REVIEW
Current prospects of hereditary adrenal tumors: towards better clinical management
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Akihiro Ohmoto1,2*, Naomi Hayashi3,4, Shunji Takahashi 1,3 and Arisa Ueki4
Abstract
Adrenocortical carcinoma (ACC) and pheochromocytoma/paraganglioma (PPGL) are two rare types of adrenal gland malignancies. Regarding hereditary tumors, some patients with ACC are associated with with Li-Fraumeni syndrome (LFS), and those with PPGL with multiple endocrine neoplasia type 2. Recent studies have expanded this spectrum to include other types of hereditary tumors, such as Lynch syndrome or familial adenomatous polyposis. Individuals harboring germline TP53 pathogenic variants that cause LFS have heterogeneous phenotypes depend- ing on the respective variant type. As an example, R337H variant found in Brazilian is known as low penetrant. While 50-80% of pediatric ACC patients harbored a LFS, such a strong causal relationship is not observed in adult patients, which suggests different pathophysiologies between the two populations. As for PPGL, because multiple driver genes, such as succinate dehydrogenase (SDH)-related genes, RET, NF1, and VHL have been identified, universal multi-gene germline panel testing is warranted as a comprehensive and cost-effective approach. PPGL pathogenesis is divided into three molecular pathways (pseudohypoxia, Wnt signaling, and kinase signaling), and this classification is expected to result in personalized medicine based on genomic profiles. It remains unknown whether clinical char- acteristics differ between cases derived from genetic predisposition syndromes and sporadic cases, or whether the surveillance strategy should be changed depending on the genetic background or whether it should be uniform. Close cooperation among medical genomics experts, endocrinologists, oncologists, and early investigators is indis- pensable for improving the clinical management for multifaceted ACC and PPGL.
Keywords Pheochromocytoma, Paraganglioma, Hereditary tumors, Phenotype, Universal multi-gene germline panel, Personalized medicine
Introduction
Adrenocortical carcinoma (ACC) and pheochromo- cytoma are the two types of adrenal gland malignan- cies. Extra-adrenal paraganglioma is pathologically
*Correspondence: Akihiro Ohmoto aohmoto15@gmail.com
1 Division of Medical Oncology, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo 1358550, Japan
2 Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, 417 East 68th Street, New York, NY 10065, USA 3 Division of Genomic Medicine, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo 1358550, Japan
4 Division of Clinical Genetic Oncology, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo 1358550, Japan
categorized into the same entity as pheochromocytoma, and these two diseases are collectively termed pheo- chromocytoma/paraganglioma (PPGL) [1]. ACC and PPGL are the major adrenal malignancies; however, they rarely occur. According to the Rare Cancers in Europe (RARECARE) project data, the annual incidences of ACC, malignant pheochromocytoma, and paragan- glioma are 0.22, 0.04, and 0.02 per 100,000 individuals per year, meeting the criteria for rare malignancies (<6 per 100,000) [2]. While surgical resection is generally recommended for localized ACC/PPGL, the approved systemic chemotherapy for advanced cases remains the conventional cytotoxic regimen (mitotane alone or a combination of etoposide, doxorubicin, and cisplatin plus mitotane for ACC; a combination of cyclophosphamide,
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vincristine, and dacarbazine [CVD]; or temozolomide alone for PPGL) [1]. Therefore, novel therapeutic strate- gies are required.
It is well known that some individuals with specific genetic pathogenic/likely pathogenic variants develop ACC or PPGL. According to a large genomic analysis of pediatric cancers, the percentage of pathogenic germline variant carriers among all types of malignancies was the highest in ACC (approximately 50%) [3]. Representa- tive hereditary genetic syndromes relevant to ACC and PPGL include Li-Fraumeni syndrome (LFS) and multi- ple endocrine neoplasia type 2 (MEN2), respectively [4]. Recent investigations have broadened this spectrum to include a wider range of syndromes, such as Lynch syn- drome. With regard to therapeutic interventions after disease onset, clinical development through elucidating molecular mechanisms is promising. Another focus is on early diagnosis through routine surveillance. There is no established treatment approach yet for hereditary adrenal tumors, unlike well-known hereditary syndromes such as breast and ovarian cancer or Lynch syndrome.
