Comparison of Akt/mTOR/4E-BP1 pathway signal activation and mutations of PIK3CA in Merkel cell polyomavirus–positive and Merkel cell polyomavirus–negative carcinomas

Iwasaki, Takeshi; Matsushita, Michiko; Nonaka, Daisuke; Kuwamoto, Satoshi; Kato, Masako; Murakami, Ichiro; Nagata, Kazuhiro; Nakajima, Hideki; Sano, Shigetoshi; Hayashi, Kazuhiko

doi:10.1016/j.humpath.2014.07.025

Cited by 27 publications

(23 citation statements)

References 20 publications

(32 reference statements)

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“…17,18 Our previous studies showed some clinicopathological differences between MCPyV-positive and -negative MCCs; MCPyV-positive MCCs showed a signifi cantly higher expression of retinoblastoma protein and less p53 expression compared to MCPyV-negative MCCs, and frequency of TP53 non-ultraviolet signature mutation was signifi cantly higher in MCPyV-negative MCCs than in MCPyV-positive MCCs. 4 And we also reported that Akt phosphorylation at T308 in activation of the Akt/ mammalian target of rapamycin (mTOR)/4E-binding protein 1 (4E-BP1) signaling pathway, was signifi cantly greater in MCPyV-negative than in MCPyV-positive MCCs 19 and that lower expression of CADM1 and higher expression of MAL in MCCs are associated with MCPyV infection and better prognosis. 15 It can be considered that MCPyV-positive and MCPyV-negative MCCs have different tumorigenic pathways; the integrated-mutated form of MCPyV is directly involved in "virus-mediated" tumorigenesis, whereas the accumulation of more complicating genetic aberrations is required for "nonviral" tumorigenesis; and both may develop under systemic/local impairment of host immune surveillance caused by UV irradiation, immunosenescence, use of immunosuppressants, and other factors.…”

Section: Discussionmentioning

confidence: 95%

Higher Expression of Activation-induced Cytidine Deaminase Is Significantly Associated with Merkel Cell Polyomavirus-negative Merkel Cell Carcinomas

et al. 2017

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Background Merkel cell carcinomas (MCCs), clinically aggressive neuroendocrine skin cancers, are divided into Merkel cell polyomavirus (MCPyV)-positive and-negative tumors, which show different clinicopathological features and may develop through different mechanisms of carcinogenesis. Aberrant expression of activation-induced cytidine deaminase (AID) as a genomic modulator was demonstrated through pathogen-related NF-κB signal in Helicobacter pylori-associated gastric cancer, adult T cell leukemia/lymphoma (HTLV-1), hepatoma (HCV), and Burkitt lymphoma (EBV). Methods To elucidate the relation of aberrant AID expression in MCPyV-positive and-negative MCCs, we evaluated immunohistochemical expressions of AID and AID-regulating factors between 24 MCPyV-positive and 17 MCPyV-negative MCCs. Results AID expression was significantly higher in MCPyV-negative MCCs than MCPyV-positive ones (P = 0.026), although expression of NF-κB p65 (phospho S536) (AID-enhancer) was significantly higher in MCPyV-positive MCCs than MCPyV-negative ones (P = 0.034). Expressions of PAX5 and c-Myb were not significantly different between these subgroups. Expressions of AID and AID-regulating factors were not correlated to prognosis of MCC patients. Conclusion Our findings suggest that although pathogen-induced AID expression through upregulation of NF-κB may be relevant to carcinogenesis of MCPyV-positive MCCs, the significantly higher aberrant AID expression in MCPyV-negative MCCs is consistent with the fact that MCPyV-negative MCCs have an extremely higher mutation burden than MCPyV-positive ones.

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Section: Discussionmentioning

confidence: 95%

Higher Expression of Activation-induced Cytidine Deaminase Is Significantly Associated with Merkel Cell Polyomavirus-negative Merkel Cell Carcinomas

et al. 2017

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“…The virus has also been demonstrated in other malignancies, including cervical carcinoma [19], chronic lymphocytic leukemia [20], cutaneous squamous cell carcinoma [21], folliculotropic mycosis fungoides [22, 23], Langerhans cell sarcoma [24], and small cell carcinoma (extrapulmonary [25] and parotid [26]). In addition, although one group of researchers have found an association between Merkel cell polyomavirus infection and epidermal growth factor hotspot mutations in non-small-cell lung cancer [27], there is currently no evidence of an association between the virus and any specific genomic aberration—including a mutation in SUFU protein—in Merkel cell carcinoma [28]. …”

Section: Discussionmentioning

confidence: 99%

Merkel Cell Carcinoma with a Suppressor of Fused (SUFU) Mutation: Case Report and Potential Therapeutic Implications

