Genetic Landscape of Sporadic Unilateral Adrenocortical Adenomas Without PRKACA p.Leu206Arg Mutation

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Genetic Landscape of Sporadic Unilateral Adrenocortical Adenomas Without PRKACA p.Leu206Arg Mutation. / European Network for the Study of Adrenocortical Tumors (ENSAT).

In: Journal of Clinical Endocrinology and Metabolism, Vol. 101, No. 9, 09.2016, p. 3526-3538.

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European Network for the Study of Adrenocortical Tumors (ENSAT). / Genetic Landscape of Sporadic Unilateral Adrenocortical Adenomas Without PRKACA p.Leu206Arg Mutation. In: Journal of Clinical Endocrinology and Metabolism. 2016 ; Vol. 101, No. 9. pp. 3526-3538.

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@article{68329e9a4ec24db49821e5a74dbfac98,
title = "Genetic Landscape of Sporadic Unilateral Adrenocortical Adenomas Without PRKACA p.Leu206Arg Mutation",
abstract = "Context:Adrenocortical adenomas (ACAs) are among the most frequent human neoplasias. Genetic alterations affecting the cAMP/protein kinase A signaling pathway are common in cortisol-producing ACAs, whereas activating mutations in the gene encoding β-catenin (CTNNB1) have been reported in a subset of both benign and malignant adrenocortical tumors. However, the molecular pathogenesis of most ACAs is still largely unclear.Objective:The aim of the study was to define the genetic landscape of sporadic unilateral ACAs.Design and Setting:Next-generation whole-exome sequencing was performed on fresh-frozen tumor samples and corresponding normal tissue samples.Patients:Ninety-nine patients with ACAs (74 cortisol-producing and 25 endocrine inactive) negative for p.Leu206Arg PRKACA mutation.Main Outcome Measures:Identification of known and/or new genetic alterations potentially involved in adrenocortical tumorigenesis and autonomous hormone secretion, genotype-phenotype correlation.Results:A total of 706 somatic protein-altering mutations were detected in 88 of 99 tumors (median, six per tumor). We identified several mutations in genes of the cAMP/protein kinase A pathway, including three novel mutations in PRKACA, associated with female sex and Cushing's syndrome. We also found genetic alterations in different genes involved in the Wnt/β-catenin pathway, associated with larger tumors and endocrine inactivity, and notably, in many genes of the Ca2+-signaling pathway. Finally, by comparison of our genetic data with those available in the literature, we describe a comprehensive genetic landscape of unilateral ACAs.Conclusions:This study provides the largest sequencing effort on ACAs to date. We thereby identified somatic alterations affecting known and novel pathways potentially involved in adrenal tumorigenesis.AbstractThis study provides the largest DNA sequencing effort in adrenocortical adenomas up to now. Somatic alterations in known and novel pathways potentially involved in adrenal tumorigenesis are reported.",
keywords = "acas trial , phenotype , adrenal glands, signal transduction, mutation, adenoma, genes , adrenal cortical , cyclic amp, genetics , whole exome sequencing, beta catenin, neoplasms , tumorigenesis",
author = "Cristina Ronchi and {Di Dalmazi}, Guido and Simon Faillot and Silviu Sbiera and Guillaume Assie and Isabel Weigand and Davide Calebiro and Thomas Schwarzmayr and Silke Appenzeller and Beatrice Rubin and Jens Waldmann and Carla Scaroni and Dirk Bartsch and Franco Mantero and Massimo Mannelli and Darko Kastelan and Iacopo Chiodini and Jerome Bertherat and Martin Reincke and Tim Strom and Martin Fassnacht and Felix Beuschlein and {European Network for the Study of Adrenocortical Tumors (ENSAT)}",
year = "2016",
month = sep,
doi = "10.1210/jc.2016-1586",
language = "English",
volume = "101",
pages = "3526--3538",
journal = "Journal of Clinical Endocrinology and Metabolism",
issn = "0021-972X",
publisher = "Endocrine Society",
number = "9",

}

RIS

TY - JOUR

T1 - Genetic Landscape of Sporadic Unilateral Adrenocortical Adenomas Without PRKACA p.Leu206Arg Mutation

AU - Ronchi, Cristina

AU - Di Dalmazi, Guido

AU - Faillot, Simon

AU - Sbiera, Silviu

AU - Assie, Guillaume

AU - Weigand, Isabel

AU - Calebiro, Davide

AU - Schwarzmayr, Thomas

AU - Appenzeller, Silke

AU - Rubin, Beatrice

AU - Waldmann, Jens

AU - Scaroni, Carla

AU - Bartsch, Dirk

AU - Mantero, Franco

AU - Mannelli, Massimo

AU - Kastelan, Darko

AU - Chiodini, Iacopo

AU - Bertherat, Jerome

AU - Reincke, Martin

AU - Strom, Tim

AU - Fassnacht, Martin

AU - Beuschlein, Felix

AU - European Network for the Study of Adrenocortical Tumors (ENSAT)