To aid clinical decision, this manuscript provides an overview of the latest information about genetic pre- disposition syndromes associated with ACC and PPGL, the molecular pathways that could result in novel
surveillance. In this review, database searches were conducted using PubMed/MEDLINE. The following keywords were used for literature retrieval: ((adrenal tumor) OR (adrenal carcinoma) OR (pheochromocy- toma) OR (paraganglioma)) AND (hereditary cancer). Regarding novel agents for adrenal tumors, we added manual searches.
Hereditary malignancies associated with adrenal tumors
The National Comprehensive Cancer Network (NCCN) guidelines for neuroendocrine and adrenal tumors include LFS, Lynch syndrome (LS), multiple endocrine neoplasia type 1 (MEN1), and familial adenomatous polyposis (APC) as hereditary cancer predisposition syndromes associated with ACC [4]. Hereditary PPGL syndrome and MEN type 2 (MEN2) were also men- tioned [4]. The clinical and genomic features of repre- sentative hereditary tumors associated with adrenal tumors are presented in Table 1, and the available sur- veillance strategies proposed in the guidelines or expert statements are listed in Table 2.
| Hereditary tumor | Relevant adrenal tumor | Causative gene | Mode of inheritance | Incidence of respective syndrome | Median onset of adrenal tumor | Percentage of patients who were diagnosed with adrenal tumor among hereditary syndrome individuals | Genotype/ phenotype relationship | References |
|---|---|---|---|---|---|---|---|---|
| LFS | ACC | TP53 | Autosomal domi- nant | 1: 5,000-20,000 | 3 years | 13% (27% in chil- dren cohort; 3% in adult cohort) | Yes | [5, 6] |
| LS | ACC | MMR genes (MLH1, | Autosomal domi- nant | 1:660-2,000 | 64 years | 0.5% | Unknown | ☒ |
| MSH2, MSH6, and PMS2) | ||||||||
| FAP | ACC | APC | Autosomal domi- nant | 1:8,000-18,000 | NA | NA | Unknown | [8] |
| BWS | ACC | Defects on chromosome 11p15.5 | Not applicable | 1: 13,700 | 10 months | 0.3% | Unknown | [9] |
| MEN2 | PPGL | RET | Autosomal domi- nant | 1: 35,000 | 39 years | 37% | Yes | [10] |
| VHL | PPGL | VHL | Autosomal domi- nant | 1: 36,000-91,000 | 27 years (mean) | 19% | Yes | [11, 12] |
| NF1 | PPGL | NF1 | Autosomal domi- nant | 1: 2,500-3,000 | 41 years; 42 years | 3% | Unknown | [13, 14] |
LFS Li-Fraumeni syndrome: LS Lynch syndrome: FAP familial adenomatous polyposis: BWS Beckwith-Wiedemann syndrome: MEN2 multiple endocrine neoplasia type
2: VHL von Hippel-Lindau disease
NF1 Neurofibromatosis type 1: ACC adrenocortical carcinoma: PPGL pheochromocytoma/paraganglioma: NA not available
treatments, and discusses prospects for treatment and
| Hereditary tumor | Surveillance method of adrenal tumor | Guidelines/ statements | References |
|---|---|---|---|
| LFS | For children: abdominal and pelvic ultrasound, and alternative blood test (total testosterone, dehydroepiandrosterone, and androstenedi- one) (every 3-4 months) | Japanese LFS medical guidelines; Toronto protocol | [15, 16] |
| LS | NA | NA | |
| FAP | NA | NA | |
| MEN2 | Annual measurement of plasma free or 24-hour urine fractionated metanephrine/normetanephrine | NCCN guidelines | [4] |
| VHL | Plasma-metanephrine/normetanephrine (every year from age 5); abdominal MRI (every 2-years from age 15, no upper limit of age) | VHL Alliance; Danish guidelines | [17,18] |
| NF1 | Biochemical testing in individual who has raised blood pressure | ERN GENTURIS guidelines | [19] |
| Hereditary PPGL syn- drome | Blood pressure monitoring at all medical visits, annual measure- ment of plasma free metanephrine or 24-hour urine for fractionated metanephrine, and whole body MRI every 2-3 years (from age 6-10 for patients with SDHB mutations and age 10-15 for patients with all other SDHx mutations) | NCCN guidelines | [4] |
LFS Li-Fraumeni syndrome: LS Lynch syndrome: FAP familial adenomatous polyposis: MEN2 multiple endocrine neoplasia type 2: VHL von Hippel-Lindau disease: NF1 Neurofibromatosis type 1: PPGL pheochromocytoma/paraganglioma: NA not available: NCCN National Comprehensive Cancer Network: ERN GENTURIS European Reference Network on Genetic Tumor Risk Syndromes
ACC
Li-Fraumeni syndrome
