Methylation of IGF2 regulatory regions to diagnose adrenocortical carcinomas
Adrenocortical carcinoma (ACC) is a rare malignancy with a poor prognosis. Discrimination of ACCs from adrenocortical adenomas (ACAs) is challenging on both imaging and histopathological grounds. High IGF2 expression is associated with malignancy, but shows large variability. In this study, we inves...
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| Veröffentlicht in: | Endocrine-related cancer 2016-09, Vol.23 (9), p.727-737 |
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| creator | Creemers, S G van Koetsveld, P M van Kemenade, F J Papathomas, T G Franssen, G J H Dogan, F Eekhoff, E M W van der Valk, P de Herder, W W Janssen, J A M J L Feelders, R A Hofland, L J |
| description | Adrenocortical carcinoma (ACC) is a rare malignancy with a poor prognosis. Discrimination of ACCs from adrenocortical adenomas (ACAs) is challenging on both imaging and histopathological grounds. High IGF2 expression is associated with malignancy, but shows large variability. In this study, we investigate whether specific methylation patterns of IGF2 regulatory regions could serve as a valuable biomarker in distinguishing ACCs from ACAs. Pyrosequencing was used to analyse methylation percentages in DMR0, DMR2, imprinting control region (ICR) (consisting of CTCF3 and CTCF6) and the H19 promoter. Expression of IGF2 and H19 mRNA was assessed by real-time quantitative PCR. Analyses were performed in 24 ACCs, 14 ACAs and 11 normal adrenals. Using receiver operating characteristic (ROC) analysis, we evaluated which regions showed the best predictive value for diagnosis of ACC and determined the diagnostic accuracy of these regions. In ACCs, the DMR0, CTCF3, CTCF6 and the H19 promoter were positively correlated with IGF2 mRNA expression (P |
| doi_str_mv | 10.1530/ERC-16-0266 |
| format | Article |
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Discrimination of ACCs from adrenocortical adenomas (ACAs) is challenging on both imaging and histopathological grounds. High IGF2 expression is associated with malignancy, but shows large variability. In this study, we investigate whether specific methylation patterns of IGF2 regulatory regions could serve as a valuable biomarker in distinguishing ACCs from ACAs. Pyrosequencing was used to analyse methylation percentages in DMR0, DMR2, imprinting control region (ICR) (consisting of CTCF3 and CTCF6) and the H19 promoter. Expression of IGF2 and H19 mRNA was assessed by real-time quantitative PCR. Analyses were performed in 24 ACCs, 14 ACAs and 11 normal adrenals. Using receiver operating characteristic (ROC) analysis, we evaluated which regions showed the best predictive value for diagnosis of ACC and determined the diagnostic accuracy of these regions. In ACCs, the DMR0, CTCF3, CTCF6 and the H19 promoter were positively correlated with IGF2 mRNA expression (P<0.05). Methylation in the most discriminating regions distinguished ACCs from ACAs with a sensitivity of 96%, specificity of 100% and an area under the curve (AUC) of 0.997±0.005. Our findings were validated in an independent cohort of 9 ACCs and 13 ACAs, resulting in a sensitivity of 89% and a specificity of 92%. Thus, methylation patterns of IGF2 regulatory regions can discriminate ACCs from ACAs with high diagnostic accuracy. This proposed test may become the first objective diagnostic tool to assess malignancy in adrenal tumours and facilitate the choice of therapeutic strategies in this group of patients.