Oncogenic MAP2K1 mutations in human epithelial tumors

Choi, Young Lim; Soda, Manabu; Ueno, Toshihide; Hamada, Toru; Higashi, Hidenori; Yamato, Azusa; Fukumura, Kazutaka; Ando, Mizuo; Kawazu, Masahito; Yamashita, Yuichi; Mano, Hiroyuki

doi:10.1093/carcin/bgs099

Cited by 40 publications

(42 citation statements)

References 23 publications

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“…In this study, we identified MEK1 mutations in poorly differentiated gastric cancer cell lines that were hypersensitive to MEK inhibitors and showed that these mutations have transformational abilities and that the growth of the cancer cells is dependent on these mutations. Specifically, the MEK1 S72Q mutation in the Okajima cell line is a novel activating mutation, whereas the MEK1 Q56P mutation in the OCUM-1 cell line has been previously reported by Choi and colleagues (17). In addition, a MEK1 Q56P mutation was identified in a clinical sample of a poorly differentiated gastric cancer; to the best of our knowledge, this is the first study in which a clinical sample of a MEK1 Q56P-mutated gastric cancer has been identified.…”

Section: Discussionsupporting

confidence: 55%

“…In contrast, all cell lines that were not sensitive to MEK inhibitors did not have any mutations. The MEK1 Q56P mutation in the OCUM-1 cell line and the KRAS G12V mutation in the HSC-44 cell line have been previously reported (17), whereas the MEK1 S72G mutation in the Okajima cell line is a novel mutation. This novel mutation was confirmed using the TOPO TA Cloning Kit (Fig.…”

Section: Resultsmentioning

confidence: 83%

“…The discovery of mutations of the BRAF gene in melanoma has further reinforced the substantial contribution of the MAPK pathway to carcinogenesis (16). However, very limited information is available about somatic MEK1 mutations in human malignancies (17). In this study, we tested the effects of MEK inhibitors in several gastric cancer cell lines in vitro and found three cell lines that were hypersensitive to the inhibitors; one of these cell lines had a novel MEK1 S72G mutation.…”

Section: Introductionmentioning

confidence: 94%

“…The ethical procedures followed met the requirements of the United Kingdom Coordinating Committee on Cancer Research guidelines. To evaluate tumorigenicity, a suspension of 1 Â 10 6 NIH-3T3 transfectant cells (in 100 mL of PBS) was subcutaneously inoculated into the right flank of each nude mouse (n ¼ 5), and tumor formation was examined after 2 weeks based on a previous report (17). To evaluate the effects of GSK1120212, a suspension of 1 Â 10 7 cells (in 50 mL of PBS) with 50 mL of Matrigel (Okajima cell line) or 5 Â 10 6 cells (in 50 mL of PBS) with 50 mL of Matrigel (SNU-16 cell line) was subcutaneously inoculated into the right flank of each NOD/SCID mouse (n ¼ 5); treatment was then initiated when the tumors in each group achieved an average volume of approximately 150 mm 3 .…”

Section: Xenograft Studiesmentioning

confidence: 99%

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MEK Inhibitor for Gastric Cancer with MEK1 Gene Mutations

Sogabe

Togashi

Katô

et al. 2014

Molecular Cancer Therapeutics

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The prognosis for patients with unresectable advanced or recurrent gastric cancer remains poor. The identification of additional oncogenes with influences similar to those of epidermal growth factor receptor gene mutations, upon which the growth of cancer cells is dependent, is needed. In this study, we evaluated sensitivity to MEK inhibitors (GSK1120212 and PD0325901) in several gastric cancer cell lines in vitro and found three poorly differentiated gastric cancer cell lines that were hypersensitive to the inhibitors. The sequence analyses in these three cell lines revealed that one cell line had a novel MEK1 mutation, while the other two had previously reported KRAS and MEK1 mutations, respectively; the gene statuses of the other resistant cell lines were all wild-type. Experiments using MEK1 expression vectors demonstrated that the MEK1 mutations induced the phosphorylation of ERK1/2 and had a transforming potential, enhancing the tumorigenicity. The MEK inhibitor dramatically reduced the phosphorylation of ERK1/2 and induced apoptosis in the cell lines with MEK1 mutations. In vivo, tumor growth was also dramatically decreased by an inhibitor. One of the 46 gastric cancer clinical samples that were examined had a MEK1 mutation; this tumor had a poorly differentiated histology. Considering the addiction of cancer cells to active MEK1 mutations for proliferation, gastric cancer with such oncogenic MEK1 mutations might be suitable for targeted therapy with MEK inhibitors.

