研究者詳細 - 井戸川　雅史

論文 - 井戸川　雅史

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MYEOV overexpression induced by demethylation of its promoter contributes to pancreatic cancer progression via activation of the folate cycle/c-Myc/mTORC1 pathway.

Shoichiro Tange, Tomomi Hirano, Masashi Idogawa, Eishu Hirata, Issei Imoto, Takashi Tokino

BMC cancer 23 ( 1 ) 85 - 85 2023年01月 [査読有り] [国際誌]

担当区分：責任著者

BACKGROUND: While molecular targeted drugs and other therapies are being developed for many tumors, pancreatic cancer is still considered to be the malignant tumor with the worst prognosis. We started this study to identify prognostic genes and therapeutic targets of pancreatic cancer. METHODS: To comprehensively identify prognostic genes in pancreatic cancer, we investigated the correlation between gene expression and cancer-specific prognosis using transcriptome and clinical information datasets from The Cancer Genome Atlas (TCGA). In addition, we examined the effects of the suppression of candidate prognostic genes in pancreatic cancer cell lines. RESULT: We found that patients with high expression levels of MYEOV, a primate-specific gene with unknown function, had significantly shorter disease-specific survival times than those with low expression levels. Cox proportional hazards analysis revealed that high expression of MYEOV was significantly associated with poor survival and was an independent prognostic factor for disease-specific survival in pancreatic cancer patients. Analysis of multiple cancer samples revealed that the MYEOV promoter region is methylated in noncancer tissues but is demethylated in tumors, causing MYEOV overexpression in tumors. Notably, the knockdown of MYEOV suppressed the expression of MTHFD2 and other folate metabolism-related enzyme genes required for the synthesis of amino acids and nucleic acids and also restored the expression of c-Myc and mTORC1 repressors. CONCLUSION: There is a significant correlation between elevated MYEOV expression and poor disease-specific survival in pancreatic cancer patients. MYEOV enhances the activation of several oncogenic pathways, resulting in the induction of pancreatic cancer cell proliferation. Overall, MYEOV acts as an oncogene in pancreatic cancer. Furthermore, MYEOV may be a prognostic biomarker and serve as an 'actionable' therapeutic target for pancreatic cancers.

Downregulation of protein kinase C gamma reduces epithelial property and enhances malignant phenotypes in colorectal cancer cells.

Reiko Satow, Yudai Suzuki, Shinobu Asada, Sae Ota, Masashi Idogawa, Shiori Kubota, Noi Ikeo, Atsuko Yoneda, Kiyoko Fukami

iScience 25 ( 12 ) 105501 - 105501 2022年12月 [査読有り] [国際誌]

Loss of epithelial integrity is associated with colorectal cancer (CRC) aggressiveness. Protein kinase C (PKC) is frequently implicated in human cancers, but the role of PKCγ in CRC remains poorly understood. Here, we show that PKCγ, a conventional PKC, is expressed in normal colonic epithelium, but this is lower in dedifferentiated CRC. PKCγ expression was downregulated by SNAI1 overexpression, and low PKCγ expression was associated with poor prognosis in patients with CRC. Transient or stable knockdown of PKCγ reduced E-cadherin expression in CRC cells. PKCγ knockdown enhanced proliferation, anchorage-independent cell growth, resistance to anti-cancer drugs, and in vivo tumor growth of DLD-1 cells. We have also identified phosphorylation substrates for PKCγ. Among them, ARHGEF18, a RhoA activator that stabilizes cell-cell junctions, was phosphorylated and stabilized by PKCγ. Thus, these results suggest that the downregulation of PKCγ decreases the epithelial property of CRC cells and enhances its malignant phenotypes.

Dual inhibition of BCL2L1 and MCL1 is highly effective against RET fusion-positive or MET exon 14 skipping mutation-positive lung adenocarcinoma cells.

