Integration of transcriptome and methylome analysis of aldosterone-producing adenomas

Murakami, Masanori; Yoshimoto, Takanobu; Nakabayashi, Kazuhiko; Tsuchiya, Kyoichiro; Minami, Isao; Bouchi, Ryotaro; Izumiyama, Hajime; Fujii, Yasuhisa; Abe, Kazutoshi; Tayama, Chiharu; Hashimoto, Kazuhito; Suganami, Takayoshi; Hata, Keiko; Kihara, Kazunori; Ogawa, Yoshihiro

doi:10.1530/eje-15-0148

Cited by 42 publications

(42 citation statements)

References 47 publications

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“…IHC with newly available specific monoclonal antibodies has been proved very useful in providing a histopathological diagnosis of PA by quantification and localization of steroidogenic enzymes, such as aldosterone synthase (cytochrome P450, family 11, subfamily B, polypeptide 2: CYP11B2) (4,5). Further in-depth molecular characterization has become possible more recently by means of high-throughput "omics" technologies, including exome sequencing, transcriptomics (6), and methylomics (7,8). In particular, exome sequencing has contributed to uncovering genes (including KCNJ5, ATP1A1, ATP2B3, CACNA1D, CACNA1H, and CTNNB1) in which specific gain-of-function mutations result in autonomous aldosterone production (9)(10)(11)(12)(13).…”

Section: Introductionmentioning

confidence: 99%

In situ metabolomics of aldosterone-producing adenomas

Murakami¹,

Rhayem²,

Kunzke³

et al. 2019

JCI Insight

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Section: Introductionmentioning

confidence: 99%

In situ metabolomics of aldosterone-producing adenomas

Murakami¹,

Rhayem²,

Kunzke³

et al. 2019

JCI Insight

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“…Recently, the molecular characteristics of APA have been widely investigated via high-throughput technologies, including exome sequencing, transcriptomics (Zennaro et al 2012) and methylomics (Howard et al 2014, Murakami et al 2015b. In particular, exome sequencing studies have uncovered that a series of somatic mutations in genes such as genes encoding the potassium inwardly rectifying channel, subfamily J, member 5 (KCNJ5), ATPase, Na + /K + transporting, alpha1-polypeptide (ATP1A1), ATPase, Ca 2+ -transporting, plasma membrane 3 (ATP2B3), calcium channel, voltage-dependent, L-type, alpha1D-subunit (CACNA1D), calcium channel, voltagedependent, T type, alpha 1H subunit (CACNA1H), and catenin beta1 (CTNNB1), lead to autonomous aldosterone production (Choi et al 2011, Azizan et al 2013, Scholl et al 2015b, Akerstrom et al 2016.…”

Section: Introductionmentioning

confidence: 99%

Molecular characteristics of the KCNJ5 mutated aldosterone-producing adenomas

Murakami¹,

Yoshimoto²,

Nakabayashi³

et al. 2017

Endocrine-Related Cancer

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The pathophysiology of aldosterone-producing adenomas (APAs) has been investigated via genetic approaches and the pathogenic significance of a series of somatic mutations, including , has been uncovered. However, how the mutational status of an APA is associated with its molecular characteristics, including its transcriptome and methylome, has not been fully understood. This study was undertaken to explore the molecular characteristics of APAs, specifically focusing on APAs with mutations as opposed to those without mutations, by comparing their transcriptome and methylome status. Cortisol-producing adenomas (CPAs) were used as reference. We conducted transcriptome and methylome analyses of 29 APAs with mutations, 8 APAs without mutations and 5 CPAs. Genome-wide gene expression and CpG methylation profiles were obtained from RNA and DNA samples extracted from these 42 adrenal tumors. Cluster analysis of the transcriptome and methylome revealed molecular heterogeneity in APAs depending on their mutational status. DNA hypomethylation and gene expression changes in Wnt signaling and inflammatory response pathways were characteristic of APAs with mutations. Comparisons between transcriptome data from our APAs and that from normal adrenal cortex obtained from the Gene Expression Omnibus suggested similarities between APAs with mutations and zona glomerulosa. The present study, which is based on transcriptome and methylome analyses, indicates the molecular heterogeneity of APAs depends on their mutational status. Here, we report the unique characteristics of APAs with mutations.

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“…In mice, the expression of the ASB4 gene has been reported in the developing placenta and the testis; however, adult tissues cease ASB4 gene expression, suggesting ASB4 functions early in development, perhaps at trophoblast differentiation (35)(36)(37). On the contrary, its increased expression has been reported in hepatocellular carcinomas and adrenal gland tumors, which may suggest another role of ASB4 in metastasis or tumorigenesis (38,39). We quantitatively compared sphere formation of SP-H in the presence and absence of ASB4 gene expression; however, silencing ASB4 gene expression did not decrease the number of spheres.…”

Section: Discussionmentioning

confidence: 99%

The Antigen ASB4 on Cancer Stem Cells Serves as a Target for CTL Immunotherapy of Colorectal Cancer

Miyamoto

Kochin

Kanaseki

et al. 2018

Cancer Immunology Research

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Colorectal cancer consists of a small number of cancer stem cells (CSC) and many non-CSCs. Although rare in number, CSCs are a target for cancer therapy, because they survive conventional chemo-and radiotherapies and perpetuate tumor formation in vivo. In this study, we conducted an HLA ligandome analysis to survey HLA-A24 peptides displayed by CSCs and non-CSCs of colorectal cancer. The analysis identified an antigen, ASB4, which was processed and presented by a CSC subset but not by nonCSCs. The ASB4 gene was expressed in CSCs of colorectal cancer, but not in cells that had differentiated into non-CSCs. Because ASB4 was not expressed by normal tissues, its peptide epitope elicited CD8 þ cytotoxic T-cell (CTL) responses, which lysed CSCs of colorectal cancer and left non-CSCs intact. Therefore, ASB4 is a tumor-associated antigen that can elicit CTL responses specific to CSCs and can discriminate between two cellular subsets of colorectal cancer. Adoptively transferred CTLs specific for the CSC antigen ASB4 could infiltrate implanted colorectal cancer cell tumors and effectively prevented tumor growth in a mouse model. As the cancer cells implanted in these mice contained very few CSCs, the elimination of a CSC subset could be the condition necessary and sufficient to control tumor formation in vivo. These results suggest that CTL-based immunotherapies against colorectal CSCs might be useful for preventing relapses.

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Integration of transcriptome and methylome analysis of aldosterone-producing adenomas

Cited by 42 publications

References 47 publications

In situ metabolomics of aldosterone-producing adenomas

In situ metabolomics of aldosterone-producing adenomas

Molecular characteristics of the KCNJ5 mutated aldosterone-producing adenomas

The Antigen ASB4 on Cancer Stem Cells Serves as a Target for CTL Immunotherapy of Colorectal Cancer

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