Comprehensive DNA methylation and extensive mutation analyses reveal an association between the CpG island methylator phenotype and oncogenic mutations in gastric cancers

Kim, Jeong Goo; Takeshima, Hideyuki; Niwa, Tohru; Rehnberg, Emil; Shigematsu, Yasuyuki; Yoda, Yukie; Yamashita, Satoshi; Kushima, Ryoji; Maekita, Takao; Ichinose, Masakazu; Katai, Hitoshi; Park, Won Sang; Hong, Young Seon; Park, Cho Hyun; Ushijima, Toshikazu

doi:10.1016/j.canlet.2012.11.022

Cited by 57 publications

(48 citation statements)

References 54 publications

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“…This mutation has been described in both meningioma (44) and gastric carcinoma (45). In ameloblastoma, this missense mutation did not alter (SMARCB1) INI-1 staining.…”

Section: Discussionmentioning

confidence: 61%

Activating FGFR2–RAS–BRAF Mutations in Ameloblastoma

Brown¹,

Rolland²,

McHugh³

et al. 2014

Clinical Cancer Research

232

367

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Purpose: Ameloblastoma is an odontogenic neoplasm whose overall mutational landscape has not been well characterized. We sought to characterize pathogenic mutations in ameloblastoma and their clinical and functional significance with an emphasis on the mitogen-activated protein kinase (MAPK) pathway.Experimental Design: A total of 84 ameloblastomas and 40 non-ameloblastoma odontogenic tumors were evaluated with a combination of BRAF V600E allele-specific PCR, VE1 immunohistochemistry, the Ion AmpliSeq Cancer Hotspot Panel, and Sanger sequencing. Efficacy of a BRAF inhibitor was evaluated in an ameloblastoma-derived cell line.Results: Somatic, activating, and mutually exclusive RAS-BRAF and FGFR2 mutations were identified in 88% of cases. Somatic mutations in SMO, CTNNB1, PIK3CA, and SMARCB1 were also identified. BRAF V600E was the most common mutation, found in 62% of ameloblastomas and in ameloblastic fibromas/ fibrodentinomas but not in other odontogenic tumors. This mutation was associated with a younger age of onset, whereas BRAF wild-type cases arose more frequently in the maxilla and showed earlier recurrences. One hundred percent concordance was observed between VE1 immunohistochemistry and molecular detection of BRAF V600E mutations. Ameloblastoma cells demonstrated constitutive MAPK pathway activation in vitro. Proliferation and MAPK activation were potently inhibited by the BRAF inhibitor vemurafenib.Conclusions: Our findings suggest that activating FGFR2-RAS-BRAF mutations play a critical role in the pathogenesis of most cases of ameloblastoma. Somatic mutations in SMO, CTNNB1, PIK3CA, and SMARCB1 may function as secondary mutations. BRAF V600E mutations have both diagnostic and prognostic implications. In vitro response of ameloblastoma to a BRAF inhibitor suggests a potential role for targeted therapy. Clin Cancer Res; 20(21); 5517-26. Ó2014 AACR.

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“…This mutation has been described in both meningioma (44) and gastric carcinoma (45). In ameloblastoma, this missense mutation did not alter (SMARCB1) INI-1 staining.…”

Section: Discussionmentioning

confidence: 61%

Activating FGFR2–RAS–BRAF Mutations in Ameloblastoma

Brown¹,

Rolland²,

McHugh³

et al. 2014

Clinical Cancer Research

232

367

View full text Add to dashboard Cite

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“…This study revealed that the Wnt pathway was potentially activated by aberrant methylation of its negative regulators, such as Dkk-3, NKD1, Sox17, WIF-1 and sFRP1. Moreover, DNA methylation and extensive mutation analyses in gastric cancers revealed an association between the CpG island methylator phenotype and oncogenic mutations in CTNNB1, ERBB2, KRAS and PIK3CA [150] . Downregulation of Sox10 by promoter methylation has also been detected in gastric cancer tissues [112] .…”

Section: Loss Of Wnt Repressor Function In Gastric Cancermentioning

confidence: 99%

Role of the Wnt/β-catenin pathway in gastric cancer: An in-depth literature review

Chiurillo

2015

WJEM

261

219

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Gastric cancer remains one of the most common cancers worldwide and one of the leading cause for cancerrelated deaths. Gastric adenocarcinoma is a multifactorial disease that is genetically, cytologically and architecturally more heterogeneous than other gastrointestinal carcinomas. The identification of specific membrane, intracellular, and extracellular components of the Wnt pathway has revealed potential targets for gastric cancer therapy. High-throughput "omics" approaches will help in the search for Wnt pathway antagonist in the near future.

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“…A total of 56 primary GC samples (32 intestinal type and 24 diffuse type) were collected from surgical specimens of patients who had undergone gastrectomy, and 30 of the samples were used for our previous studies [1,16]. Genome-wide DNA methylation and TP53 mutation data of the 30 GCs were obtained from one of the studies [1].…”

Section: Gc Cell Lines and Tissue Samplesmentioning

confidence: 99%

“…Genome-wide DNA methylation and TP53 mutation data of the 30 GCs were obtained from one of the studies [1]. Peripheral leukocyte samples were collected from five healthy volunteers by a centrifugation method.…”

Section: Gc Cell Lines and Tissue Samplesmentioning

confidence: 99%

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Establishment of a DNA methylation marker to evaluate cancer cell fraction in gastric cancer

Zong

Hattori²,

Yoda³

et al. 2015

Gastric Cancer

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Background Tumor samples are unavoidably contaminated with coexisting normal cells. Here, we aimed to establish a DNA methylation marker to estimate the fraction of gastric cancer (GC) cells in any DNA sample by isolating genomic regions specifically methylated in GC cells. Methods Genome-wide and gene-specific methylation analyses were conducted with an Infinium HumanMethylation450 BeadChip array and by quantitative methylationspecific PCR, respectively. Purified cancer and noncancer cells were prepared by laser-capture microdissection. TP53 mutation data were obtained from our previous study using next-generation target sequencing. Results Genome-wide DNA methylation analysis of 12 GC cell lines, 30 GCs, six normal gastric mucosae, one sample of peripheral leukocytes, and four noncancerous gastric mucosae identified OSR2, PPFIA3, and VAV3 as barely methylated in normal cells and highly methylated in cancer cells. Quantitative methylation-specific PCR using 26 independent GCs validated that one or more of them was highly methylated in all of the GCs. Using four pairs of purified cells, we confirmed the three genes were highly methylated (85 % or more) in cancer cells and barely methylated (5 % or less) in noncancer cells. The cancer cell fraction assessed by the panel of the three genes showed good correlation with that assessed by the TP53 mutant allele frequency in 13 GCs (r = 0.77). After correction of the GC cell fraction, unsupervised clustering analysis of the genome-wide DNA methylation profiles yielded clearer clustering. Conclusions A DNA methylation marker-namely, the panel of the three genes-is useful to estimate the cancer cell fraction in GCs.

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Comprehensive DNA methylation and extensive mutation analyses reveal an association between the CpG island methylator phenotype and oncogenic mutations in gastric cancers

Cited by 57 publications

References 54 publications

Activating FGFR2–RAS–BRAF Mutations in Ameloblastoma

Activating FGFR2–RAS–BRAF Mutations in Ameloblastoma

Role of the Wnt/β-catenin pathway in gastric cancer: An in-depth literature review

Establishment of a DNA methylation marker to evaluate cancer cell fraction in gastric cancer

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