KRAS, BRAF oncogene mutations and tissue specific promoter hypermethylation of tumor suppressor SFRP2, DAPK1, MGMT, HIC1 and p16 genes in colorectal cancer patients

Bağcı, Binnur; Sari, Musa; Karadayı, Kürşat; Turan, Mustafa; Özdemir, Öztürk; Bağci, Gökhan

doi:10.3233/cbm-160624

Cited by 30 publications

(20 citation statements)

References 49 publications

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“…However, hormone replacement therapy does not significantly affect PGR methylation [48], and the protective effect of hormone replacement therapy may be due to oestrogen receptor rather than progesterone receptor function. HIC1 has been investigated mainly as part of a CIMP panel [49], but its methylation is not associated with clinicopathologic features [50]. EN1 methylation is also not associated with clinicopathologic features [51].…”

Section: Discussionmentioning

confidence: 99%

DNA methylation changes that precede onset of dysplasia in advanced sessile serrated adenomas

et al. 2019

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Background Sessile serrated adenomas (SSAs) are common polyps which give rise to 20–30% of colorectal cancer (CRC). SSAs display clinicopathologic features which present challenges in surveillance, including overrepresentation in young patients, proclivity for the proximal colon and rarity of histologic dysplasia (referred to then as SSAs with dysplasia, SSADs). Once dysplasia develops, there is rapid progression to CRC, even at a small size. There is therefore a clinical need to separate the “advanced” SSAs at high risk of progression to SSAD and cancer from ordinary SSAs. Since SSAs are known to accumulate methylation over time prior to the development of dysplasia, SSAD backgrounds (the remnant SSA present within an SSAD) likely harbour additional methylation events compared with ordinary SSAs. We therefore performed MethyLight and comprehensive methylation array (Illumina MethylationEPIC) on 40 SSAD backgrounds and 40 matched ordinary SSAs, and compared the methylation results with CRC methylation, CRC expression and immunohistochemical data. Results SSAD backgrounds demonstrated significant hypermethylation of CpG islands compared with ordinary SSAs, and the proportion of hypermethylated probes decreased progressively in the shore, shelf and open sea regions. Hypomethylation occurred in concert with hypermethylation, which showed a reverse pattern, increasing progressively away from the island regions. These methylation changes were also identified in BRAF -mutant hypermethylated CRCs. When compared with CRC expression data, SV2B , MLH1 / EPM2AIP1 , C16orf62 , RCOR3 , BAIAP3 , OGDHL , HDHD3 and ATP1B2 demonstrated both promoter hypermethylation and decreased expression. Although SSAD backgrounds were histologically indistinguishable from ordinary SSAs, MLH1 methylation was detectable via MethyLight in 62.9% of SSAD backgrounds, and focal immunohistochemical MLH1 loss was seen in 52.5% of SSAD backgrounds. Conclusions Significant hyper- and hypomethylation events occur during SSA progression well before the development of histologically identifiable changes. Methylation is a heterogeneous process within individual SSAs, as typified by MLH1 , where both MLH1 methylation and focal immunohistochemical MLH1 loss can be seen in the absence of dysplasia. This heterogeneity is likely a generalised phenomenon and should be taken into account in future methylation-based studies and the development of clinical methylation panels. Electronic supplementary material The online version of this article (10.1186/s13148-019-0691-4) contains supplementary material, which is avail...

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Section: Discussionmentioning

confidence: 99%

DNA methylation changes that precede onset of dysplasia in advanced sessile serrated adenomas

et al. 2019

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“…As a WNT signaling-associated EMT modulator, SFRP2 is down-regulated in various malignancies due to the promoter hypermethylation 21. Typically, the methylation status of SFRP2 gene is a tumor-specific epigenetic marker in human breast cancer and CRC,22,23 which may play a central role in the chemoprevention of CRC 24. Besides, it is also the critical paracrine factor released by the AKT-mesenchymal stem, which can mediate myocardial survival and repair 25.…”

Section: Discussionmentioning

confidence: 99%

<p>A novel LARCassigner3 classification predicts outcomes in patients with locally advanced rectal cancer treated with neoadjuvant chemoradiotherapy: a retrospective training and validation analysis</p>

