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 |
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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. 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><subject>ACTH-Secreting Pituitary Adenoma - genetics</subject><subject>ACTH-Secreting Pituitary Adenoma - metabolism</subject><subject>ACTH-Secreting Pituitary Adenoma - pathology</subject><subject>Adenoma - blood</subject><subject>Adenoma - genetics</subject><subject>Adenoma - pathology</subject><subject>Adult</subject><subject>Aged</subject><subject>Aged, 80 and over</subject><subject>Antineoplastic Agents, Alkylating - pharmacology</subject><subject>Clinical Study</subject><subject>DNA Modification Methylases</subject><subject>DNA Repair Enzymes</subject><subject>Endopeptidases - genetics</subject><subject>Endosomal Sorting Complexes Required for Transport - genetics</subject><subject>Female</subject><subject>Humans</subject><subject>Japan</subject><subject>Male</subject><subject>Middle Aged</subject><subject>Mutation</subject><subject>Pituitary ACTH Hypersecretion - genetics</subject><subject>Pituitary ACTH Hypersecretion - metabolism</subject><subject>Pituitary ACTH Hypersecretion - pathology</subject><subject>Pro-Opiomelanocortin</subject><subject>Receptors, Somatostatin</subject><subject>Sex Factors</subject><subject>Somatostatin - pharmacology</subject><subject>Tumor Suppressor Proteins</subject><subject>Ubiquitin Thiolesterase - genetics</subject><subject>Young Adult</subject><issn>0804-4643</issn><issn>1479-683X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kEFr3DAQhUVoSTZpTrkX3VoIbkeWLNnHsmyTlkALTaA3I8vjrIptORr5sP--Cpv02NM8ho_H42PsSsAnUUn4vPu-K0RVgK6bE7YRyjSFruXvN2wDNahCaSXP2DnRHwCRM5yys1JXptay3rD9_R75w6-fNZ_WZJMPsx055bQSn-yBLxF77xLv4_rIaSWHS_KdH306cD9zF2LyLqQYlj23Pc5hssTDwLcr7f38-IF47wkt4Tv2drAj4eXLvWAPX3f329vi7sfNt-2Xu6JTRqfCYlPXWA6mAqMqcLaTvQQY0HSIKEuLOv8MKGe1bSTYTpVSgDIdlMooIS_Yx2PvEsPTipTayefV42hnDCu1wlRCNFoYndHrI-piIIo4tEv0k42HVkD7rLbNanNon9Vm-v1L8dpN2P9jX11mQByBzgdyHufkB-_sf0v_AltUhVg</recordid><startdate>201602</startdate><enddate>201602</enddate><creator>Hayashi, Kyohei</creator><creator>Inoshita, Naoko</creator><creator>Kawaguchi, Kohei</creator><creator>Ibrahim Ardisasmita, Arif</creator><creator>Suzuki, Hisanori</creator><creator>Fukuhara, Noriaki</creator><creator>Okada, Mitsuo</creator><creator>Nishioka, Hiroshi</creator><creator>Takeuchi, Yasuhiro</creator><creator>Komada, Masayuki</creator><creator>Takeshita, Akira</creator><creator>Yamada, Shozo</creator><general>Bioscientifica Ltd</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>201602</creationdate><title>The USP8 mutational status may predict drug susceptibility in corticotroph adenomas of Cushing's disease</title><author>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</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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