Identification of a CpG Island Methylator Phenotype in Adrenocortical Carcinomas

Barreau, Olivia; Assié, Guillaume; Wilmot-Roussel, H.; Ragazzon, Bruno; Baudry, Camille; Perlemoine, Karine; René-Corail, Fernande; Bertagna, Xavier; Dousset, B.; Hamzaoui, Nadim; Tissier, Frédérique; Reyniès, Aurélien de; Bertherat, Jérôme

doi:10.1210/jc.2012-2993

Cited by 110 publications

(141 citation statements)

References 39 publications

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“…This hypomethylation is mainly related to hypomethylation in intergenic regions of DNA, probably contributing to the genome instability, as seen in cancer in general (58). Beyond this global hypomethylation, a subset of ACC shows specific patterns of methylation, with hypermethylation in CpG islands of gene promoter regions (59). This point will be detailed in the next paragraph.…”

Section: Common Molecular Features Of Accmentioning

confidence: 94%

“…Indeed some ACC are hypermethylated in these regions, evoking a CpG island methylator phenotype (CIMP), as described in other malignancies such as colon cancer (65). In ACC, CIMP is associated with a poor outcome (59).…”

Section: Genomics Identify Different Molecular Groups Of Accmentioning

confidence: 99%

“…Table 2 Principal genomics publications on adrenocortical tumors. www.eje-online.org At the DNA methylation level, an important variability occurs when focusing on the methylation of gene promoter regions, in regions enriched in 'CG' bases (called CpG islands) (57,59). Indeed some ACC are hypermethylated in these regions, evoking a CpG island methylator phenotype (CIMP), as described in other malignancies such as colon cancer (65).…”

Section: Genomics Identify Different Molecular Groups Of Accmentioning

confidence: 99%

“…The link between driver mutations and transcriptome can probably be partially explained: mutations in drivers such as TP53 or CDKN2A probably contribute to the cell-cycle signature identified in the subgroup of poor outcome, as observed in other cancer types, though the precise transcriptome signature induced by each driver mutation in adrenal cells is not precisely established. Finally, concerning the link between methylation and transcriptome, the CIMP is potentially responsible for modulating the expression level of 15% of genes (59).…”

Section: The Molecular Group Of Aggressive Accmentioning

confidence: 99%

“…As stated before, gene expression, but also miRNAs can be conveniently assayed by quantitative RT-PCR. 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).…”

Section: Genetic Counseling For the New Genetic Diseasesmentioning

confidence: 99%

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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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Section: Common Molecular Features Of Accmentioning

confidence: 94%

Section: Genomics Identify Different Molecular Groups Of Accmentioning

confidence: 99%

Section: Genomics Identify Different Molecular Groups Of Accmentioning

confidence: 99%

Section: The Molecular Group Of Aggressive Accmentioning

confidence: 99%

Section: Genetic Counseling For the New Genetic Diseasesmentioning

confidence: 99%

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ENDOCRINE TUMOURS: The genomics of adrenocortical tumors

Faillot

Assié

2016

European Journal of Endocrinology

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Value of Molecular Classification for Prognostic Assessment of Adrenocortical Carcinoma