</description><identifier>ISSN: 1351-0088</identifier><identifier>EISSN: 1479-6821</identifier><identifier>DOI: 10.1530/ERC-16-0266</identifier><identifier>PMID: 27535174</identifier><language>eng</language><publisher>England: Bioscientifica Ltd</publisher><subject>Adolescent ; Adrenal Cortex Neoplasms - diagnosis ; Adrenal Cortex Neoplasms - genetics ; Adrenocortical Adenoma - diagnosis ; Adrenocortical Adenoma - genetics ; Adrenocortical Carcinoma - diagnosis ; Adrenocortical Carcinoma - genetics ; Adult ; Aged ; Antimetabolites, Antineoplastic - pharmacology ; Azacitidine - analogs & derivatives ; Azacitidine - pharmacology ; Cell Line, Tumor ; Child ; DNA Methylation ; Female ; Humans ; Insulin-Like Growth Factor II - genetics ; Male ; Middle Aged ; Regulatory Sequences, Nucleic Acid ; RNA, Messenger - metabolism ; Young Adult</subject><ispartof>Endocrine-related cancer, 2016-09, Vol.23 (9), p.727-737</ispartof><rights>2016 Society for Endocrinology</rights><rights>2016 Society for Endocrinology.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-b401t-c1dccc77fda0162a7e039a3a7495f73c70ea1a0c7e3123e4762c5a9809102d3f3</citedby><cites>FETCH-LOGICAL-b401t-c1dccc77fda0162a7e039a3a7495f73c70ea1a0c7e3123e4762c5a9809102d3f3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,3936,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27535174$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Creemers, S G</creatorcontrib><creatorcontrib>van Koetsveld, P M</creatorcontrib><creatorcontrib>van Kemenade, F J</creatorcontrib><creatorcontrib>Papathomas, T G</creatorcontrib><creatorcontrib>Franssen, G J H</creatorcontrib><creatorcontrib>Dogan, F</creatorcontrib><creatorcontrib>Eekhoff, E M W</creatorcontrib><creatorcontrib>van der Valk, P</creatorcontrib><creatorcontrib>de Herder, W W</creatorcontrib><creatorcontrib>Janssen, J A M J L</creatorcontrib><creatorcontrib>Feelders, R A</creatorcontrib><creatorcontrib>Hofland, L J</creatorcontrib><title>Methylation of IGF2 regulatory regions to diagnose adrenocortical carcinomas</title><title>Endocrine-related cancer</title><addtitle>Endocr Relat Cancer</addtitle><description>Adrenocortical carcinoma (ACC) is a rare malignancy with a poor prognosis. Discrimination of ACCs from adrenocortical adenomas (ACAs) is challenging on both imaging and histopathological grounds. High IGF2 expression is associated with malignancy, but shows large variability. In this study, we investigate whether specific methylation patterns of IGF2 regulatory regions could serve as a valuable biomarker in distinguishing ACCs from ACAs. Pyrosequencing was used to analyse methylation percentages in DMR0, DMR2, imprinting control region (ICR) (consisting of CTCF3 and CTCF6) and the H19 promoter. Expression of IGF2 and H19 mRNA was assessed by real-time quantitative PCR. Analyses were performed in 24 ACCs, 14 ACAs and 11 normal adrenals. Using receiver operating characteristic (ROC) analysis, we evaluated which regions showed the best predictive value for diagnosis of ACC and determined the diagnostic accuracy of these regions. In ACCs, the DMR0, CTCF3, CTCF6 and the H19 promoter were positively correlated with IGF2 mRNA expression (P<0.05). Methylation in the most discriminating regions distinguished ACCs from ACAs with a sensitivity of 96%, specificity of 100% and an area under the curve (AUC) of 0.997±0.005. Our findings were validated in an independent cohort of 9 ACCs and 13 ACAs, resulting in a sensitivity of 89% and a specificity of 92%. Thus, methylation patterns of IGF2 regulatory regions can discriminate ACCs from ACAs with high diagnostic accuracy. This proposed test may become the first objective diagnostic tool to assess malignancy in adrenal tumours and facilitate the choice of therapeutic strategies in this group of patients.