Aldosterone-Producing Adenoma With a Somatic KCNJ5 Mutation Revealing APC-Dependent Familial Adenomatous Polyposis

Vouillarmet, Julien; Fernandes-Rosa, Fábio Luiz; Graeppi-Dulac, J.; Lantelme, Pierre; Decaussin‐Petrucci, Myriam; Thivolet, Charles; Peix, Jean‐Louis; Boulkroun, Sheerazed; Clauser, Éric; Zennaro, Maria-Christina

doi:10.1210/jc.2016-1874

Cited by 37 publications

(22 citation statements)

References 16 publications

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“…Taken together, all these results suggest that somatic mutations responsible for aldosterone biosynthesis could be a secondary event in APA development. In agreement with this possibility, we have described the concurrence of different germline and somatic mutations leading to APA development (Vouillarmet et al 2016). A young patient with severe PA aged 26 years, bilateral macronodular adrenal hyperplasia seen on CT, and lateralized aldosterone secretion, showed clinical improvement of PA after right adrenalectomy.…”

Section: Molecular and Histopathological Heterogeneity Of Apasupporting

confidence: 73%

“…A FDG-PET performed after surgery revealed abnormal rectal activity despite the absence of clinical symptoms, and gastrointestinal exploration revealed familial adenomatous polyposis. We identified the presence of a germline heterozygous APC gene mutation associated with nodular biallelic APC inactivation due to loss of heterozygosity (Vouillarmet et al 2016). This case supports a two-hit model for APA formation whereby the first hit (APC germline mutation) drives the nodule development, whereas the second hit (KCNJ5 somatic mutation) specifies the pattern of hormonal secretion.…”

Section: Molecular and Histopathological Heterogeneity Of Apasupporting

confidence: 66%

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Somatic and inherited mutations in primary aldosteronism

Fernandes-Rosa

Boulkroun

Zennaro

2017

Journal of Molecular Endocrinology

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Primary aldosteronism (PA), the most common form of secondary hypertension, is caused in the majority of cases by unilateral aldosterone-producing adenoma (APA) or bilateral adrenal hyperplasia. Over the past few years, somatic mutations in KCNJ5, CACNA1D, ATP1A1 and ATP2B3 have been proven to be associated with APA development, representing more than 50% of sporadic APA. The identification of these mutations has allowed the development of a model for APA involving modification on the intracellular ionic equilibrium and regulation of cell membrane potential, leading to autonomous aldosterone overproduction. Furthermore, somatic CTNNB1 mutations have also been identified in APA, but the link between these mutations and APA development remains unknown. The sequence of events responsible for APA formation is not completely understood, in particular, whether a single hit or a double hit is responsible for both aldosterone overproduction and cell proliferation. Germline mutations identified in patients with early-onset PA have expanded the classification of familial forms (FH) of PA. The description of germline KCNJ5 and CACNA1H mutations has identified FH-III and FH-IV based on genetic findings; germline CACNA1D mutations have been identified in patients with very early-onset PA and severe neurological abnormalities. This review summarizes current knowledge on the genetic basis of PA, the association of driver gene mutations and clinical findings and in the contribution to patient care, plus the current understanding on the mechanisms of APA development.

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Section: Molecular and Histopathological Heterogeneity Of Apasupporting

confidence: 73%

Section: Molecular and Histopathological Heterogeneity Of Apasupporting

confidence: 66%

Somatic and inherited mutations in primary aldosteronism

Fernandes-Rosa

Boulkroun

Zennaro

2017

Journal of Molecular Endocrinology

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“…The somatic mutation in KCNJ5 has been implicated in the pathogenesis process of familial adenomatous polyposis. 14 Per our study, KCNJ5 might have a pivotal role in tumor immune infiltration and, thus, tumor progression. To explore the chemotaxis effect of KCNJ5, we performed the transwell assay.…”