Sachie Hirai, Masashi Idogawa, Toshiyuki Sumi, Miki Yamaguchi, Toshiro Niki, Yuji Sakuma

Biochemical and biophysical research communications 630 24 - 29 2022年11月 [査読有り] [国際誌]

Non-small cell lung carcinomas (NSCLCs), especially lung adenocarcinomas (LUADs), harbor several driver mutations against which highly effective tyrosine kinase inhibitors (TKIs) are available. Although TKIs are generally effective against certain NSCLCs, primary or acquired resistance almost always develops. Driver mutations include RET fusion (∼1-2% of NSCLC cases) and MET exon 14 skipping mutation (METΔex14; ∼3-4%). Surprisingly, the LUAD cell line LC-2/ad with CCDC6-RET fusion thrived independently of RET signaling, and Hs-746T cells harboring METΔex14 plus amplification survived MET silencing. However, these two cell lines were highly sensitive to dual silencing of the representative anti-apoptotic BCL2 family members BCL2L1 and MCL1, undergoing extensive apoptosis in monolayer or 3D on-top culture systems. Moreover, we found that most LUAD cell lines and tissues expressed high levels of BCL2L1 and MCL1 mRNA but extremely low levels of BCL2. Together, these findings suggest that inhibiting BCL2L1 plus MCL1 may represent a new approach to treating LUAD cells irrespective of their driver mutations.

Impact of sensitive circulating tumor DNA monitoring on CT scan intervals during postoperative colorectal cancer surveillance

Tomoko Sasaki, Takeshi Iwaya, Mizunori Yaegashi, Masashi Idogawa, Hayato Hiraki, Masakazu Abe, Yuka Koizumi, Noriyuki Sasaki, Akiko Yashima-Abo, Ryosuke Fujisawa, Fumitaka Endo, Shoichiro Tange, Tomomi Hirano, Koki Otsuka, Akira Sasaki, Mari Masuda, Masashi Fujita, Hidewaki Nakagawa, Fumiaki Takahashi, Yasushi Sasaki, Takashi Tokino, Satoshi S. Nishizuka

2022年09月 [査読有り]

Multiomics identifies the link between intratumor steatosis and the exhausted tumor immune microenvironment in hepatocellular carcinoma.

Hiroki Murai, Takahiro Kodama, Kazuki Maesaka, Shoichiro Tange, Daisuke Motooka, Yutaka Suzuki, Yasuyuki Shigematsu, Kentaro Inamura, Yoshihiro Mise, Akio Saiura, Yoshihiro Ono, Yu Takahashi, Yota Kawasaki, Satoshi Iino, Shogo Kobayashi, Masashi Idogawa, Takashi Tokino, Tomomi Hashidate-Yoshida, Hideo Shindou, Masanori Miyazaki, Yasuharu Imai, Satoshi Tanaka, Eiji Mita, Kazuyoshi Ohkawa, Hayato Hikita, Ryotaro Sakamori, Tomohide Tatsumi, Hidetoshi Eguchi, Eiichi Morii, Tetsuo Takehara

Hepatology (Baltimore, Md.) 77 ( 1 ) 77 - 91 2022年05月 [査読有り] [国際誌]

BACKGROUND AND AIMS: Immunotherapy has become the standard-of-care treatment for hepatocellular carcinoma (HCC), but its efficacy remains limited. To identify immunotherapy-susceptible HCC, we profiled the molecular abnormalities and tumor immune microenvironment (TIME) of rapidly increasing nonviral HCC. APPROACHES AND RESULTS: We performed RNA-seq of tumor tissues in 113 patients with nonviral HCC and cancer genome sequencing of 69 genes with recurrent genetic alterations reported in HCC. Unsupervised hierarchical clustering classified nonviral HCCs into three molecular classes (Class I, II, III), which stratified patient prognosis. Class I, with the poorest prognosis, was associated with TP53 mutations, whereas class III, with the best prognosis, was associated with cadherin-associated protein beta 1 (CTNNB1) mutations. Thirty-eight percent of nonviral HCC was defined as an immune class characterized by a high frequency of intratumoral steatosis and a low frequency of CTNNB1 mutations. Steatotic HCC, which accounts for 23% of nonviral HCC cases, presented an immune-enriched but immune-exhausted TIME characterized by T cell exhaustion, M2 macrophage and cancer-associated fibroblast (CAF) infiltration, high PD-L1 expression, and TGF-β signaling activation. Spatial transcriptome analysis suggested that M2 macrophages and CAFs may be in close proximity to exhausted CD8+ T cells in steatotic HCC. An in vitro study showed that palmitic acid-induced lipid accumulation in HCC cells upregulated PD-L1 expression and promoted immunosuppressive phenotypes of cocultured macrophages and fibroblasts. Patients with steatotic HCC, confirmed by chemical-shift MR imaging, had significantly longer PFS with combined immunotherapy using anti-PD-L1 and anti-VEGF antibodies. CONCLUSIONS: Multiomics stratified nonviral HCCs according to prognosis or TIME. We identified the link between intratumoral steatosis and immune-exhausted immunotherapy-susceptible TIME.

