€ URRENT PINION
Adrenal tumors: when to search for a germline abnormality?
Anne-Paule Gimenez-Roqueploa,b,c,d
Purpose of review
Over the last 20 years, the genetic landscape of adrenal tumours has been transformed by the identification of multiple susceptibility genes for the various tumour types. We review these recent developments here, and describe current recommendations for genetic testing in patients with tumours of the adrenal medulla and extra-adrenal paraganglia or the adrenal cortex.
Recent findings
Phaeochromocytomas (adrenal medulla tumours) and paragangliomas, aldosterone-producing adenomas, primary macronodular adrenal hyperplasia, primary pigmented nodular adrenocortical disease and adrenocortical carcinoma (adrenal cortex tumours) may all be caused by a germline mutation in a specific gene, regardless of the presence/absence of a family history or syndromic disease at initial diagnosis. Dedicated genetic testing is now indicated in all these conditions, and in patients with clinical features suggestive of a specific inherited disease.
Summary
Genetic testing should be considered in all patients with adrenal tumours, and is crucial for correct management. The identification of a germline mutation in a susceptibility gene guides treatment in patients with adrenal cancer and will facilitate risk-adapted screening/surveillance protocols in mutation carriers.
Keywords
adrenal tumours, Carney complex, familial hyperaldosteronism, genetic testing, hereditary paraganglioma, Li-Fraumeni syndrome, Lynch syndrome
INTRODUCTION
Adrenal tumours can occur in the context of a familial or syndromic disease, but they may also have an apparently syndromic presentation, while being genetically determined. Genetic counsel- ling is now a key step in the routine management of patients with adrenal tumours, because the identification of a germline mutation modifies patient management and follow-up. Since the start of the century, a large number of genes con- ferring predisposition to adrenal tumours have been identified and can now be genotyped in patients. The worldwide implementation of next-generation sequencing (NGS) technologies in molecular genetics laboratories has heralded a new era of genetic testing for adrenal tumours, favouring the rapid sequencing of a large number of genes in a single assay. We review in brief here the most recent advances in the genetics of adre- nal tumours and summarize current indications for genetic testing in the context of tumours (or cancers) arising from the adrenal medulla or adrenal cortex.
Tumours of the adrenal medulla and extra- adrenal paraganglia
According to the most recent update of the WHO classification of endocrine tumours, a phaeochro- mocytoma is a paraganglioma located in the adre- nal medulla that produces catecholamines. It may be unique, bilateral, multiple (associated with extra-adrenal sympathetic or parasympathetic par- agangliomas) or associated with other syndromic lesions. The term ‘malignant phaeochromocytoma or paraganglioma (PPGL)’ has been replaced by
ªINSERM, UMR970, Equipe Génétique et Métabolisme des cancers rares, bEquipe Labellisée Ligue Contre le Cancer, “Faculté de Médecine, Université Paris Descartes, Sorbonne Paris Cité and ªAssistance Pub- lique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Service de Génétique, Paris, France
Correspondence to Pr Anne-Paule Gimenez-Roqueplo, Service de Génétique, Hôpital Européen Georges Pompidou, 20-40 rue Leblanc, F-75015 Paris, France. Tel: +33 1 56 09 38 81 ; fax: +33 1 56 09 38 84; e-mail: anne-paule.gimenez-roqueplo@aphp.fr
Curr Opin Oncol 2019, 31:230-235 DOI:10.1097/CCO.0000000000000525
KEY POINTS
· Genetic testing should be considered in all patients diagnosed with adrenal tumours.
· Phaeochromocytoma or paraganglioma genetic testing is essential at initial phaeochromocytoma or paraganglioma diagnosis.
· A diagnosis of adrenocortical cancer is an indication for TP53 genetic testing and for microsatellite instability testing, with positive results leading to screening for Lynch syndrome susceptibility genes.
· ARMC5 can be screened for mutations in patients with primary macronodular adrenal hyperplasia.
· Early or severe primary aldosteronism is an indication for attesting for glucocorticoid- remediable aldosteronism.
· Positive genetic test results can lead to modifications to the management of the index case and mutations carriers in the patient’s family.
