The USP8 mutational status may predict drug susceptibility in corticotroph adenomas of Cushing's disease

ContextSomatic mutations in the ubiquitin-specific peptidase USP8 gene were recently detected in one- to two-third(s) of corticotroph adenomas of Cushing's disease (CD). These mutations may lead to the deubiquitination of EGFR, thereby increasing EGFR signaling, which has been implicated in ACT...

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Veröffentlicht in:European journal of endocrinology 2016-02, Vol.174 (2), p.213-226
Hauptverfasser: Hayashi, Kyohei, Inoshita, Naoko, Kawaguchi, Kohei, Ibrahim Ardisasmita, Arif, Suzuki, Hisanori, Fukuhara, Noriaki, Okada, Mitsuo, Nishioka, Hiroshi, Takeuchi, Yasuhiro, Komada, Masayuki, Takeshita, Akira, Yamada, Shozo
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container_issue 2
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container_title European journal of endocrinology
container_volume 174
creator Hayashi, Kyohei
Inoshita, Naoko
Kawaguchi, Kohei
Ibrahim Ardisasmita, Arif
Suzuki, Hisanori
Fukuhara, Noriaki
Okada, Mitsuo
Nishioka, Hiroshi
Takeuchi, Yasuhiro
Komada, Masayuki
Takeshita, Akira
Yamada, Shozo
description ContextSomatic mutations in the ubiquitin-specific peptidase USP8 gene were recently detected in one- to two-third(s) of corticotroph adenomas of Cushing's disease (CD). These mutations may lead to the deubiquitination of EGFR, thereby increasing EGFR signaling, which has been implicated in ACTH hypersecretion.ObjectiveOur objective was to determine the impact of USP8 mutations on the clinicopathological features of CD.Subjects and methodsUSP8 mutations as well as clinicopathological characteristics were examined in 60 corticotroph adenomas including 15 Crooke's cell adenomas (CCAs), a rare histological variant presenting with generally aggressive behavior, using qRT-PCR and/or immunohistochemistry.ResultsUSP8 mutations were exclusively detected in women, except for one case, with a prevalence of 42.2% in non-CCA and 13.3% in CCA (overall 35%). Clinically well-behaved presentations including microadenoma and curative resection were more common in mutated cases. The expression of EGFR was not associated with the mutation status. In contrast, mutated tumors expressed significantly higher levels of POMC, SSTR5, and MGMT.ConclusionsMicroadenomas that strongly express POMC were common among mutated tumors, which may lead to the mechanisms by which very small adenomas secrete excess ACTH to present overt CD. While USP8 mutations were less likely to enhance tumorous ACTH hypersecretion via EGFR-mediated activation, the presence of USP8 mutations may predict favorable responses to the somatostatin analog pasireotide, which exhibits high affinity for SSTR5. In contrast, non-mutated aggressive tumors such as CCA may respond better to the alkylating agent temozolomide because of their significantly weak expression of MGMT.
doi_str_mv 10.1530/EJE-15-0689
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These mutations may lead to the deubiquitination of EGFR, thereby increasing EGFR signaling, which has been implicated in ACTH hypersecretion.ObjectiveOur objective was to determine the impact of USP8 mutations on the clinicopathological features of CD.Subjects and methodsUSP8 mutations as well as clinicopathological characteristics were examined in 60 corticotroph adenomas including 15 Crooke's cell adenomas (CCAs), a rare histological variant presenting with generally aggressive behavior, using qRT-PCR and/or immunohistochemistry.ResultsUSP8 mutations were exclusively detected in women, except for one case, with a prevalence of 42.2% in non-CCA and 13.3% in CCA (overall 35%). Clinically well-behaved presentations including microadenoma and curative resection were more common in mutated cases. The expression of EGFR was not associated with the mutation status. In contrast, mutated tumors expressed significantly higher levels of POMC, SSTR5, and MGMT.ConclusionsMicroadenomas that strongly express POMC were common among mutated tumors, which may lead to the mechanisms by which very small adenomas secrete excess ACTH to present overt CD. While USP8 mutations were less likely to enhance tumorous ACTH hypersecretion via EGFR-mediated activation, the presence of USP8 mutations may predict favorable responses to the somatostatin analog pasireotide, which exhibits high affinity for SSTR5. In contrast, non-mutated aggressive tumors such as CCA may respond better to the alkylating agent temozolomide because of their significantly weak expression of MGMT.