Anthrax toxin receptor 2 is a potential therapeutic target for non-small cell lung carcinoma with MET exon 14 skipping mutations.

Miki Yamaguchi, Sachie Hirai, Masashi Idogawa, Hiroaki Uchida, Yuji Sakuma

Experimental cell research 413 ( 2 ) 113078 - 113078 2022年04月 [査読有り] [国際誌]

Although MET tyrosine kinase inhibitors (TKIs) are generally effective against non-small cell lung carcinoma (NSCLC) with MET exon 14 skipping mutations (METΔex14), resistance to MET TKIs can occur, indicating the need to develop other therapeutic options. We found that Hs-746 T cells, which harbor METΔex14 plus amplification, were able to survive and grow in the absence of MET signaling, exhibiting primary resistance to MET TKIs. We also found a moderately positive correlation between MET and anthrax toxin receptor 2 (ANTXR2) mRNA expression in NSCLC cell lines using data from the Cancer Dependency Map database. As expected, Hs-746 T cells were positive for ANTXR2 expression. We used an antibody-drug conjugate (ADC) analog in the form of an anti-ANTXR2 monoclonal antibody, H8R23, conjugated to DT3C recombinant protein which consists of diphtheria toxin (DT) lacking the receptor-binding domain but containing the C1, C2, and C3 domains of streptococcal protein G (3C). H8R23-DT3C conjugates, which function in vitro like an ADC, induced Hs-746 T cells to undergo apoptosis, resulting in decreased viability. These findings collectively suggest that an ADC targeting ANTXR2 could be effective for the treatment of METΔex14-positive NSCLC.

Individualized circulating tumor DNA monitoring in head and neck squamous cell carcinoma

Ryunosuke Kogo, Tomomi Manako, Takeshi Iwaya, Satoshi Nishizuka, Hayato Hiraki, Yasushi Sasaki, Masashi Idogawa, Takashi Tokino, Ayaka Koide, Noritaka Komune, Ryuji Yasumatsu, Takashi Nakagawa

Cancer Medicine ( Wiley ) 2022年03月 [査読有り]

Estimation of the true infection rate and infection fatality rate of coronavirus disease 2019 in each country.

Masahiro Sonoo, Takamichi Kanbayashi, Takayoshi Shimohata, Masahito Kobayashi, Masashi Idogawa, Hideyuki Hayashi

Journal of infection and public health 15 ( 2 ) 210 - 213 2021年12月 [査読有り] [国際誌]

The True Infection Rate (TIR) in the whole population of each country and the Infection Fatality Rate (IFR) for coronavirus disease 2019 (COVID-19) are unknown although they are important parameters. We devised a simple method to infer TIR and IFR based on the open data. The prevalence rate of the Polymerase Chain Reaction (PCR) tests among the population (Examination Rate; ER) and the positive rate of PCR tests (Infection Rate; IR) for 66 countries were picked up at a website 5 times from April 10th to June 13th, 2020, and the trajectory of each country was drawn over the IR vs. ER plot. IR and ER showed a strong negative correlation for some countries, and TIR was estimated by extrapolating the regression line when the correlation coefficient was between -0.99 and -1. True/Identified Case Ratio (TICR) and IFR were also calculated using the estimated TIR. The estimated TIR well coincided with local antibody surveys. Estimated IFR took on a wide range of values up to 10%: generally high in the Western countries. The estimated IFR of Singapore was very low (0.018%), which may be related to the reported gene mutation causing the attenuation of the viral virulence.