LFS is a genetically predisposed syndrome involv- ing TP53 germline pathogenic variants (gTP53) and is inherited in an autosomal-dominant manner. TP53 is a tumor suppressor gene that plays a central role in medi- ating the cellular response to genotoxic stress and onco- gene activation and activates pathways involved in cell cycle arrest and DNA damage repair [20]. The incidence of LFS is as frequent as one in 5000-20,000 individuals [21]. According to the National Cancer Institute’s refer- ral-based longitudinal LFS study, individuals with LFS have a nearly 24-fold higher incidence of cancer than the general population [22]. ACC is included in the core tumors of LFS, along with bone and soft tissue sarcomas and breast and brain cancers [15]. The Chompret Crite- ria designates ACC along with choroid plexus tumor or rhabdomyosarcoma of the embryonal anaplastic sub- type [15]. The tumor distribution in affected gTP53 car- riers differs between children and adults. According to a French database analysis, ACC was observed in 13% of affected gTP53 carriers (27% in children, n=132; 3% in adults, n=219; total n=322) [5]. A US study including 286 individuals harboring gTP53 showed that the cumu- lative incidence of any cancer was 50% by age 31 among females and by age 46 among males; it approached 100% by age 70 in both groups [23]. Among the 403 cancer diagnoses, the most common malignancy type was breast cancer, and five patients with ACC were diagnosed at age 17 or earlier [23]. A study of 88 children with ACC detected gTP53 in 50% of the cases, regardless of family history [24]. Similar to the French study above, mutations
were prevalent in young patients (51% at 0-4 years, 73% at 4-12 years, 29% at 12-20 years, and 6% at 20-30 years). A single-center prospective analysis in the US showed that 7.5% of 53 unselected patients with ACC had gTP53 [25]. In the clinical sequencing data from the Memorial Sloan Kettering Cancer Center, four of 1566 (0.2%) indi- viduals harbored gTP53 [26]. According to an analysis by the Japanese LFS Special Committee, 68 individuals from 48 families harboring gTP53 were found [6]. Nine of these 68 patients (13%) developed ACC at a median of 3.0 years (range, 0-31 years). ACC onset was the earliest among all tumor types (median=26.0 years). Further- more, there are endemic geographic areas for pediatric ACC. In southern Brazil, the incidence of ACC is 10-15 times higher than the global incidence, and most patients have the gTP53 variant R337H [27]. In a large popula- tion-based screening study including 171,649 newborns from Paraná State (Brazil), the R337H variant was identi- fied in 461 individuals (0.3%) [28].
One focus is on the genotype-phenotype relationship in LFS. In a study by Wasserman et al., gTP53 was found in a wide range of positions beyond hotspots. Patients harboring alleles with severe loss-of-function (LOF) mutations (e.g., Y163C, H193P, C275X, and E285V) have a strong family history, whereas those harboring alleles without LOF (e.g., R337H) have a relatively weak family history [24]. Bougeard et al. revealed that the age at first tumor onset varied depending on the type of gTP53 alter- ation [5]. Briefly, dominant-negative missense mutations drastically alter the transcriptional response to DNA damage that occurred during childhood. In contrast, the onset of LOF mutations and genomic rearrangements are
mostly observed in adults. Additionally, heterogeneity in onset was observed among variants, where individuals harboring the R337H variant mostly developed the first tumor in around 40 years or later. The aforementioned US observational cohort study showed that gTP53 LOF variants, regardless of their dominant-negative effect (DNE), were associated with an earlier onset of first and second cancers than non-LOF variants, regardless of DNE [22]. According to another pooled analysis of 427 gTP53 carriers who underwent multi-gene panel test- ing and 154 gTP53 carriers with TP53 single-gene test- ing, carriers of truncated and hotspot variants tended to present with LFS cancers and had a shorter time to first cancer diagnosis than carriers of missense variants [29]. These data highlight the functional significance of these variants. On the other hand, it should be noted that the evidence about genotype-phenotype relationship is not robust to assist with clinical management (risk stratifica- tion or personalized screening) of TP53 carriers.