‘metastatic PPGL’ [1”]. More than 15 genes confer- ring predisposition to PPGL are now known, and it has been shown that about 40% of patients with PPGL carry a germline mutation of one of these
genes [2,3]. The most recent published interna- tional guidelines for PPGL recommend genetic test- ing for all patients with PPGL [4"",5”], to be performed by NGS methods, with target gene panels for the screening of germline DNA [6”]. The list of PPGL susceptibility genes is long (Table 1) and is likely to continue to grow in the next few years (for review, see [7]). Germline mutations of SDHB, FH and SLC25A11 genes, all of which encode Krebs’ cycle proteins, are associated with malignancy, and strict life-long follow-up should be performed for all carriers of such mutations. The benefits to affected patients of PPGL genetic testing at initial PPGL diagnosis were recently demonstrated in a large multicentre study showing that patients of known genetic status have better follow-up, with the detec- tion of smaller new PPGL and metastases, and better 5-year survival than patients not undergoing genetic testing for PPGL until several years after initial diagnosis [8""]. In particular, in patients with metastatic PPGL, the identification of a germline mutation in a PPGL susceptibility gene can guide the choice of effective targeted therapy (for review, see [2]). Finally, the benefits of predictive genetic testing for PPGL in asymptomatic relatives, leading to careful follow-up in mutation carriers, remain to be established.
| Table 1. Predisposing genes to adrenal medulla (pheochromocytomas) and extra-adrenal (paragangliomas) tumours | |
| Genes | Proteins |
| SDHBª | Succinate dehydrogenase (ubiquinone) iron-sulfur subunit, mitochondrial |
| VHLª | von Hippel-Lindau disease tumour suppressor |
| SDHDª | Succinate dehydrogenase (ubiquinone) cytochrome b small subunit, mitochondrial |
| RETª | Proto-oncogene tyrosine-protein kinase receptor Ret |
| SDHCª | Succinate dehydrogenase cytochrome b560 subunit, mitochondrial |
| NF1ª | Neurofibromin |
| TMEM127ª | Transmembrane protein 127 |
| MAXª | Protein max |
| SDHAb | Succinate dehydrogenase (ubiquinone) flavoprotein subunit, mitochondrial |
| FHb | Fumarate hydratase, mitochondrial |
| EPAS7b | Endothelial PAS domain-containing protein 1 |
| SLC25A11b | Mitochondrial 2-oxoglutarate/malate carrier protein |
| GOT2b | Aspartate aminotransferase, mitochondrial |
| MDH2b | Malate dehydrogenase, mitochondrial |
| PHD2ª | Egl nine homolog 1 |
| KIF1BBC | Kinesin-like protein KIF1B |
| MERTKC | Tyrosine-protein kinase Mer |
| METª | Hepatocyte growth factor receptor |
| H3F3AC | Histone H3.3 |
“Genes frequently mutated at germline level.
bGenes rarely mutated at germline level.
“Genes exceptionally mutated at germline level.
Tumours of the adrenal cortex
Aldosterone-producing adenomas
Aldosterone-producing adenomas (APA), which develop from the zona glomerula of the adrenal gland, are the leading cause of primary aldosteron- ism, underlying secondary hypertension. Whole- exome sequencing in large international series of patients with APA has recently revealed a high fre- quency of somatic mutations in genes encoding various ion channels (KCNJ5, CACNA1D) or ATPases (ATP1A1, ATP2B3), providing important evidence for new therapeutic targets (for review see [9]). How- ever, very few cases of patients carrying a germline mutation in one of these genes have been reported (Table 2) and, as described below, genetic testing should therefore be reserved for only a small number of patients. Familial forms of primary aldosteronism are rare, accounting for less than 5% of primary aldosteronism cases, and are of four different types (for review see [10,11]). The first of these types to be described was glucocorticoid-remediable aldoste- ronism, or familial hyperaldosteronism type I (FH- I), an autosomal dominant disorder caused by a chimeric gene, in which the CYP11B2 (encoding aldosterone synthase) coding sequences are under the control of the CYP11B1 (encoding 11ß hydrox- ylase) promoter. Affected patients present early severe hypertension, with bilateral adrenal hyper- plasia or adrenal nodules. Genetic diagnosis by long- PCR is straightforward, and the positive detection of a chimeric CYP11B1-CYP11B2 gene is an indication
for glucocorticoid treatment. The genetic cause of FH-II has recently been identified [12,13] by an exome-sequencing strategy. The causal gene is CLCN2, which encodes a voltage-gated chloride channel, CIC-2. The presentation of this disease is similar to that of FH-I. The third familial form (FH- III) is due to germline gain-of-function mutations of KCNJ5, which encodes a potassium channel, leading to increases in aldosterone production. The last known familial form is FH-IV, which is caused by germline mutations of CACNA1H. However, only a few patients with FH-III and FH-IV have been reported to date. Thus, tests for germline abnormal- ities in a context of primary aldosteronism should be limited to patients with primary hyperaldosteron- ism and bilateral hyperplasia or adrenal nodules and early-onset and/or severe hypertension and/or a family history of primary aldosteronism.