BHLHE41/DEC2 Expression Induces Autophagic Cell Death in Lung Cancer Cells and Is Associated with Favorable Prognosis for Patients with Lung Adenocarcinoma.

Toshiyuki Nagata, Kentaro Minami, Masatatsu Yamamoto, Tsubasa Hiraki, Masashi Idogawa, Katsumi Fujimoto, Shun Kageyama, Kazuhiro Tabata, Kohichi Kawahara, Kazuhiro Ueda, Ryuji Ikeda, Yukio Kato, Masaaki Komatsu, Akihide Tanimoto, Tatsuhiko Furukawa, Masami Sato

International journal of molecular sciences 22 ( 21 ) 2021年10月 [査読有り] [国際誌]

Lung cancer constitutes a threat to human health. BHLHE41 plays important roles in circadian rhythm and cell differentiation as a negative regulatory transcription factor. This study investigates the role of BHLHE41 in lung cancer progression. We analyzed BHLHE41 function via in silico and immunohistochemical studies of 177 surgically resected non-small cell lung cancer (NSCLC) samples and 18 early lung squamous cell carcinoma (LUSC) cases. We also examined doxycycline (DOX)-inducible BHLHE41-expressing A549 and H2030 adenocarcinoma cells. BHLHE41 expression was higher in normal lung than in lung adenocarcinoma (LUAD) tissues and was associated with better prognosis for the overall survival (OS) of patients. In total, 15 of 132 LUAD tissues expressed BHLHE41 in normal lung epithelial cells. Staining was mainly observed in adenocarcinoma in situ and the lepidic growth part of invasive cancer tissue. BHLHE41 expression constituted a favorable prognostic factor for OS (p = 0.049) and cause-specific survival (p = 0.042) in patients with LUAD. During early LUSC, 7 of 18 cases expressed BHLHE41, and this expression was inversely correlated with the depth of invasion. DOX suppressed cell proliferation and increased the autophagy protein LC3, while chloroquine enhanced LC3 accumulation and suppressed cell death. In a xenograft model, DOX suppressed tumor growth. Our results indicate that BHLHE41 expression prevents early lung tumor malignant progression by inducing autophagic cell death in NSCLC.

Functional Depletion of HSP72 by siRNA and Quercetin Enhances Vorinostat-Induced Apoptosis in an HSP72-Overexpressing Cutaneous T-Cell Lymphoma Cell Line, Hut78.

Kazuyasu Fujii, Masashi Idogawa, Norihiro Suzuki, Keiji Iwatsuki, Takuro Kanekura

International journal of molecular sciences 22 ( 20 ) 2021年10月 [査読有り] [国際誌]

Histone deacetylase inhibitors (HDACis) are one of the therapeutic options for cutaneous T-cell lymphoma (CTCL), but they have limited effects. We previously demonstrated that HSP72 overexpression is associated with chemoresistance to HDACis in lymphoma cells. The purpose of this study was to investigate whether the functional depletion of HSP72 enhances the effect of the HDACi vorinostat. First, we established a stable HSP72-knockdown CTCL cell line and confirmed the influence of HSP72 reduction on the antitumor effects of vorinostat. Next, we studied the effect of quercetin, an inhibitor of HSP72, on the antineoplastic effects of vorinostat. In five CTCL cell lines examined, HSP72 expression was highest in Hut78 cells, and HSP72 knockdown enhanced vorinostat-induced apoptosis in these cells. Low-dose quercetin reduced HSP72 expression, increased HDAC activity, and enhanced vorinostat-induced suppression of Hut78 cell proliferation. A single low dose of quercetin induced G2 arrest and only slightly increased the sub-G1 cell fraction. Quercetin also significantly enhanced vorinostat-induced apoptosis, caspase-3, caspase-8, and caspase-9 activity, and the loss of mitochondrial membrane potential. HSP72 knockdown enhanced vorinostat-induced apoptosis in an HSP72-overexpressing CTCL cell line, and thus, quercetin may be a suitable candidate for combination therapy with vorinostat in clinical settings.

