Next-generation sequencing of adrenocortical carcinoma reveals new routes to targeted therapies

Ross, Jeffrey S.; Wang, K; Rand, Janne; Gay, Laurie M.; Presta, Marco; Sheehan, Christine E.; Ali, Siraj M.; Elvin, Julia A.; LaBrecque, Elaine; Hiemstra, Christine N; Buell, Jamie; Otto, Geoffrey A.; Yelensky, Roman; Lipson, Doron; Morosini, Deborah; Chmielecki, Juliann; Miller, Vincent A.; Stephens, Phil

doi:10.1136/jclinpath-2014-202514

Cited by 53 publications

(40 citation statements)

References 40 publications

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“…In this report of a precision medicine approach for advanced ACCs, including NGS, IHC, and FISH, we sought to verify our results in the light of previously published precision medicine studies for ACC [11, 12]. We identified 4 samples with at least 1 mutation in our 50-gene panel.…”

Section: Discussionmentioning

confidence: 66%

Analysis of 10 Adrenocortical Carcinoma Patients in the Cohort of the Precision Medicine Platform MONDTI

et al. 2018

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Objective: Adrenocortical carcinoma (ACC) is a rare disease with a dismal prognosis. We aimed to evaluate if a personalized medicine approach may be useful for matching patients with ACC to targeted therapies. Methods: This is an analysis of 10 molecularly profiled ACCs that were progressing under standard of care treatment. The profile consisted of a 50-gene next-generation sequencing panel, immunohistochemistry (IHC), and fluorescence in situ hybridization for several proteins or chromosomal aberrations. Results: In 6 (60%) tumor samples, no somatic mutation was detected, while in 3 (30%) tumors 1 mutation was detected and in 1 (10%) tumor 2 mutations were detected. These mutations were CTNNB1 (2 samples), TP53 (1 sample), RB1 (1 sample) and APC (1 sample). Expression of phospho-mTOR and of EGFR was commonly detected by IHC (87.5 and 62.5%). In 4 (50%) samples, IHC revealed a weak expression of progesterone receptor. Less frequent alterations were expression of PDGFR-α, c-KIT, and estrogen receptor, each in 1 case. Conclusions: Based on the molecular profile, no recommendation for targeted therapy was made by the multi-disciplinary team. Currently, ACC might not be suitable for a precision medicine approach according to our tests.

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Section: Discussionmentioning

confidence: 66%

Analysis of 10 Adrenocortical Carcinoma Patients in the Cohort of the Precision Medicine Platform MONDTI

et al. 2018

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“…Overall, 19/40 ACCs (47.5%) had at least one molecular abnormality (De Martino et al 2013). In a second study, Ross et al (2014) recently performed a comprehensive genomic profiling of 29 ACC samples and found at least one alteration (a mutation, amplification, deletion, or truncation) in 22 cases (76%). Genomic alterations in NF1 (14%), CDKN2A (14%), ATM (10%), CCND2 (7%), CDK4 (7%) and DNMT3A (7%) were considered as the most common and potentially clinically relevant at the same time (Ross et al 2014).…”

Section: Geneticsmentioning

confidence: 99%

“…In a second study, Ross et al (2014) recently performed a comprehensive genomic profiling of 29 ACC samples and found at least one alteration (a mutation, amplification, deletion, or truncation) in 22 cases (76%). Genomic alterations in NF1 (14%), CDKN2A (14%), ATM (10%), CCND2 (7%), CDK4 (7%) and DNMT3A (7%) were considered as the most common and potentially clinically relevant at the same time (Ross et al 2014). The third study showed, considering the different omics classifications, a strong correlation between clustering of patients with different prognosis based on transcriptome clusters, DNA methylation and miRNA expression .…”

Section: Geneticsmentioning

confidence: 99%

Future directions in the diagnosis and medical treatment of adrenocortical carcinoma