Primary macronodular adrenal hyperplasia
Primary macronodular adrenal hyperplasia is char- acterized by bilateral adrenal macronodules and pituitary ACTH-independent corticol secretion. Pri- mary macronodular adrenal hyperplasia (PMAH) is a rare cause of adrenal Cushing’s syndrome or sub- clinical hypercortisolism, and may be genetically determined, particularly in cases of bilateral disease and in patients with a family history of Cushing’s disease or a personal or family history of other lesions, such as endocrine tumours or digestive polyps (for review, see [14]). Germline mutations of four different causal genes should be sought:
| Genes | Proteins |
|---|---|
| Aldosterone-producing adenomas | |
| chimeric CYP11B1-CYP11B2ª | Cytochrome P450 11B1, mitochondrial/Cytochrome P450 11B2, mitochondrial |
| CLCN2ª | Chloride channel protein 2 |
| KCNJ5ª | G protein-activated inward rectifier potassium channel 4 |
| CACNATHª | Voltage-dependent T-type calcium channel subunit alpha-1H |
| Primary macronodular adrenal hyperplasia | |
| ARMC5ª | Armadillo repeat-containing protein 5 |
| MEN1b | Menin |
| APCb | Adenomatous polyposis coli protein |
| FHb | Fumarate hydratase, mitochondrial |
| Micronodular adrenal hyperplasia (Carney complex) | |
| PRKAR 1Aª | cAMP-dependent protein kinase type I-alpha regulatory subunit |
| Adrenocortical cancer | |
| TP53ª | Cellular tumour antigen p53 |
cAMP, cyclic adenosine monophosate.
“Genes rarely mutated at germline level.
bGenes exceptionally mutated at germline level.
MEN1 (the causal gene for multiple endocrine neo- plasia type 1), APC (causal gene for familial adeno- matous polyposis), FH (causal gene for hereditary leiomyomatosis and renal cell carcinoma) and ARMC5, the most recently identified susceptibility gene for this condition and the causal gene with the highest frequency of germline mutations [15] (Table 2). Primary aldosteronism and meningiomas have also been reported in a few patients with germ- line ARMC5 mutations. The disease displays autoso- mal dominant transmission with incomplete penetrance. Germline mutations of ARMC5 account for most familial and apparently sporadic cases of PMAH. Genotyping of the ARMC5 gene should therefore be considered in all patients diagnosed with PMAH.
Micronodular adrenal hyperplasia
Bilateral micronodular adrenal hyperplasia groups together primary pigmented nodular adrenocortical disease (PPNAD) or Carney complex and isolated micronodular adrenocortical disease. Carney com- plex is a familial lentiginosis syndrome characterized by various manifestations, including pigmented lesions, myxomas and PPNAD (for review, see [16]). Most cases can be explained by inactivating germline mutations of the PRKAR1A gene, encoding the regu- latory type 1a subunit of protein kinase A, leading to haploinsufficiency and a loss of the regulatory func- tion of this enzyme, together with the inappropriate proliferation of cyclic adenosine monophosate- responsive cells. By contrast, isolated micronodular adrenocortical disease rarely has a genetic cause. Only a few cases to date have been explained by a germline mutation in a gene encoding a phosphodiesterase (PDE11A, PDE8B) or another regulatory subunit of protein kinase A (PRKACA) (for review, see [17]).