DLEU1 promotes oral squamous cell carcinoma progression by activating interferon-stimulated genes.

Yui Hatanaka, Takeshi Niinuma, Hiroshi Kitajima, Koyo Nishiyama, Reo Maruyama, Kazuya Ishiguro, Mutsumi Toyota, Eiichiro Yamamoto, Masahiro Kai, Akira Yorozu, Shohei Sekiguchi, Kazuhiro Ogi, Hironari Dehari, Masashi Idogawa, Yasushi Sasaki, Takashi Tokino, Akihiro Miyazaki, Hiromu Suzuki

Scientific reports 11 ( 1 ) 20438 - 20438 2021年10月 [査読有り] [国際誌]

Long noncoding RNAs (lncRNAs) are deeply involved in cancer development. We previously reported that DLEU1 (deleted in lymphocytic leukemia 1) is one of the lncRNAs overexpressed in oral squamous cell carcinoma (OSCC) cells, where it exhibits oncogenic activity. In the present study, we further clarified the molecular function of DLEU1 in the pathogenesis of OSCC. Chromatin immunoprecipitation-sequencing (ChIP-seq) analysis revealed that DLEU1 knockdown induced significant changes in the levels of histone H3 lysine 4 trimethylation (H3K4me3) and H3K27 acetylation (H3K27ac) in OSCC cells. Notably, DLEU1 knockdown suppressed levels of H3K4me3/ H3K27ac and expression of a number of interferon-stimulated genes (ISGs), including IFIT1, IFI6 and OAS1, while ectopic DLEU1 expression activated these genes. Western blot analysis and reporter assays suggested that DLEU1 upregulates ISGs through activation of JAK-STAT signaling in OSCC cells. Moreover, IFITM1, one of the ISGs induced by DLUE1, was frequently overexpressed in primary OSCC tumors, and its knockdown inhibited OSCC cell proliferation, migration and invasion. These findings suggest that DLEU1 exerts its oncogenic effects, at least in part, through activation of a series ISGs in OSCC cells.

Early dynamics of circulating tumor DNA predict chemotherapy responses for patients with esophageal cancer.

Ryosuke Fujisawa, Takeshi Iwaya, Fumitaka Endo, Masashi Idogawa, Noriyuki Sasaki, Hayato Hiraki, Shoichiro Tange, Tomomi Hirano, Yuka Koizumi, Masakazu Abe, Tomoko Takahashi, Mizunori Yaegashi, Yuji Akiyama, Mari Masuda, Akira Sasaki, Fumiaki Takahashi, Yasushi Sasaki, Takashi Tokino, Satoshi S Nishizuka

Carcinogenesis 42 ( 10 ) 1239 - 1249 2021年09月 [査読有り] [国際誌]

We investigated whether early circulating tumor DNA (ctDNA) changes, measured using digital PCR (dPCR), can predict later chemotherapy responses in esophageal squamous cell cancer (ESCC). We compared the dynamics of ctDNA and tumor volumes during chemotherapy in 42 ESCC. The accuracy of predictions of later chemotherapy responses were evaluated by the ratio of the variant allele frequency (VAF) of ctDNA (post-/pre-ctDNA) and the total tumor volume (post-/pre-volume) before and after an initial chemotherapy cycle using a receiver-operating characteristic curve analysis. Total positive and negative objective responses (ORs) were defined as either >50% or ≤50% reductions, respectively, in the total tumor volume at the end of first-line chemotherapy. Mutation screening of 43 tumors from 42 patients revealed 96 mutations. The pretreatment dPCR-ctDNA data were informative in 38 patients, using 70 selected mutations (1-3 per patient). The areas under the curve (AUCs) for the post-/pre-volume and post-/pre-ctDNA levels used in predicting the total OR were 0.85 and 0.88, respectively. The optimal cutoff value of post-/pre-ctDNA was 0.13. In 20 patients with post-/pre-volume ≥50%, the total OR could be predicted by the post-/pre-ctDNA with high accuracy; the AUC by post-/pre-ctDNA was higher than that by post-/pre-volume (0.85 vs 0.76, respectively). Patients with low post-/pre-ctDNA (n = 18) had a significantly better overall survival rate than those with high post-/pre-ctDNA (n = 20; P = 0.03). Early ctDNA changes after an initial cycle of chemotherapy predict later responses to treatment with high accuracy in ESCC patients.