</description><subject>Adolescent</subject><subject>Adrenal Cortex Neoplasms - diagnosis</subject><subject>Adrenal Cortex Neoplasms - genetics</subject><subject>Adrenocortical Adenoma - diagnosis</subject><subject>Adrenocortical Adenoma - genetics</subject><subject>Adrenocortical Carcinoma - diagnosis</subject><subject>Adrenocortical Carcinoma - genetics</subject><subject>Adult</subject><subject>Aged</subject><subject>Antimetabolites, Antineoplastic - pharmacology</subject><subject>Azacitidine - analogs & derivatives</subject><subject>Azacitidine - pharmacology</subject><subject>Cell Line, Tumor</subject><subject>Child</subject><subject>DNA Methylation</subject><subject>Female</subject><subject>Humans</subject><subject>Insulin-Like Growth Factor II - genetics</subject><subject>Male</subject><subject>Middle Aged</subject><subject>Regulatory Sequences, Nucleic Acid</subject><subject>RNA, Messenger - metabolism</subject><subject>Young Adult</subject><issn>1351-0088</issn><issn>1479-6821</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkMFLwzAUh4Mobk5P3qVHQarvJW2SHmVsczARRM8lS9MZaZuZtIf992ZsehRP7_F-Hz8eHyHXCPeYM3iYvU5T5ClQzk_IGDNRpFxSPI07yzEFkHJELkL4BAAu8_ycjKjIYySyMVk9m_5j16jeui5xdbJczGnizWaIJ-d3-zUmIeldUlm16Vwwiaq86Zx2vrdaNYlWXtvOtSpckrNaNcFcHeeEvM9nb9OndPWyWE4fV-k6A-xTjZXWWoi6UoCcKmGAFYopkRV5LZgWYBQq0MIwpMxkglOdq0JCgUArVrMJuT30br37Gkzoy9YGbZpGdcYNoURJRUEp4_IfKFIpIf4V0bsDqr0LwZu63HrbKr8rEcq96TKaLpGXe9ORvjkWD-vWVL_sj9oI4AFYWxe0NV1v6-jrz9JvmbGIPw</recordid><startdate>20160901</startdate><enddate>20160901</enddate><creator>Creemers, S G</creator><creator>van Koetsveld, P M</creator><creator>van Kemenade, F J</creator><creator>Papathomas, T G</creator><creator>Franssen, G J H</creator><creator>Dogan, F</creator><creator>Eekhoff, E M W</creator><creator>van der Valk, P</creator><creator>de Herder, W W</creator><creator>Janssen, J A M J L</creator><creator>Feelders, R A</creator><creator>Hofland, L J</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><scope>7TO</scope><scope>H94</scope></search><sort><creationdate>20160901</creationdate><title>Methylation of IGF2 regulatory regions to diagnose adrenocortical carcinomas</title><author>Creemers, S G ; van Koetsveld, P M ; van Kemenade, F J ; Papathomas, T G ; Franssen, G J H ; Dogan, F ; Eekhoff, E M W ; van der Valk, P ; de Herder, W W ; Janssen, J A M J L ; Feelders, R A ; Hofland, L J</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-b401t-c1dccc77fda0162a7e039a3a7495f73c70ea1a0c7e3123e4762c5a9809102d3f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Adolescent</topic><topic>Adrenal Cortex Neoplasms - diagnosis</topic><topic>Adrenal Cortex Neoplasms - genetics</topic><topic>Adrenocortical Adenoma - diagnosis</topic><topic>Adrenocortical Adenoma - genetics</topic><topic>Adrenocortical Carcinoma - diagnosis</topic><topic>Adrenocortical Carcinoma - genetics</topic><topic>Adult</topic><topic>Aged</topic><topic>Antimetabolites, Antineoplastic - pharmacology</topic><topic>Azacitidine - analogs & derivatives</topic><topic>Azacitidine - pharmacology</topic><topic>Cell Line, Tumor</topic><topic>Child</topic><topic>DNA Methylation</topic><topic>Female</topic><topic>Humans</topic><topic>Insulin-Like Growth Factor II - genetics</topic><topic>Male</topic><topic>Middle Aged</topic><topic>Regulatory Sequences, Nucleic Acid</topic><topic>RNA, Messenger - metabolism</topic><topic>Young Adult</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Creemers, S G</creatorcontrib><creatorcontrib>van Koetsveld, P M</creatorcontrib><creatorcontrib>van Kemenade, F J</creatorcontrib><creatorcontrib>Papathomas, T G</creatorcontrib><creatorcontrib>Franssen, G J H</creatorcontrib><creatorcontrib>Dogan, F</creatorcontrib><creatorcontrib>Eekhoff, E