Regarding the surveillance of children with ACC, the Toronto Protocol implemented in Canada and the USA and the Japanese LFS medical guidelines recommend abdominal and pelvic ultrasound every 3-4 months and alternative blood tests (total testosterone, dehydroepi- androsterone, and androstenedione) every 3-4 months [15, 16]. However, no definite recommendations exist for adult ACC, partly because the causality is not always strong in adults. For LFS, priority should be placed on surgical or ablative treatment, and radiotherapy should be avoided when possible; non-genotoxic chemothera- pies have also been adopted [30]. Moreover, whole-body MRI is recommended as a regular screening method [30, 31].
Lynch syndrome
LS derived from pathogenic germline variants (PGV) of DNA mismatch repair (MMR) genes (MLH1, MSH2, MSH6, and PMS2) or EPCAM deletion leading to the silencing of MSH2 are inherited in an autosomal-domi- nant manner [32]. LS causes several types of malignan- cies, such as colorectal and endometrial cancers, and clinical information is gradually accumulating in the con- text of ACC [32]. A Spanish LS cohort analysis included 634 individuals from 220 families with LS and identified three (0.5%) patients with ACC [7]. These patients har- bored MSH2 PGV and presented with MSH2 and MSH6 protein loss. Raymond et al. analyzed 84 patients with ACC who underwent genetic counseling and identified three patients (3%) with family histories suggestive of LS [33]. All three families had MMR PGVs (MSH2 p.R711X, MLH1 p.L749P, and MSH6 p.S714C). The prevalence of LS among ACC cases (3%) exhibited in this study was comparable to colorectal cancer or endometrial cancer
[34]. Furthermore, there have been case reports of ACC harboring MMR PGVs [35-39]. However, the clinical evi- dence for routine ACC screening is insufficient for indi- viduals with LS.
Familial adenomatous polyposis (FAP) and Beckwith-Wiedemann syndrome (BWS)
FAP and BWS are hereditary syndromes associated with adult and childhood ACC, respectively [40]. In both syn- dromes, Wnt/B-catenin pathway regulation contributes to the oncogenesis of adrenocortical tumors (ACT) [8]. In contrast to the LFS, information on the link between FAP/BWS and ACC is limited. Gaujoux et al. identified four ACT, including one ACC, in three individuals with FAP and showed that ACT tumorigenesis was medi- ated by biallelic APC inactivation [8]. BWS is a genetic disorder characterized by overgrowth. This syndrome is caused by defects in chromosome 11p15.5, which result in the overexpression of insulin-like growth factor 2 (IGF2) [41]. Several molecular mechanisms including imprinting control region 1 (IC1) gain of methylation or paternal uniparental disomy of 11p15 induce overex- pression of IGF2 [42]. Any malignancy occurred in 5% of patients with BWS, dependent on the molecular mecha- nisms [43]. Cöktü et al. analyzed 321 individuals with BWS and identified 13 cases of cancer (33-fold increased risk compared with expected number of cases) [9]. The major cancer types were hepatoblastoma (n=6) and nephroblastoma (Wilms tumor) (n=4), and ACC (n=1). An international consensus statement for the clinical management of BWS mentioned a screening strategy using clinical evaluation, adrenal ultrasound, and evalu- ating serum dehydroepiandrosterone sulfate levels every 4-6 months [44]. However, as presented here, the inci- dence of ACC is low in patients with BWS, and there are no data on the utility of such screening strategies.