Section: Resultsmentioning

confidence: 53%

“…The somatic mutation in KCNJ5 is associated with the pathogenesis of familial adenomatous polyposis. 14 Adenomatous polyposis predisposes patients toward colon cancer. Combined with our former analysis and prediction, we found that KCNJ5 is an IDPV in colon cancer and might be a pivotal factor in tumor immune infiltration and tumor progression.…”

Section: Discussionmentioning

confidence: 99%

Identification of Novel Tumor-Microenvironment-Regulating Factor That Facilitates Tumor Immune Infiltration in Colon Cancer

Wang

et al. 2020

Molecular Therapy - Nucleic Acids

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Colon cancer is one of the most common malignancies causing death worldwide. It is well known that the cells of the tumor microenvironment contribute to the progression and prognosis of colon cancer. However, the gene alterations and potential remodeling mechanisms in the tumor microenvironment of colon cancer remain largely unknown. In this study, immune scores from the ESTIMATE algorithm were used to discriminate between patients with high or low immune-cell infiltration. There were 42 immune differentially expressed genes (DEGs) of prognostic value identified in this study. Among them, KCNJ5 is a key factor in promoting M2 macrophage recruitment and tumor immune infiltration in colon cancer. These findings may provide novel insights for decoding the complicated interplay between cancer cells and the tumor microenvironment as well as for developing new avenues for therapeutic intervention in colon cancer.

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“…A recent case report describes the co-occurrence of a germline APC variant and a somatic KCNJ5 variant in a young PA patient with multinodular adrenal hyperplasia (Vouillarmet et al 2016). In the resected adrenal from the patient, the KCNJ5 variant was identified only in a CYP11B2-expressing nodule, whereas biallelic APC inactivation due to LOH was observed in both CYP11B2-positive and -negative nodules (Vouillarmet et al 2016), indicating 'two-hit' model as a possible mechanism of APA development at least for some cases. Epigenetic event may also be involved in adrenal nodule formation in some APAs.…”

Section: Discussionmentioning

confidence: 99%

Genetics of aldosterone-producing adenomas with pathogenic KCNJ5 variants

Lerário

Nanba

Blinder

et al. 2019

Endocrine-Related Cancer

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Somatic variants in genes that regulate intracellular ion homeostasis have been identified in aldosterone-producing adenomas (APAs). Although the mechanisms leading to increased aldosterone production in APA cells have been well studied, the molecular events that cause cell proliferation and tumor formation are poorly understood. In the present study, we have performed whole-exome sequencing (WES) to characterize the landscape of somatic alterations in a homogeneous series of APA with pathogenic KCNJ5 variants. In the WES analysis on 11 APAs, 84 exonic somatic events were called by 3 different somatic callers. Besides the KCNJ5 gene, only two genes (MED13 and ZNF669) harbored somatic variants in more than one APA. Unlike adrenocortical carcinomas, no chromosomal instability was observed by the somatic copy-number alteration and loss of heterozygosity analyses. The estimated tumor purity ranged from 0.35 to 0.67, suggesting a significant proportion of normal cell infiltration. Based on the results of PureCN analysis, the KCNJ5 variants appear to be clonal. In conclusion, in addition to KCNJ5 somatic pathogenic variants, no significant somatic event that would obviously explain proliferation or tumor growth was observed in our homogeneous cohort of KCNJ5-mutated APA. The molecular mechanisms causing APA growth and tumorigenesis remain to be elucidated.

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Aldosterone-Producing Adenoma With a Somatic KCNJ5 Mutation Revealing APC-Dependent Familial Adenomatous Polyposis

Cited by 37 publications

References 16 publications

Somatic and inherited mutations in primary aldosteronism

Somatic and inherited mutations in primary aldosteronism

Identification of Novel Tumor-Microenvironment-Regulating Factor That Facilitates Tumor Immune Infiltration in Colon Cancer

Genetics of aldosterone-producing adenomas with pathogenic KCNJ5 variants

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