et al. 2019

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The risk stratification of adrenocortical carcinoma (ACC) based on tumor proliferation index and stage is limited. Adjuvant therapy after surgery is recommended for most patients. Pan-genomic studies have identified distinct molecular groups closely associated with outcome. OBJECTIVE To compare the molecular classification for prognostic assessment of ACC with other known prognostic factors. DESIGN, SETTING, AND PARTICIPANTS In this retrospective biomarker analysis, ACC tumor samples from 368 patients who had undergone surgical tumor removal were collected from March 1, 2005, to September 30, 2015 (144 in the training cohort and 224 in the validation cohort) at 21 referral centers with a median follow-up of 35 months (interquartile range, 18-74 months). Data were analyzed from March 2016 to March 2018. EXPOSURES Meta-analysis of pan-genomic studies (transcriptome, methylome, chromosome alteration, and mutational profiles) was performed on the training cohort. Targeted biomarker analysis, including targeted gene expression (BUB1B and PINK1), targeted methylation (PAX5, GSTP1, PYCARD, and PAX6), and targeted next-generation sequencing, was performed on the training and validation cohorts. MAIN OUTCOMES AND MEASURES Disease-free survival. Cox proportional hazards regression and C indexes were used to assess the prognostic value of each model. RESULTS Of the 368 patients (mean [SD] age, 49 [16] years), 144 were in the training cohort (100 [69.4%] female) and 224 were in the validation cohort (142 [63.4%] female). In the training cohort, pan-genomic measures classified ACC into 3 molecular groups (A1, A2, and A3-B), with 5-year survival of 9% for group A1, 45% for group A2, and 82% for group A3-B (log-rank P < .001). Molecular class was an independent prognostic factor of recurrence in stage I to III ACC after complete surgery (hazard ratio, 55.91; 95% CI, 8.55-365.40; P < .001). The combination of European Network for the Study of Adrenal Tumors (ENSAT) stage, tumor proliferation index, and molecular class provided the most discriminant prognostic model (C index, 0.88). In the validation cohort, the molecular classification, determined by targeted biomarker measures, was confirmed as an independent prognostic factor of recurrence (hazard ratio, 5.96 [95% CI, 1.81-19.58], P = .003 for the targeted classifier combining expression, methylation, and chromosome alterations; and 2.61 [95% CI, 1.31-5.19], P = .006 for the targeted classifier combining methylation, chromosome alterations, and mutational profile). The prognostic value of the molecular markers was limited for patients with stage IV ACC. CONCLUSIONS AND RELEVANCE The findings suggest that in localized ACC, targeted classifiers may be used as independent markers of recurrence. The determination of molecular class may improve individual prognostic assessment and thus may spare unnecessary adjuvant treatment.

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HPV‐related methylation‐based reclassification and risk stratification of cervical cancer

Yang

Wang

et al. 2020

Molecular Oncology

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Human papillomavirus (HPV) is a clear etiology of cervical cancer (CC). However, the associations between HPV infection and DNA methylation have not been thoroughly investigated. Additionally, it remains unknown whether HPV‐related methylation signatures can identify subtypes of CC and stratify the prognosis of CC patients. DNA methylation profiles were obtained from The Cancer Genome Atlas to identify HPV‐related methylation sites. Unsupervised clustering analysis of HPV‐related methylation sites was performed to determine the different CC subtypes. CC patients were categorized into cluster 1 (Methylation‐H), cluster 2 (Methylation‐M), and cluster 3 (Methylation‐L). Compared to Methylation‐M and Methylation‐L, Methylation‐H exhibited a significantly improved overall survival (OS). Gene set enrichment analysis (GSEA) was conducted to investigate the functions that correlated with different CC subtypes. GSEA indicated that the hallmarks of tumors, including KRAS signaling, TNFα signaling via NF‐κB, inflammatory response, epithelial–mesenchymal transition, and interferon‐gamma response, were enriched in Methylation‐M and Methylation‐L. Based on mutation and copy number variation analyses, we found that aberrant mutations, amplifications, and deletions among the MYC, Notch, PI3K‐AKT, and RTK‐RAS pathways were most frequently detected in Methylation‐H. Additionally, mutations, amplifications, and deletions within the Hippo, PI3K‐AKT, and TGF‐β pathways were presented in Methylation‐M. Genes within the cell cycle, Notch, and Hippo pathways possessed aberrant mutations, amplifications, and deletions in Methylation‐L. Moreover, the analysis of tumor microenvironments revealed that Methylation‐H was characterized by a relatively low degree of immune cell infiltration. Finally, a prognostic signature based on six HPV‐related methylation sites was developed and validated. Our study revealed that CC patients could be classified into three heterogeneous clusters based on HPV‐related methylation signatures. Additionally, we derived a prognostic signature using six HPV‐related methylation sites that stratified the OS of patients with CC into high‐ and low‐risk groups.

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Identification of a CpG Island Methylator Phenotype in Adrenocortical Carcinomas

Abstract: This genome-wide methylation analysis reveals the existence of hypermethylated adrenocortical carcinomas, with a poorer prognosis. Hypermethylation in these tumors is important for silencing specific tumor suppressor genes.

Cited by 110 publications

References 39 publications

ENDOCRINE TUMOURS: The genomics of adrenocortical tumors

ENDOCRINE TUMOURS: The genomics of adrenocortical tumors

Value of Molecular Classification for Prognostic Assessment of Adrenocortical Carcinoma

HPV‐related methylation‐based reclassification and risk stratification of cervical cancer

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