Adrenocortical cancer
Adrenocortical cancer (ACC) can be a component of Li-Fraumeni syndrome, due to germline muta- tions of the TP53 gene, characterized by a broad spectrum of tumours, including soft-tissue sarco- mas, osteosarcomas, brain tumours, choroid plexus tumours, leukaemias, premenopausal breast can- cers, lung cancers and ACC [18]. Germline TP53 mutations are found in about half the patients with ACC diagnosed during childhood. The current rec- ommendations suggest TP53 genetic testing for all patients diagnosed with ACC, independently of family or other cancer history, because a risk- adapted cancer screening/surveillance protocol should be proposed as soon as the diagnosis of Li- Fraumeni syndrome is established [19]. Moreover, the identification of mutations of the gene encoding
p53, which is known to play a key role in the response to DNA damage, is crucial to prevent the development of a new cancer in TP53 mutation carriers, as the presence of such mutations is an indication for preferential surgical and non- genotoxic treatments and for the avoidance of radiotherapy and genotoxic chemotherapies, which significantly increase the risk of tumour develop- ment [20].
The second inherited disease in this group is Lynch syndrome, caused by germline mutations of genes (MLH1, MSH2, MSH6, PMS2, EPCAM) encoding DNA-mismatch repair proteins, leading to the devel- opment of colorectal and endometrial cancers. A recent pan-cancer study, including more than 15 000 individual patients with different solid can- cers, showed that 50% of patients with Lynch syn- drome had tumours other than classical digestive and gynaecological cancers (urothelial, prostate, pan- creas, small bowel, sarcoma, mesothelioma, mela- noma, gastric, germ cell tumours and ACC), justifying microsatellite instability (MSI) and/or mis- match repair deficiency testing for all patients with these tumours, regardless of cancer type or family cancer history [21]. The results of this study were consistent with those of a previous study in which MSI-high ACC was found to have a higher mean mutational burden than microsatellite-stable ACC [22]. MSI-high/mismatch repair -deficient ACC is an indication for NGS testing for germline mutations of a panel of genes including the genes conferring predisposition to Lynch syndrome, because the iden- tification of a causal mutation paves the way for immunotherapy in affected patients and for cancer screening and prevention measures in mutation carriers. ACC has also been described in rare cases in other inherited syndromes, such as multiple endocrine neoplasia type 1, familial adenomatous polyposis, Beckwith-Wiedemann syndrome and neurofibromatosis type 1. In most of these cases, other syndromic manifestations are present at the time of ACC diagnosis, and dedicated genetic testing is indicated only in the presence of clinical manifes- tations or a family history suggestive of one of these diagnoses (for review, see [23]).
CONCLUSION
Recent discoveries in the field of the genetics of adrenal tumours and the development of NGS methods, which are now routinely used in molecu- lar genetics laboratories, have led to changes in the recommendations for genetic testing at initial diag- nosis (summarized on Fig. 1). Dedicated genetic testing should be immediately considered in patients diagnosed with PPGL (screening for all
| CORTEX | ALDOSTERONE-PRODUCING ADENOMA | Genetic testing only in few cases if early onset and/ or severe hypertension and/or familial history |
| ADRENOCORTICAL CANCER | TP53 genotyping + microsatellite instability testing | |
| MICRONODULAR ADRENAL HYPERPLASIA | PRKAR1A genotyping | |
| PRIMARY MACRONODULAR ADRENAL HYPERPLASIA | ARMC5 genotyping | |
| MEDULLA | PHEOCHROMOCYTOMA PARAGANGLIOMA | PPGL genetic testing in all cases |
genes associated with a predisposition to PPGL), PMAH (screening of AMRC5), PPNAD (screening of PRKAR1A) and ACC (screening of TP53 and, in MSI-positive tumours, of all the genes conferring predisposition to Lynch syndrome). Patients with early-onset and/or severe primary aldosteronism should first be screened for a CYP11B1-CYP11B2 chimeric gene. In all cases, the identification of a germline mutation should lead to dedicated surveil- lance and the possibility of presymptomatic genetic testing in relatives, and, of particular importance for patients with metastatic PPGL or ACC, will guide treatment according to genetic status. Almost two decades into the new century, geneticists are now playing a key role, alongside oncologists and endo- crinologists, in the multidisciplinary teams respon- sible for the management of patients with adrenal tumours/cancers.
Acknowledgements
We thank Dr Julie Sappa for English-language assis- tance. We apologise to colleagues in the field whose contributions were not cited due to space limitations or oversight.
Financial support and sponsorship
Our team has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement no. 633983 (ENSAT-HT) and from the Institut National du Cancer and the Direction Générale de l’Offre de Soins (PRT-K 2014, COMETE- TACTIC, INCa-DGOS_8663). The team is supported by the Ligue Nationale contre le Cancer (Equipe Labellisée).
Conflicts of interest
There are no conflicts of interest.
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