Dead or alive? Pitfall of survival analysis with TCGA datasets.

Masashi Idogawa, Masayo Koizumi, Tomomi Hirano, Shoichiro Tange, Hiroshi Nakase, Takashi Tokino

Cancer biology & therapy 22 ( 10-12 ) 1 - 2 2021年09月 [査読有り] [国際誌]

担当区分：筆頭著者 , 責任著者

We often encounter situations in which data from the TCGA that have been analyzed in papers we read or reviewed cannot be reproduced, even when TCGA datasets are used, especially in survival analyses. Therefore, we attempted to confirm the data source for TCGA survival analysis and found that several websites used to analyze the survival data of TCGA datasets inappropriately handle the survival data, causing differences in statistical analyses. This causes the misinterpretation of results because figures of survival analysis results in several papers are sometimes exactly as generated by these sites, and the results depend on only the tools provided by these sites. We would like to make this situation widely known and raise the problem for scientific soundness.

Genetic analyses of a secondary poroma and trichoblastoma in a HRAS-mutated sebaceous nevus.

Tomoyuki Minowa, Takafumi Kamiya, Tokimasa Hida, Masae Okura, Junji Kato, Masashi Idogawa, Shoichiro Tange, Tomomi Hirano, Takashi Tokino, Hisashi Uhara

The Journal of dermatology 48 ( 8 ) 1268 - 1272 2021年08月 [査読有り] [国際誌]

A sebaceous nevus is a congenital skin hamartoma caused by postzygotic HRAS or KRAS mosaic mutations. With age, affected individuals may develop secondary tumors within a sebaceous nevus. RAS mutations are harbored from the onset of sebaceous nevus, and further mutations can be expected to be required in order to explain the initiation of secondary tumors. However, genetic analyses of the secondary tumors have not been conducted. Herein, we describe the rare coexistence of a poroma and a trichoblastoma arising in a sebaceous nevus. This is the first report of an investigation of multiple genes in a secondary tumor in an SN. First, HRAS c.37G>C, which is the common mutation in sebaceous nevus, was detected in all three lesions (sebaceous nevus, poroma, and trichoblastoma). Next, to elucidate the potential second-hit mutations in the secondary poroma and trichoblastoma, we applied a panel sequencing for skin cancers that was newly developed in our institution. Our comparison of the mutational profile of 95 skin cancer-related genes in each of the three lesions newly revealed TP53 p.R158P in the poroma and NOTCH2 p.G329S in the trichoblastoma. TP53 p.R158P has been determined as a pathogenic mutation in other tumors, and NOTCH2 p.G329S was a novel mutation. We identified two novel mutations that may have contributed to the pathogenesis of the secondary tumor's development. The roles of the mutations remain unclear.

ALK-positive atypical Spitz tumour with conspicuous rosette-like structures.

Tomoyuki Minowa, Tokimasa Hida, Kohei Horimoto, Junji Kato, Takafumi Kamiya, Shintaro Sugita, Masashi Idogawa, Toshiaki Saida, Tadashi Hasegawa, Takashi Tokino, Hisashi Uhara

European journal of dermatology : EJD 31 ( 2 ) 256 - 258 2021年04月 [査読有り] [国際誌]

Correlation between polymerase chain reaction (PCR) examination rate among the population and the containment of the COVID-19 pandemic.

M Sonoo, T Kanbayashi, M Idogawa, T Shimohata, H Hayashi

Public health 191 31 - 32 2021年02月 [査読有り] [国際誌]

Neurofibromatosis type 1 without cutaneous neurofibromas: a rare genotype-phenotype correlation?