PY - 2016/9

Y1 - 2016/9

N2 - Context:Adrenocortical adenomas (ACAs) are among the most frequent human neoplasias. Genetic alterations affecting the cAMP/protein kinase A signaling pathway are common in cortisol-producing ACAs, whereas activating mutations in the gene encoding β-catenin (CTNNB1) have been reported in a subset of both benign and malignant adrenocortical tumors. However, the molecular pathogenesis of most ACAs is still largely unclear.Objective:The aim of the study was to define the genetic landscape of sporadic unilateral ACAs.Design and Setting:Next-generation whole-exome sequencing was performed on fresh-frozen tumor samples and corresponding normal tissue samples.Patients:Ninety-nine patients with ACAs (74 cortisol-producing and 25 endocrine inactive) negative for p.Leu206Arg PRKACA mutation.Main Outcome Measures:Identification of known and/or new genetic alterations potentially involved in adrenocortical tumorigenesis and autonomous hormone secretion, genotype-phenotype correlation.Results:A total of 706 somatic protein-altering mutations were detected in 88 of 99 tumors (median, six per tumor). We identified several mutations in genes of the cAMP/protein kinase A pathway, including three novel mutations in PRKACA, associated with female sex and Cushing's syndrome. We also found genetic alterations in different genes involved in the Wnt/β-catenin pathway, associated with larger tumors and endocrine inactivity, and notably, in many genes of the Ca2+-signaling pathway. Finally, by comparison of our genetic data with those available in the literature, we describe a comprehensive genetic landscape of unilateral ACAs.Conclusions:This study provides the largest sequencing effort on ACAs to date. We thereby identified somatic alterations affecting known and novel pathways potentially involved in adrenal tumorigenesis.AbstractThis study provides the largest DNA sequencing effort in adrenocortical adenomas up to now. Somatic alterations in known and novel pathways potentially involved in adrenal tumorigenesis are reported.

AB - Context:Adrenocortical adenomas (ACAs) are among the most frequent human neoplasias. Genetic alterations affecting the cAMP/protein kinase A signaling pathway are common in cortisol-producing ACAs, whereas activating mutations in the gene encoding β-catenin (CTNNB1) have been reported in a subset of both benign and malignant adrenocortical tumors. However, the molecular pathogenesis of most ACAs is still largely unclear.Objective:The aim of the study was to define the genetic landscape of sporadic unilateral ACAs.Design and Setting:Next-generation whole-exome sequencing was performed on fresh-frozen tumor samples and corresponding normal tissue samples.Patients:Ninety-nine patients with ACAs (74 cortisol-producing and 25 endocrine inactive) negative for p.Leu206Arg PRKACA mutation.Main Outcome Measures:Identification of known and/or new genetic alterations potentially involved in adrenocortical tumorigenesis and autonomous hormone secretion, genotype-phenotype correlation.Results:A total of 706 somatic protein-altering mutations were detected in 88 of 99 tumors (median, six per tumor). We identified several mutations in genes of the cAMP/protein kinase A pathway, including three novel mutations in PRKACA, associated with female sex and Cushing's syndrome. We also found genetic alterations in different genes involved in the Wnt/β-catenin pathway, associated with larger tumors and endocrine inactivity, and notably, in many genes of the Ca2+-signaling pathway. Finally, by comparison of our genetic data with those available in the literature, we describe a comprehensive genetic landscape of unilateral ACAs.Conclusions:This study provides the largest sequencing effort on ACAs to date. We thereby identified somatic alterations affecting known and novel pathways potentially involved in adrenal tumorigenesis.AbstractThis study provides the largest DNA sequencing effort in adrenocortical adenomas up to now. Somatic alterations in known and novel pathways potentially involved in adrenal tumorigenesis are reported.

KW - acas trial

KW - phenotype

KW - adrenal glands

KW - signal transduction

KW - mutation

KW - adenoma

KW - genes

KW - adrenal cortical

KW - cyclic amp

KW - genetics

KW - whole exome sequencing

KW - beta catenin

KW - neoplasms

KW - tumorigenesis

U2 - 10.1210/jc.2016-1586

DO - 10.1210/jc.2016-1586

M3 - Article

VL - 101

SP - 3526

EP - 3538

JO - Journal of Clinical Endocrinology and Metabolism

JF - Journal of Clinical Endocrinology and Metabolism

SN - 0021-972X

IS - 9

ER -