M W</creatorcontrib><creatorcontrib>van der Valk, P</creatorcontrib><creatorcontrib>de Herder, W W</creatorcontrib><creatorcontrib>Janssen, J A M J L</creatorcontrib><creatorcontrib>Feelders, R A</creatorcontrib><creatorcontrib>Hofland, L J</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><collection>Oncogenes and Growth Factors Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><jtitle>Endocrine-related cancer</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Creemers, S G</au><au>van Koetsveld, P M</au><au>van Kemenade, F J</au><au>Papathomas, T G</au><au>Franssen, G J H</au><au>Dogan, F</au><au>Eekhoff, E M W</au><au>van der Valk, P</au><au>de Herder, W W</au><au>Janssen, J A M J L</au><au>Feelders, R A</au><au>Hofland, L J</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Methylation of IGF2 regulatory regions to diagnose adrenocortical carcinomas</atitle><jtitle>Endocrine-related cancer</jtitle><addtitle>Endocr Relat Cancer</addtitle><date>2016-09-01</date><risdate>2016</risdate><volume>23</volume><issue>9</issue><spage>727</spage><epage>737</epage><pages>727-737</pages><issn>1351-0088</issn><eissn>1479-6821</eissn><abstract>Adrenocortical carcinoma (ACC) is a rare malignancy with a poor prognosis. Discrimination of ACCs from adrenocortical adenomas (ACAs) is challenging on both imaging and histopathological grounds. High IGF2 expression is associated with malignancy, but shows large variability. In this study, we investigate whether specific methylation patterns of IGF2 regulatory regions could serve as a valuable biomarker in distinguishing ACCs from ACAs. Pyrosequencing was used to analyse methylation percentages in DMR0, DMR2, imprinting control region (ICR) (consisting of CTCF3 and CTCF6) and the H19 promoter. Expression of IGF2 and H19 mRNA was assessed by real-time quantitative PCR. Analyses were performed in 24 ACCs, 14 ACAs and 11 normal adrenals. Using receiver operating characteristic (ROC) analysis, we evaluated which regions showed the best predictive value for diagnosis of ACC and determined the diagnostic accuracy of these regions. In ACCs, the DMR0, CTCF3, CTCF6 and the H19 promoter were positively correlated with IGF2 mRNA expression (P<0.05). Methylation in the most discriminating regions distinguished ACCs from ACAs with a sensitivity of 96%, specificity of 100% and an area under the curve (AUC) of 0.997±0.005. Our findings were validated in an independent cohort of 9 ACCs and 13 ACAs, resulting in a sensitivity of 89% and a specificity of 92%. Thus, methylation patterns of IGF2 regulatory regions can discriminate ACCs from ACAs with high diagnostic accuracy. This proposed test may become the first objective diagnostic tool to assess malignancy in adrenal tumours and facilitate the choice of therapeutic strategies in this group of patients.</abstract><cop>England</cop><pub>Bioscientifica Ltd</pub><pmid>27535174</pmid><doi>10.1530/ERC-16-0266</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Adolescent Adrenal Cortex Neoplasms - diagnosis Adrenal Cortex Neoplasms - genetics Adrenocortical Adenoma - diagnosis Adrenocortical Adenoma - genetics Adrenocortical Carcinoma - diagnosis Adrenocortical Carcinoma - genetics Adult Aged Antimetabolites, Antineoplastic - pharmacology Azacitidine - analogs & derivatives Azacitidine - pharmacology Cell Line, Tumor Child DNA Methylation Female Humans Insulin-Like Growth Factor II - genetics Male Middle Aged Regulatory Sequences, Nucleic Acid RNA, Messenger - metabolism Young Adult |
| title | Methylation of IGF2 regulatory regions to diagnose adrenocortical carcinomas |
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