cancer

Protein phosphorylation and kinome profiling reveal altered regulation of multiple signaling pathways in B lymphocytes from patients with systemic lupus erythematosus

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