PPGL
Multiple endocrine neoplasia type 2 (MEN2)
MEN2 is an autosomal dominant genetic syndrome with germline RET-activating alterations and can be further classified into MEN2A and MEN2B. MEN2 accounts for approximately 5% of PPGL cases [45], with an incidence of one in 35,000 individuals. Although the penetrance of medullary thyroid carcinoma (MTC) is approximately 100%, PPGL occurs in up to 50% of indi- viduals [46], the genotype-phenotype correlation of MEN2 is noteworthy. The penetrance and onset age of MEN2 depend on the type of RET variants present [47]. The penetrance of PPGL is particularly high in the RET p.D631Y, p.C634F/G/R/S/W/Y, p.A883F, and M918T variants. Those with the M918T variant have the high- est risk of aggressive MTC [48]. According to an analysis
by the MEN Consortium of Japan, 144 (37%) out of 390 individuals with MEN2 developed PPGL [10]. In that study, the penetrance of pheochromocytoma was high in RET pathogenic variants in codons 918 (100% by age 56) and 634 (88% by age 77); the rate was lower in other variants (<32% for in codons 611, 618, 620, and 768). Consistent with this, Qi et al. reported that PPGL penetrance was higher in individuals harboring RET p.C634F/G/R/S/W/Y variants in exon 11 than in those harboring pathogenic variants in exon 10 (e.g., p.C609R, p.C611F/Y, p.C618G/R/S/Y, and p.C620R/S) [49]. Tho- sani et al. analyzed 319 individuals with MEN2 at the MD Anderson Cancer Center and compared the clinical features between 59 PPGL patients with RET codon 634 variants and 48 individuals without PPGL but harbored codon 634 variants [50]. In their study, the clinical stage distribution of MTC at the initial diagnosis and overall survival were not significantly different between the two groups. NCCN guidelines recommend surveillance for PPGL using plasma-free or 24-hour urine-fractionated metanephrine and normetanephrine levels [4]. However, these guidelines do not include imaging modalities, such as computed tomography or ultrasound.
von Hippel-Lindau disease (VHL)
VHL is an autosomal dominant genetic syndrome char- acterized by hemangioblastoma of the retina, central nervous system and renal cell carcinomas, neuroendo- crine pancreatic tumors, endolymphatic sac tumors, and pheochromocytoma [18]. VHL is a tumor suppressor gene that causes this syndrome. The incidence of VHL is one in 36,000-91,000 individuals. Regarding PPGL, the estimated lifetime risk is 10-25% [11]. According to a systematic review and meta-analysis of VHL-associated PPGL that included 4263 VHL cases, the pooled fre- quency of PPGL was 19.4% [12]. VHL is classified into types 1 and 2; only patients with type 2 VHL develop PPGL. A genotype-phenotype relationship was observed between type 1 and type 2 VHL. While protein-trun- cating mutations are detected in type 1 VHL, missense mutations that generally do not affect protein structure are unique to type 2 VHL [11, 51].
Regarding tumor surveillance for VHL-associated PPGL, the VHL Alliance recommends annual plasma- free metanephrine or urinary-fractionated metanephrine monitoring from 5 years of age, abdominal MRI every 2 years from the age of 15 years, and annual blood pressure and pulse monitoring from 2years of age [17]. Consist- ently, the Danish guidelines propose the annual measure- ment of plasma metanephrine/normetanephrine from age 5 and imaging of the abdomen every 2 years from age 15 [18].
Neurofibromatosis type 1 (NF1)
NF1 is a dominantly inherited genetic disorder caused by PGV in the tumor suppressor gene NF1. Individuals with NF1 characteristically develop benign and malig- nant tumors of the central and peripheral nervous sys- tems (gliomas of the optic pathway, glioblastomas, and malignant peripheral nerve sheath tumors) [52]. This syndrome is also associated with an increased incidence of other malignancies (gastrointestinal stromal tumors, breast cancer, leukemia, duodenal carcinoid tumors, rhabdomyosarcomas, and pheochromocytoma) [52]. The prevalence of NF1 is one in 2500-3000 births, and 5-7% of individuals with NF1 are estimated to develop PPGL in their lifetime. Several studies have described the clinical features of NF-1-associated PPGL. Gruber et al. reported that the prevalence of PPGL in patients with NF1 was 2.9% (41/1415) [13]. The median age at diagno- sis was 41 years, and metastatic or recurrent disease was detected in 7% of cases. According to a US single-center retrospective analysis of 17 patients with NF-1-associ- ated PPGL, the average age at diagnosis was 42 years, and two patients had metastatic disease [14]. Al-Sharefi et al. reviewed 27 patients with NF1 who developed PPGL and reported that PPGL diagnosis was incidental in 48% of the cases [53]. The European Reference Network on Genetic Tumor Risk Syndromes (ERN GENTURIS) tumor surveillance guidelines state that biochemical test- ing for PPGL should be conducted in any individual with NF1 who has elevated blood pressure, while routine bio- chemical screening for PPGL is not recommended except in pregnant women [19].
Finally, according to the American College of Medical Genetics and Genomics (ACMG) statement, hereditary PPGL syndrome characterized by succinate dehydroge- nase (SDH)-related gene mutations is categorized as an independent type of genetic predisposition syndrome [54]. Their molecular features are discussed in the fol- lowing sections. Regarding surveillance, annual meas- urements of plasma-free metanephrine or 24-hour urine-fractionated metanephrine and whole-body MRI every 2-3 years are recommended. Notably, the surveil- lance start age differs between SDHB-mutated individu- als (6-10years) and other SDHx-mutated individuals (10-15 years) [4].