</description><identifier>ISSN: 0804-4643</identifier><identifier>EISSN: 1479-683X</identifier><identifier>DOI: 10.1530/EJE-15-0689</identifier><identifier>PMID: 26578638</identifier><language>eng</language><publisher>England: Bioscientifica Ltd</publisher><subject>ACTH-Secreting Pituitary Adenoma - genetics ; ACTH-Secreting Pituitary Adenoma - metabolism ; ACTH-Secreting Pituitary Adenoma - pathology ; Adenoma - blood ; Adenoma - genetics ; Adenoma - pathology ; Adult ; Aged ; Aged, 80 and over ; Antineoplastic Agents, Alkylating - pharmacology ; Clinical Study ; DNA Modification Methylases ; DNA Repair Enzymes ; Endopeptidases - genetics ; Endosomal Sorting Complexes Required for Transport - genetics ; Female ; Humans ; Japan ; Male ; Middle Aged ; Mutation ; Pituitary ACTH Hypersecretion - genetics ; Pituitary ACTH Hypersecretion - metabolism ; Pituitary ACTH Hypersecretion - pathology ; Pro-Opiomelanocortin ; Receptors, Somatostatin ; Sex Factors ; Somatostatin - pharmacology ; Tumor Suppressor Proteins ; Ubiquitin Thiolesterase - genetics ; Young Adult</subject><ispartof>European journal of endocrinology, 2016-02, Vol.174 (2), p.213-226</ispartof><rights>2016 European Society of Endocrinology</rights><rights>2016 European Society of Endocrinology.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-b476t-ae988e2f7507450cab3d300fe7beee32ae6cab704ca6a930ab4231047b0247413</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,781,785,27929,27930</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26578638$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Hayashi, Kyohei</creatorcontrib><creatorcontrib>Inoshita, Naoko</creatorcontrib><creatorcontrib>Kawaguchi, Kohei</creatorcontrib><creatorcontrib>Ibrahim Ardisasmita, Arif</creatorcontrib><creatorcontrib>Suzuki, Hisanori</creatorcontrib><creatorcontrib>Fukuhara, Noriaki</creatorcontrib><creatorcontrib>Okada, Mitsuo</creatorcontrib><creatorcontrib>Nishioka, Hiroshi</creatorcontrib><creatorcontrib>Takeuchi, Yasuhiro</creatorcontrib><creatorcontrib>Komada, Masayuki</creatorcontrib><creatorcontrib>Takeshita, Akira</creatorcontrib><creatorcontrib>Yamada, Shozo</creatorcontrib><title>The USP8 mutational status may predict drug susceptibility in corticotroph adenomas of Cushing's disease</title><title>European journal of endocrinology</title><addtitle>Eur J Endocrinol</addtitle><description>ContextSomatic mutations in the ubiquitin-specific peptidase USP8 gene were recently detected in one- to two-third(s) of corticotroph adenomas of Cushing's disease (CD). These mutations may lead to the deubiquitination of EGFR, thereby increasing EGFR signaling, which has been implicated in ACTH hypersecretion.ObjectiveOur objective was to determine the impact of USP8 mutations on the clinicopathological features of CD.Subjects and methodsUSP8 mutations as well as clinicopathological characteristics were examined in 60 corticotroph adenomas including 15 Crooke's cell adenomas (CCAs), a rare histological variant presenting with generally aggressive behavior, using qRT-PCR and/or immunohistochemistry.ResultsUSP8 mutations were exclusively detected in women, except for one case, with a prevalence of 42.2% in non-CCA and 13.3% in CCA (overall 35%). Clinically well-behaved presentations including microadenoma and curative resection were more common in mutated cases. The expression of EGFR was not associated with the mutation status. In contrast, mutated tumors expressed significantly higher levels of POMC, SSTR5, and MGMT.ConclusionsMicroadenomas that strongly express POMC were common among mutated tumors, which may lead to the mechanisms by which very small adenomas secrete excess ACTH to present overt CD. While USP8 mutations were less likely to enhance tumorous ACTH hypersecretion via EGFR-mediated activation, the presence of USP8 mutations may predict favorable responses to the somatostatin analog pasireotide, which exhibits high affinity for SSTR5. 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Inoshita, Naoko ; Kawaguchi, Kohei ; Ibrahim Ardisasmita, Arif ; Suzuki, Hisanori ; Fukuhara, Noriaki ; Okada, Mitsuo ; Nishioka, Hiroshi ; Takeuchi, Yasuhiro ; Komada, Masayuki ; Takeshita, Akira ; Yamada, Shozo</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-b476t-ae988e2f7507450cab3d300fe7beee32ae6cab704ca6a930ab4231047b0247413</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>ACTH-Secreting Pituitary Adenoma - genetics</topic><topic>ACTH-Secreting Pituitary Adenoma - metabolism</topic><topic>ACTH-Secreting Pituitary Adenoma - pathology</topic><topic>Adenoma - blood</topic><topic>Adenoma - genetics</topic><topic>Adenoma - pathology</topic><topic>Adult</topic><topic>Aged</topic><topic>Aged, 80 and over</topic><topic>Antineoplastic Agents, Alkylating - pharmacology</topic><topic>Clinical Study</topic><topic>DNA Modification Methylases</topic><topic>DNA Repair Enzymes</topic><topic>Endopeptidases - genetics</topic><topic>Endosomal Sorting Complexes Required for Transport - genetics</topic><topic>Female</topic><topic>Humans</topic><topic>Japan</topic><topic>Male</topic><topic>Middle