Creemers¹,

Hofland²,

Korpershoek³

et al. 2015

Endocrine-Related Cancer

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Adrenocortical carcinoma (ACC) is a rare disease with a poor prognosis. Discrimination between ACCs and adrenocortical adenomas (ACAs) remains challenging, with the current gold standard being the Weiss score, consisting of several histopathological characteristics. However, new markers like Ki67, a marker for proliferation, and the staining of reticulins are promising not only as it comes to identifying malignancy but also as prognostic markers in patients with ACC. Currently, surgery is still the only curative treatment for ACC. Mitotane, an adrenolytic drug, is used in the adjuvant setting and in case of metastatic or advanced disease. Patients with progressive disease are frequently treated with mitotane, alone or in combination with etoposide, doxorubicine and cisplatin. Radiotherapy is indicated in selected cases. The low response rates and high toxicity of the systemic therapies emphasize the need for markers that enable the identification of responders and non-responders. Consequently, research is focusing on predictive factors varying from the expression of DNA repair genes to clinical patient characteristics. Subgroups of ACC with different prognosis have been identified based on transcriptome characteristics. As a conclusion from large molecular studies, ACCs appear to harbor many abnormalities compared to ACAs. Altered pathways driving ACC pathogenesis include the IGF, TP53 and the Wnt signaling pathway, allowing these as new potential targets for medical therapy. However, despite efforts in preclinical and clinical studies investigating efficacy of targeting these pathways, most novel therapies appear to be effective in only a subset of patients with ACC. New treatment concepts are therefore urgently needed.

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“…These studies converge on a reduced list of recurrent ACC drivers (Table 1). Two other studies used next generation sequencing to characterize the mutations in ACC, analyzing the genetic variation of a limited number of cancer-related genes, and restricting the analysis to the tumor DNA (35,36).…”

Section: The Mutation Landscape Of Acc: a Reduced Number Of Genes Witmentioning

confidence: 99%

“…Concerning methylation, the CIMP can be recapitulated by focal measurements of methylation, using methylation-specific multiplex ligation probe assay, a technique widely available in oncogenetic departments (59). Finally targeted sequencing of driver genes can be performed by next generation sequencing (35,36). In theory all these techniques are easily applicable.…”

Section: Genetic Counseling For the New Genetic Diseasesmentioning

confidence: 99%

ENDOCRINE TUMOURS: The genomics of adrenocortical tumors

Faillot

Assié

2016

European Journal of Endocrinology

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The last decade witnessed the emergence of genomics, a set of high-throughput molecular measurements in biological samples. These pan-genomic and agnostic approaches have revolutionized the molecular biology and genetics of malignant and benign tumors. These techniques have been applied successfully to adrenocortical tumors. Exome sequencing identified new major drivers in all tumor types, including KCNJ5, ATP1A1, ATP2B3 and CACNA1D mutations in aldosterone-producing adenomas (APA), PRKACA mutations in cortisol-producing adenomas (CPA), ARMC5 mutations in primary bilateral macronodular adrenocortical hyperplasia (PBMAH) and ZNRF3 mutations in adrenocortical carcinomas (ACC). Moreover, the various genomic approaches -including exome sequencing, transcriptome, miRNome, genome and methylome -converge into a single molecular classification of adrenocortical tumors. Especially for ACC, two main molecular groups have emerged, showing major differences in outcomes. These ACC groups differ by their gene expression profiles, but also by recurrent mutations and specific DNA hypermethylation patterns in the subgroup of poor outcome. The clinical impact of these findings is just starting. The main altered signaling pathways now become therapeutic targets. The molecular groups of diseases individualize robust subtypes within diseases such as APA, CPA, PBMAH and ACC. A revised nosology of adrenocortical tumors should impact the clinical research. Obvious consequences also include genetic counseling for the new genetic diseases such as ARMC5 mutations in PBMAH, and a better prognostication of ACC based on targeted measurements of a few discriminant molecular alterations. Identifying the main molecular groups of adrenocortical tumors by extensively gathering the molecular variations is a significant step forward towards precision medicine.

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Next-generation sequencing of adrenocortical carcinoma reveals new routes to targeted therapies

Cited by 53 publications

References 40 publications

Analysis of 10 Adrenocortical Carcinoma Patients in the Cohort of the Precision Medicine Platform MONDTI

Analysis of 10 Adrenocortical Carcinoma Patients in the Cohort of the Precision Medicine Platform MONDTI

Future directions in the diagnosis and medical treatment of adrenocortical carcinoma

ENDOCRINE TUMOURS: The genomics of adrenocortical tumors

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