Molecular features and druggable mutated genes for adrenal tumors ACC
A comprehensive genomic analysis of 91 ACC cases revealed its genomic landscape [55]. The two major sign- aling cascades involved in ACC oncogenesis are the p53/ Rb and Wnt/B-catenin pathways (Fig. 1). Deactivating mutations in TP53, CDKN2A, and ZNRF3 and activating
mutations in CTNNB1 were detected in 21, 16, 19, and 16% of cases, respectively. CDKN2A participates in the p53/Rb pathway, while ZNRF3 and CTNNB1 participate in the ß-catenin pathway. In addition, alterations in his- tone modification genes (MLL, MLL2, and MLL4) and chromatin remodeling genes (ATRX and DAXX) were detected in 22% of cases. Another study, which included 45 ACC cases, identified ZNRF3 alterations in 21% [56].
Although the genomic features of ACC have been grad- ually uncovered, there are currently no approved molec- ular-targeted agents for ACC. The NCCN and European Society of Medical Oncology (ESMO) guidelines only recommend conventional cytotoxic regimens for advanced ACC [1, 4]. Under the current status, transcrip- tional analysis showed that IGF2 expression is enhanced in 80-90% of ACC cases. This finding suggests the util- ity of type 1 IGF receptor (IGF-1R) antagonists for ACC, in which IGF-2 is the ligand of IGF-1R [57]. However, a phase 3 trial of linsitinib, a dual inhibitor of IGF-1R and the insulin receptor, did not demonstrate a survival ben- efit over the placebo for patients with locally advanced or metastatic ACC [58].
Unfortunately, advances in genomic medicine have not always improved the outcomes of ACC. Current issues include inadequate patient selection and pharmaco- logical interactions between novel agents and already- approved mitotanes [59]. Considering the heterogeneous molecular features of ACC, personalized treatment based on individual genomic information is essential. Immune checkpoint inhibitors are promising options for the treat- ment of LS-associated ACC. According to a phase 2 trial of pembrolizumab in 39 patients with advanced ACC, the overall response rate (ORR) and disease control rate were 23 and 52%, respectively [60]. Unexpectedly, genetic
alterations, tumor mutation burden, tumor programmed death-ligand 1 expression, and microsatellite-high and/ or mismatch repair-deficient status were not associ- ated with ORR. In addition, Wnt/ß-catenin signaling is a major molecular pathway in ACC. Hence, clinical inves- tigations using Wnt signaling inhibitors, such as those ongoing for colorectal cancer, are warranted for ACC in the future [61].
PPGL
Owing to recent advances in molecular classification methods, universal germline panel testing in patients with PPGL has been actively discussed. This information is helpful not only for the active surveillance of mutation carriers but also for treatment selection. PPGL pathogen- esis is broadly divided into the pseudohypoxia pathway, kinase signaling, and Wnt signaling (Fig. 1) [62]. The fol- lowing mutated genes were included in each pathway: (pseudohypoxia signaling) SDH-related genes such as SDHB, SDHD, and SDHC encoding succinate dehydro- genase subunits, FH, and VHL/EPAS1; (kinase signal- ing) RET, NF1, TMEM127, MAX, and HRAS; and (Wnt signaling) CSDE1 and MAML3. Regarding mutation distribution, 40% of PPGL cases harbor PGV and 30% harbor somatic mutations in predisposition genes [63]. Amar et al. sequenced five major PPGL susceptibility genes (RET, VHL, SDHB, SDHD, and SDHC) in blood samples from 314 patients with PPGL [45] and identi- fied heterozygous PGV in 73 patients (23%) and diag- nosed NF1 in 13 patients (4%). In total, 86 patients (27%) were diagnosed with hereditary PPGL. The prevalence of PGVs was 5% for RET, 8% for VHL, 7% for SDHB, and 4% for SDHD. Remarkably, 12% of seemingly sporadic cases without a family history and syndromic presentation
Adrenal gland
Kidney
Adrenal cortex
Adrenal medulla
ACC
PPGL
Molecular pathway
p53/Rb
Wnt/B- catenin
