A KRAS-directed transcriptional silencing pathway that mediates the CpG island methylator phenotype

Serra, Ryan W.; Mao, Fang; Park, Sung Mi; Hutchinson, Lloyd; Green, Michael R.

doi:10.7554/elife.02313

Cited by 149 publications

(157 citation statements)

References 58 publications

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“…Another interesting recent study (48) concludes that approximately 70% of KRAS-positive tumors are thought to have a CIMP characterized by aberrant methylation of the DNA of multiple genes, including p14, p15, p16. Therefore, this could be used as a link between KRAS status and p16 expression, especially in different stages of the cancer pathway.…”

Section: Discussionmentioning

confidence: 99%

KRAS Mutant Status, p16 and β-catenin Expression May Predict Local Recurrence in Patients Who Underwent Transanal Endoscopic Microsurgery (TEMS) for Stage I Rectal Cancer

Sideris

Moorhead

Díaz‐Cano

et al. 2016

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Abstract. Background The method of local excision, that has recently, gained wider acceptance, in early rectal cancer, is transanal endoscopic microsurgery (TEMS). TEMS generally offers advantages in operative access and oncological clearance over transanal resection (TAR), but recently a number of similar logic techniques with various rectal ports for endoscopic excision of rectal tumours has been invented. Those methods are collectively named transanal minimal-invasive surgery (TAMIS) and for oncological purposes they share the same features of local excision as TEMS (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14).TEMS is a minimally invasive technique that was introduced by Buess in the early 1980's (2). Through the new rectoscope with 3D binocular optic and the endoscopic instruments, it offers better access to proximal lesions with lower margin positivity and fragmentation and magnification of the operative field (2, 15). TEMS is a safe procedure that offers low complication rates and peri-operative morbidity (10.7%) (4). There have been multiple studies to suggest that TEMS is the operation of choice for rectal adenomas (1), retrorectal and submucosal rectal lesions (5). Furthermore, TEMS offers the advantage of not damaging the anorectal function (7).TEMS is indicated as a curative treatment for malignant neoplasms that are histologically confirmed as pT1 sm1 carcinomas, whereas T1 sm2-3 and T2 lesions are still under question (8). A number of studies have shown that TEMS can have comparable results with radical surgery (1,8,12,16) for rectal cancer.There has been concern about oncologic outcomes following TEMS (17). Some studies support that there is potentially a higher risk of local recurrence rate with TEMS (8,10,18). Efforts have been made to classify risk with morphological and histological criteria with better patients' selection (1, 6-9); however, the risk stratification remains 5315

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Section: Discussionmentioning

confidence: 99%

KRAS Mutant Status, p16 and β-catenin Expression May Predict Local Recurrence in Patients Who Underwent Transanal Endoscopic Microsurgery (TEMS) for Stage I Rectal Cancer

Sideris

Moorhead

Díaz‐Cano

et al. 2016

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“…So far, more than 30 genes have been shown to be required to establish RAS-mediated CIMP, many of which seem to act in a tissue-specific manner. The most recurrently identified genes in this context are DNMTs, EED, EZH2, and BMI1 [16][17][18]45 .…”

Section: Discussionmentioning

confidence: 99%

“…However, the affected RAS pathway gene alone does not fully explain clinical outcome. Evidence from the literature suggests that oncogenic RAS-signaling is able to modify epigenetic patterns [16][17][18] . Indeed, investigations of DNA methylation in JMML at the level of candidate gene promoters (AKAP12, BMP4, CALCA, CDKN2A, RARB, and RASA4) identified DNA hypermethylation to be associated with poor clinical outcome [19][20][21] .…”

mentioning

confidence: 99%

Ras-pathway mutation patterns define epigenetic subclasses in juvenile myelomonocytic leukemia

Lipka

Witte

Tóth

et al. 2017

Experimental Hematology

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Juvenile myelomonocytic leukemia (JMML) is an aggressive myeloproliferative disorder of early childhood characterized by mutations activating RAS signaling. Established clinical and genetic markers fail to fully recapitulate the clinical and biological heterogeneity of this disease. Here we report DNA methylome analysis and mutation profiling of 167 JMML samples. We identify three JMML subgroups with unique molecular and clinical characteristics. The high methylation group (HM) is characterized by somatic PTPN11 mutations and poor clinical outcome. The low methylation group is enriched for somatic NRAS and CBL mutations, as well as for Noonan patients, and has a good prognosis. The intermediate methylation group (IM) shows enrichment for monosomy 7 and somatic KRAS mutations. Hypermethylation is associated with repressed chromatin, genes regulated by RAS signaling, frequent co-occurrence of RAS pathway mutations and upregulation of DNMT1 and DNMT3B, suggesting a link between activation of the DNA methylation machinery and mutational patterns in JMML.

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“…If however, the status of A maps to the B locus, or to the heterochromatin, or even to the nucleoplasm, then there is no reason (and in fact no justification) to claim that A's expression state is epigenetic. It is likely instead controlled, through well-understood mechanisms, e.g., by the presence of another factor (Ptashne 2013;Serra et al 2014;Struhl 2014). In these cases, there is nothing meaningfully "dependent" about the "sequence" of A in terms of its regulation.…”

Section: The Test(s)mentioning

confidence: 99%

What Do You Mean, “Epigenetic”?

2015

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Interest in the field of epigenetics has increased rapidly over the last decade, with the term becoming more identifiable in biomedical research, scientific fields outside of the molecular sciences, such as ecology and physiology, and even mainstream culture. It has become increasingly clear, however, that different investigators ascribe different definitions to the term. Some employ epigenetics to explain changes in gene expression, others use it to refer to transgenerational effects and/or inherited expression states. This disagreement on a clear definition has made communication difficult, synthesis of epigenetic research across fields nearly impossible, and has in many ways biased methodologies and interpretations. This article discusses the history behind the multitude of definitions that have been employed since the conception of epigenetics, analyzes the components of these definitions, and offers solutions for clarifying the field and mitigating the problems that have arisen due to these definitional ambiguities.

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A KRAS-directed transcriptional silencing pathway that mediates the CpG island methylator phenotype

Cited by 149 publications

References 58 publications

KRAS Mutant Status, p16 and β-catenin Expression May Predict Local Recurrence in Patients Who Underwent Transanal Endoscopic Microsurgery (TEMS) for Stage I Rectal Cancer

KRAS Mutant Status, p16 and β-catenin Expression May Predict Local Recurrence in Patients Who Underwent Transanal Endoscopic Microsurgery (TEMS) for Stage I Rectal Cancer

Ras-pathway mutation patterns define epigenetic subclasses in juvenile myelomonocytic leukemia

What Do You Mean, “Epigenetic”?

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