Aged</topic><topic>Mutation</topic><topic>Pituitary ACTH Hypersecretion - genetics</topic><topic>Pituitary ACTH Hypersecretion - metabolism</topic><topic>Pituitary ACTH Hypersecretion - pathology</topic><topic>Pro-Opiomelanocortin</topic><topic>Receptors, Somatostatin</topic><topic>Sex Factors</topic><topic>Somatostatin - pharmacology</topic><topic>Tumor Suppressor Proteins</topic><topic>Ubiquitin Thiolesterase - genetics</topic><topic>Young Adult</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Hayashi, Kyohei</creatorcontrib><creatorcontrib>Inoshita, Naoko</creatorcontrib><creatorcontrib>Kawaguchi, Kohei</creatorcontrib><creatorcontrib>Ibrahim Ardisasmita, Arif</creatorcontrib><creatorcontrib>Suzuki, Hisanori</creatorcontrib><creatorcontrib>Fukuhara, Noriaki</creatorcontrib><creatorcontrib>Okada, Mitsuo</creatorcontrib><creatorcontrib>Nishioka, Hiroshi</creatorcontrib><creatorcontrib>Takeuchi, Yasuhiro</creatorcontrib><creatorcontrib>Komada, Masayuki</creatorcontrib><creatorcontrib>Takeshita, Akira</creatorcontrib><creatorcontrib>Yamada, Shozo</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>European journal of endocrinology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Hayashi, Kyohei</au><au>Inoshita, Naoko</au><au>Kawaguchi, Kohei</au><au>Ibrahim Ardisasmita, Arif</au><au>Suzuki, Hisanori</au><au>Fukuhara, Noriaki</au><au>Okada, Mitsuo</au><au>Nishioka, Hiroshi</au><au>Takeuchi, Yasuhiro</au><au>Komada, Masayuki</au><au>Takeshita, Akira</au><au>Yamada, Shozo</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The USP8 mutational status may predict drug susceptibility in corticotroph adenomas of Cushing's disease</atitle><jtitle>European journal of endocrinology</jtitle><addtitle>Eur J Endocrinol</addtitle><date>2016-02</date><risdate>2016</risdate><volume>174</volume><issue>2</issue><spage>213</spage><epage>226</epage><pages>213-226</pages><issn>0804-4643</issn><eissn>1479-683X</eissn><abstract>ContextSomatic mutations in the ubiquitin-specific peptidase USP8 gene were recently detected in one- to two-third(s) of corticotroph adenomas of Cushing's disease (CD). These mutations may lead to the deubiquitination of EGFR, thereby increasing EGFR signaling, which has been implicated in ACTH hypersecretion.ObjectiveOur objective was to determine the impact of USP8 mutations on the clinicopathological features of CD.Subjects and methodsUSP8 mutations as well as clinicopathological characteristics were examined in 60 corticotroph adenomas including 15 Crooke's cell adenomas (CCAs), a rare histological variant presenting with generally aggressive behavior, using qRT-PCR and/or immunohistochemistry.ResultsUSP8 mutations were exclusively detected in women, except for one case, with a prevalence of 42.2% in non-CCA and 13.3% in CCA (overall 35%). Clinically well-behaved presentations including microadenoma and curative resection were more common in mutated cases. The expression of EGFR was not associated with the mutation status. In contrast, mutated tumors expressed significantly higher levels of POMC, SSTR5, and MGMT.ConclusionsMicroadenomas that strongly express POMC were common among mutated tumors, which may lead to the mechanisms by which very small adenomas secrete excess ACTH to present overt CD. While USP8 mutations were less likely to enhance tumorous ACTH hypersecretion via EGFR-mediated activation, the presence of USP8 mutations may predict favorable responses to the somatostatin analog pasireotide, which exhibits high affinity for SSTR5. In contrast, non-mutated aggressive tumors such as CCA may respond better to the alkylating agent temozolomide because of their significantly weak expression of MGMT.</abstract><cop>England</cop><pub>Bioscientifica Ltd</pub><pmid>26578638</pmid><doi>10.1530/EJE-15-0689</doi><tpages>14</tpages><oa>free_for_read</oa></addata></record>
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subjects ACTH-Secreting Pituitary Adenoma - genetics
ACTH-Secreting Pituitary Adenoma - metabolism
ACTH-Secreting Pituitary Adenoma - pathology
Adenoma - blood
Adenoma - genetics
Adenoma - pathology
Adult
Aged
Aged, 80 and over
Antineoplastic Agents, Alkylating - pharmacology
Clinical Study
DNA Modification Methylases
DNA Repair Enzymes
Endopeptidases - genetics
Endosomal Sorting Complexes Required for Transport - genetics
Female
Humans
Japan
Male
Middle Aged
Mutation
Pituitary ACTH Hypersecretion - genetics
Pituitary ACTH Hypersecretion - metabolism
Pituitary ACTH Hypersecretion - pathology
Pro-Opiomelanocortin
Receptors, Somatostatin
Sex Factors
Somatostatin - pharmacology
Tumor Suppressor Proteins
Ubiquitin Thiolesterase - genetics
Young Adult
title The USP8 mutational status may predict drug susceptibility in corticotroph adenomas of Cushing's disease
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