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Section: Discussionsupporting

confidence: 55%

Section: Resultsmentioning

confidence: 83%

Section: Introductionmentioning

confidence: 94%

Section: Xenograft Studiesmentioning

confidence: 99%

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MEK Inhibitor for Gastric Cancer with MEK1 Gene Mutations

Sogabe

Togashi

Katô

et al. 2014

Molecular Cancer Therapeutics

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“…numerous cellular and developmental processes. 18,19 The somatic mutations we identified cluster within or adjacent to the protein's negative regulatory domain ( Figure 2); they have been observed in neoplasms, including melanoma, lung cancer, and hematopoietic malignancies, [20][21][22][23][24][25] and have been shown to constitutively increase MEK1 activity. [26][27][28] MEK1 and its paralog MEK2 phosphorylate ERK1 and ERK2.…”

mentioning

confidence: 99%

Somatic MAP2K1 Mutations Are Associated with Extracranial Arteriovenous Malformation

Couto

Huang

Konczyk

et al. 2017

The American Journal of Human Genetics

221

171

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Arteriovenous malformation (AVM) is a fast-flow, congenital vascular anomaly that may arise anywhere in the body. AVMs typically progress, causing destruction of surrounding tissue and, sometimes, cardiac overload. AVMs are difficult to control; they often re-expand after embolization or resection, and pharmacologic therapy is unavailable. We studied extracranial AVMs in order to identify their biological basis. We performed whole-exome sequencing (WES) and whole-genome sequencing (WGS) on AVM tissue from affected individuals. Endothelial cells were separated from non-endothelial cells by immune-affinity purification. We used droplet digital PCR (ddPCR) to confirm mutations found by WES and WGS, to determine whether mutant alleles were enriched in endothelial or non-endothelial cells, and to screen additional AVM specimens. In seven of ten specimens, WES and WGS detected and ddPCR confirmed somatic mutations in mitogen activated protein kinase kinase 1 (MAP2K1), the gene that encodes MAP-extracellular signal-regulated kinase 1 (MEK1). Mutant alleles were enriched in endothelial cells and were not present in blood or saliva. 9 of 15 additional AVM specimens contained mutant MAP2K1 alleles. Mutations were missense or small in-frame deletions that affect amino acid residues within or adjacent to the protein's negative regulatory domain. Several of these mutations have been found in cancers and shown to increase MEK1 activity. In summary, somatic mutations in MAP2K1 are a common cause of extracranial AVM. The likely mechanism is endothelial cell dysfunction due to increased MEK1 activity. MEK1 inhibitors, which are approved to treat several forms of cancer, are potential therapeutic agents for individuals with extracranial AVM.Arteriovenous malformation (AVM) is a congenital vascular anomaly, comprised of abnormal connections between arteries and veins that are missing normal high-resistance capillary beds (Figure 1). 1 Sporadic extracranial AVMs are solitary and may be localized or regional. Rapid blood flow is demonstrable by Doppler ultrasonography. Magnetic resonance imaging reveals signal voids consistent with fast-flow, while angiography shows the early filling of draining veins (Figure 1). With time, arterial to venous shunting causes tissue ischemia that leads to pain, ulceration, bleeding, and destruction of adjacent tissues. Treatment for AVM has been discouraging. Embolization and/or resection are often followed by expansion; there are no drug treatments. 2 The purpose of this study was to identify the genetic basis for sporadic, extracranial AVM in an effort to devise a new therapeutic strategy.The Committee on Clinical Investigation at Boston Children's Hospital approved this study and informed consent was obtained from study participants. Ten AVM specimens that had been collected during a clinically indicated procedure, including matched unaffected tissue specimens from three of the study participants, had DNA extracted using the DNeasy Blood & Tissue Kit (QIAGEN); saliva DNA was extracted using the pr...

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The association of blood ctDNA levels to mutations of marker genes in colorectal cancer

Bai

Zou

et al. 2023

Cancer Reports

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Background Colorectal cancer (CRC) is a deadly and commonly diagnosed cancer. Cell‐free circulating tumor DNAs (ctDNA) have been used in the diagnosis and treatment of CRC, but there are open questions about the relationship between ctDNAs and CRC. Although mutations of genes detected by ctDNA in CRC have been studied, the quantitative relationship between ctDNA mutations and ctDNA concentration has not been addressed. Aims We hypothesized that there was an association between mutations of genes identified in ctDNAs and ctDNA concentration. His study examined this association in a population of CRC patients. Methods In 85 CRC patients, we sampled 282 mutations in 36 genes and conducted an association study based on a Random forest model between mutations and ctDNA concentrations in all patients. Results This association study showed that mutations on five genes, ALK, PMS2, KDR, MAP2K1, and MSH2, were associated with the ctDNA concentrations in CRC patients’ blood samples. Because ctDNA mutations correlate with ctDNA level, we can infer the tumor burden or tumor size from ctDNA mutations, as well as the survival time for prognosis. Conclusion Our findings shed light on the associations between mutations of genes identified in ctDNAs and ctDNA concentration in the blood of CRC patients. This discovery provides information regarding the tumor burden or tumor size based on ctDNA mutations.

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Oncogenic MAP2K1 mutations in human epithelial tumors

Cited by 40 publications

References 23 publications

MEK Inhibitor for Gastric Cancer with MEK1 Gene Mutations

MEK Inhibitor for Gastric Cancer with MEK1 Gene Mutations

Somatic MAP2K1 Mutations Are Associated with Extracranial Arteriovenous Malformation

The association of blood ctDNA levels to mutations of marker genes in colorectal cancer

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