Tokimasa Hida, Masashi Idogawa, Aki Ishikawa, Miyako Mizukami, Junji Kato, Yasuyuki Sumikawa, Masae Okura, Takashi Tokino, Hisashi Uhara

European journal of dermatology : EJD 30 ( 5 ) 608 - 609 2020年10月 [査読有り] [国際誌]

Interactive Web-based Graphs of Coronavirus Disease 2019 Cases and Deaths per Population by Country.

Masashi Idogawa, Shoichiro Tange, Hiroshi Nakase, Takashi Tokino

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 71 ( 15 ) 902 - 903 2020年07月 [査読有り] [国際誌]

担当区分：筆頭著者 , 責任著者

Genetic analyses of mosaic neurofibromatosis type 1 with giant café-au-lait macule, plexiform neurofibroma and multiple melanocytic nevi.

Tokimasa Hida, Masashi Idogawa, Masae Okura, Shintaro Sugita, Taro Sugawara, Yasushi Sasaki, Takashi Tokino, Toshiharu Yamashita, Hisashi Uhara

The Journal of dermatology 47 ( 6 ) 658 - 662 2020年04月 [査読有り] [国際誌]

Neurofibromatosis type 1 (NF1) is a genodermatosis caused by heterozygous germ line variations in the NF1 gene. A second-hit NF1 aberration results in the formation of café-au-lait macules, cutaneous neurofibroma and plexiform neurofibroma (PNF). Mosaic NF1 (mNF1), caused by a postzygotic NF1 mutation, is characterized by localized or generalized NF1-related manifestations. Although NF1 and mNF1 are associated with pigmentary skin lesions, clinically recognizable melanocytic nevi that developed over PNF have not been reported. Here, we report the first case of multiple melanocytic nevi that developed on a giant café-au-lait macule and PNF. The PNF had biallelic NF1 deletions, a whole deletion of NF1 and a novel intragenic deletion involving exons 25-30. The deletions were not detected in the blood, which resulted in the diagnosis of mNF1. Furthermore, the nevus cells had not only biallelic NF1 deletions but also NRAS Q61R, a common mutation found in congenital melanocytic nevi. These analyses revealed the coexistence of the two different mosaic diseases, mNF1 and congenital melanocytic nevi. For a diagnosis of cases with atypical NF1-like symptoms, genetic analyses using blood and lesional tissues are useful and aid in genetic counseling.

Renal angiomyolipoma (AML) harboring a missense mutation of TSC2 with copy-neutral loss of heterozygosity (CN-LOH).

Masashi Idogawa, Tokimasa Hida, Toshiaki Tanaka, Noriaki Ohira, Shoichiro Tange, Yasushi Sasaki, Hisashi Uhara, Naoya Masumori, Takashi Tokino, Hiroshi Natori

Cancer biology & therapy 1 - 5 2019年12月 [査読有り] [国際誌]

担当区分：筆頭著者 , 責任著者

Angiomyolipoma (AML) is classified as a perivascular epithelioid cell neoplasm, mostly occurring in the kidney. Twenty percent of patients with renal AML have tuberous sclerosis complex (TSC) caused by germline variation in the TSC1 or TSC2 gene. In this paper, we report the first case of renal AML harboring somatic missense mutations of the TSC2 gene and concomitant copy-neutral loss of heterozygosity (CN-LOH). The patient presented with solitary renal AML and pulmonary lymphangiomyomatosis and without other findings suggestive of TSC. Exome sequencing analysis of the renal AML, however, identified a pathogenic somatic missense mutation in the TSC2 gene (NM_000548:c.5228G>A:p. R1743Q), although no other somatic mutation was detected. Furthermore, no germline mutation in TSC1 or TSC2 was detected. Interestingly, the mutant allele ratio was too high for a somatic heterozygous mutation without loss of heterozygosity (LOH). Furthermore, no copy number variation was detected around the TSC2 locus (16p13.3). To clarify the allelic status, we analyzed heterozygous single-nucleotide polymorphisms (SNPs) in chromosome 16. In these SNPs, an unbalanced allele ratio was accumulated inside the 16p13.3 region. These results suggested copy-neutral LOH (CN-LOH). Consequently, we concluded that the missense mutation of the TSC2 gene and CN-LOH of the TSC2 locus caused renal AML.

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