Cohen

Kurzrock

2015

Dermatol Ther (Heidelb)

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IntroductionMerkel cell carcinoma is a neuroendocrine malignancy. Suppressor of fused (SUFU) is a tumor suppressor oncogene that participates in the Hedgehog (Hh) signaling pathway. The aim of the study was to describe a patient whose Merkel cell carcinoma demonstrated a SUFU genomic alteration.Case StudyThe Hh signaling pathway is involved in the pathogenesis of several tumors, including nevoid basal cell carcinoma syndrome that is associated with an alteration of the patched-1 (PTCH1) gene. Targeted molecular therapy against smoothened (SMO) with vismodegib has been shown to be an effective therapeutic intervention for patients with PTCH-1 mutation. The reported patient was presented with metastatic Merkel cell carcinoma. Analysis of his tumor, using a next-generation sequencing-based assay, demonstrated a genomic aberration of SUFU protein, a component of the Hh signaling pathway that acts downstream to SMO and, therefore, is unlikely to be responsive to vismodegib. Of interest, arsenic trioxide or bromo and extra C-terminal inhibitors impact signals downstream to SUFU, making this aberration conceivably druggable. His tumor has initially been managed with chemotherapy (carboplatin and etoposide) and subsequent radiation therapy is planned.ConclusionThe pathogenesis of Merkel cell carcinoma is multifactorial, and related to ultraviolet radiation exposure, immunosuppression, and Merkel cell polyomavirus. We report a patient with a mutation in SUFU, a potentially actionable component of the Hh signaling pathway.Electronic supplementary materialThe online version of this article (doi:10.1007/s13555-015-0074-5) contains supplementary material, which is available to authorized users.

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“…Also in the PI3K-related kinase pathway, AKT and mTOR have been found to be inappropriately activated in MCC, more commonly in MCV-negative tumors [74]. Specifically targeting both mTOR complex 1 and complex 2, the dual mTOR inhibitor, MLN0128, was able to inhibit MCC xenograft tumor growth in vivo [75].…”

Section: Emerging Treatmentsmentioning

confidence: 99%

Merkel Cell Carcinoma Therapeutic Update

Cassler

Merrill

Bichakjian

et al. 2016

Curr. Treat. Options in Oncol.

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Opinion statement Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine tumor of the skin. Early-stage disease can be cured with surgical resection and radiotherapy (RT). Sentinel lymph node biopsy (SLNB) is an important staging tool, as a microscopic MCC is frequently identified. Adjuvant RT to the primary excision site and regional lymph node bed may improve locoregional control. However, newer studies confirm that patients with biopsy-negative sentinel lymph nodes may not benefit from regional RT. Advanced MCC currently lacks a highly effective treatment as responses to chemotherapy are not durable. Recent work suggests that immunotherapy targeting the programmed cell death receptor 1/programmed cell death ligand 1 (PD-1/PD-L1) checkpoint holds great promise in treating advanced MCC and may provide durable responses in a portion of patients. At the same time, high-throughput sequencing studies have demonstrated significant differences in the mutational profiles of tumors with and without the Merkel cell polyomavirus (MCV). An important secondary endpoint in the ongoing immunotherapy trials for MCC will be determining if there is a response difference between the virus-positive MCC tumors that typically lack a large mutational burden and the virus-negative tumors that have a large number of somatic mutations and predicted tumor neoantigens. Interestingly, sequencing studies have failed to identify a highly recurrent activated driver pathway in the majority of MCC tumors. This may explain why targeted therapies can demonstrate exceptional responses in case reports but fail when treating all comers with MCC. Ultimately, a precision medicine approach may be more appropriate for treating MCC, where identified driver mutations are used to direct targeted therapies. At a minimum, stratifying patients in future clinical trials based on tumor viral status should be considered as virus-negative tumors are more likely to harbor activating driver mutations.

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Comparison of Akt/mTOR/4E-BP1 pathway signal activation and mutations of PIK3CA in Merkel cell polyomavirus–positive and Merkel cell polyomavirus–negative carcinomas

Cited by 27 publications

References 20 publications

Higher Expression of Activation-induced Cytidine Deaminase Is Significantly Associated with Merkel Cell Polyomavirus-negative Merkel Cell Carcinomas

Higher Expression of Activation-induced Cytidine Deaminase Is Significantly Associated with Merkel Cell Polyomavirus-negative Merkel Cell Carcinomas

Merkel Cell Carcinoma with a Suppressor of Fused (SUFU) Mutation: Case Report and Potential Therapeutic Implications

Merkel Cell Carcinoma Therapeutic Update

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