Zhang¹,

Shen²,

Deng³

et al. 2019

CMAR

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Purpose: To build and validate a predictive model of outcome for patients with locally advanced rectal cancer (LARC) treated with neoadjuvant chemoradiotherapy. Materials and methods: We developed a LARCassigner3 classifier based on tumor and paired normal tissues of patients treated with neoadjuvant chemoradiation and surgery from January 2007 to December 2012 in Fudan University Shanghai Cancer Center. Excluding 23 pairs of tissues failed in the RNA quality test, rested 197 patients were divided into discovery (n=98) and validation (n=99) cohorts randomly. Median follow-up time was 58 months. We used the Kaplan–Meier method to estimate disease-free survival (DFS), overall survival (OS), local recurrent, and distant metastatic rate We constructed a multivariate Cox model to identify the variables independently associated with progression-free and OS. Results: We identified three classifier genes related to relevant colorectal cancer features (CXCL9, SFRP2, and CD44) that formed the LARCassigner3 classifier assay. In the discovery set, the median DFS was 48.1 months (95% confidence interval (CI) 47.3–49.5) in the low-risk group and 23.4 months (95% CI 22.1–24.8) in the high-risk group ( p =0.0134); the median OS was 39.2 months (95% CI 38.4–40.3) in the high-risk group and 19.1 months (95% CI 18.3–20.7) in the low-risk group ( p =0.0134); 5-year distant metastasis was 13.9% (95% CI 9.0–21.3) in the low-risk group and 49.8% (95% CI 38.7–60.9) in the high-risk group ( p =0.0072). Additionally, the different responses to neoadjuvant chemoradiotherapy and the LARCassigner3 low-risk and high-risk groups was statistically significant ( p =0.004) in the discovery cohort. Similar results were obtained in the internal evaluation cohort. Conclusions: Patients with LARCassigner3 low-risk tumors were associated with a good prognosis. The clinical utility of using LARCassigner3 subtyping for the identification of patients for neoadjuvant chemoradiotherapy requires validation in dependent clinical trial cohorts.

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“…DAPK1 acts as a tumor suppressor to play a rate-limiting effector in an endoplasmic reticulum (ER) stress-dependent apoptotic pathway [23]. Its expression is epigenetically suppressed in several tumors [24]. Lee et al [10] reported that DAPK1 acts as a kinase responsible for the phosphorylation of Pin 1 on Ser71 in the catalytic active site.…”

Section: Discussionmentioning

confidence: 99%

“…DAPK1 acts as a tumor suppressor to play a rate‐limiting effector in an endoplasmic reticulum (ER) stress‐dependent apoptotic pathway . Its expression is epigenetically suppressed in several tumors . Lee et al.…”

Section: Discussionmentioning

confidence: 99%

BCR‐ABL enhances the prolyl isomerase activity of Pin 1 by interacting with DAPK1 in ph⁺ALL

Cao

Feng

et al. 2018

Cancer Medicine

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Philadelphia chromosome (Ph)/BCR‐ABL‐positive (ph+) ALL is the most common genetic abnormality associated with ALL and has been shown to confer the worst prognosis to both children and adults. Increasing evidence has revealed that the dysregulation of prolyl isomerase Pin 1 contributes to multicancer development and progression, including ALL, although the underlying molecular mechanisms remain unclear. Here, we report that the expression of Pin 1 was enhanced in ph+ ALL patient samples and was associated positively with the expression of BCR‐ABL. Genetically or pharmacologically inhibiting Pin 1 expression or activity produces potent therapeutic efficacy against ph+ ALL. We further demonstrated that BCR‐ABL enhances the prolyl isomerase activity of Pin 1 by decreasing the phosphorylated level of Pin 1 at Ser 71 and interacting with DAPK1. The inhibition of BCR‐ABL activity by imatinib in human ph+ ALL cells reduces the prolyl isomerase activity of Pin 1, further suggesting a key role of the newly identified BCR‐ABL‐Pin 1 axis in ph+ ALL progression. Thus, the combined suppression of Pin 1 and BCR‐ABL proteins may be exploited as an additional target therapy for ph+ ALL.

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KRAS, BRAF oncogene mutations and tissue specific promoter hypermethylation of tumor suppressor SFRP2, DAPK1, MGMT, HIC1 and p16 genes in colorectal cancer patients

Abstract: Results of the current study have confirmed that KRAS mutations and SFRP2 hypermethylation can be used as genetic markers in colorectal cancer.

Cited by 30 publications

References 49 publications

DNA methylation changes that precede onset of dysplasia in advanced sessile serrated adenomas

DNA methylation changes that precede onset of dysplasia in advanced sessile serrated adenomas

<p>A novel LARCassigner3 classification predicts outcomes in patients with locally advanced rectal cancer treated with neoadjuvant chemoradiotherapy: a retrospective training and validation analysis</p>

BCR‐ABL enhances the prolyl isomerase activity of Pin 1 by interacting with DAPK1 in ph⁺ALL

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KRAS, BRAF oncogene mutations and tissue specific promoter hypermethylation of tumor suppressor SFRP2, DAPK1, MGMT, HIC1 and p16 genes in colorectal cancer patients

Abstract: Results of the current study have confirmed that KRAS mutations and SFRP2 hypermethylation can be used as genetic markers in colorectal cancer.

Cited by 30 publications

References 49 publications

DNA methylation changes that precede onset of dysplasia in advanced sessile serrated adenomas

DNA methylation changes that precede onset of dysplasia in advanced sessile serrated adenomas

<p>A novel LARCassigner3 classification predicts outcomes in patients with locally advanced rectal cancer treated with neoadjuvant chemoradiotherapy: a retrospective training and validation analysis</p>

BCR‐ABL enhances the prolyl isomerase activity of Pin 1 by interacting with DAPK1 in ph+ALL

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BCR‐ABL enhances the prolyl isomerase activity of Pin 1 by interacting with DAPK1 in ph⁺ALL