Pseudohypoxia
Kinase signaling
Wnt signaling
Representative mutated genes
TP53, and CDKN2A
ZNRF3, and CTNNB1
SDHB, SDHC, SDHD, FH, and VHL/EPAS1
RET, NF1, TMEM127, MAX, and HRAS
CSDE1, and MAML3
Investigational agents
IGF-1R antagonist
HIF2a inhibitor
mTORC1 inhibitor (everolimus)
Tyrosine kinase inhibitor (sunitinib, cabozantinib)
harbored PPGL-associated PGVs. Patients with germline SDHB pathogenic variants had larger, more frequent extra-adrenal and malignant PPGL. Yonamine et al. also showed that 32% of 370 patients with PPGL had PGVs in seven susceptibility genes (MAX, SDHB, SDHC, SDHD, TMEM127, VHL, and RET), with a prevalence of 25% in seemingly sporadic cases [64]. The incidence of meta- static PPGL was high in SDHB carriers (37%). According to a large cohort study assessing 1727 individuals sus- pected to have hereditary PPGL and underwent multi- gene panel testing, 28% had PGVs, of which the common causative genes were SDHB (40%), SDHD (21%), SDHA (10%), VHL (8%), SDHC (7%), RET (4%), and MAX (4%) [65]. In a prospective cohort study based on the Euro- pean-American-Asian PPGL Registry, 6% individuals (58/972) had PGVs, including 29 with SDHA PGVs, 20 in TMEM127, and eight in MAX, and one in SDHAF [66].
Regarding genetic heterogeneity in PPGL, targeted next-generation sequencing (NGS) custom panels using blood samples are considered the gold standard for genetic diagnosis [63]. The PPGL Study Group stated that targeted NGS is a favored approach in terms of turnaround time, autonomy of individual laboratories, assay flexibility, scalability, bioinformatics needs, data storage, and interpretation, regardless of the required cost [67]. Based on current evidence, they advocated three NGS options: a basic panel of 10 genes (FH, MAX, NF1, RET, SDHA, SDHB, SDHC, SDHD, TMEM127, and VHL), an extended panel of 15 genes (the 10 genes in the basic panel plus EGLN1/PHD2, EPAS1, KIF1B, MET, and SDHAF2), and a comprehensive panel of 27 genes (the 15 genes in the extended panel plus ATRX, BRAF, CDKN2A, EGLN2/PHD1, FGFR1, H3F3A, HRAS, IDH2, KMT2D, MDH2, MERTK, and TP53). While the basic and extended panels aim to detect PGVs in blood sam- ples, a comprehensive panel incorporates somatic muta- tion detection in tumor samples.
Because precision oncology with NGS is pervasive in clinical practice, issues regarding incidental findings are inevitable. Several mutations detected in tumor samples suggest the possibility of genetic predisposition syn- dromes. The ACMG statements published in 2013 and 2017 recommend the return of incidental findings in clin- ical sequencing, in which four genes (SDHD, SDHAF2, SDHC, and SDHB) are specified for hereditary PPGL syn- drome [68, 69]. In the latest version (version 3.1), pub- lished in 2022, the number of target genes for hereditary PPGL syndrome was increased to six (SDHD, SDHAF2, SDHC, SDHB, MAX, TMEM127) [54]. Identifying these potentially actionable genes is essential for active surveil- lance and therapeutic interventions.
In the context of novel treatments, pseudohypoxia- related PPGL is a promising candidate for blocking
vascular endothelial growth factor or hypoxia-inducible factor 2-alpha (HIF-2a) signaling (Fig. 1). The first pla- cebo-controlled phase 2 trial of the tyrosine kinase inhib- itor (TKI) sunitinib (FIRSTMAPPP trial) demonstrated a higher progression-free survival (PFS) rate at 12 months in the sunitinib group (36% vs. 19%) [70]. Interestingly, the ORR of 12 patients with SDHB mutations was prom- ising (50%). HIF-2a is activated by sensitizing mutations in SDH-related genes (SDHA, SDHB, SDHC, SDHD, and SDHAF2), VHL, and EPAS1, as a HIF-2a-encoding gene [71]. The selective HIF-2a inhibitor belzutifan has been approved in the US to treat VHL-driven cancers. A phase 2 trial of belzutifan in patients with renal cell car- cinoma associated with VHL exhibited an ORR of 49% [72]. A phase 2 study of belzutifan for PPGL, pancreatic neuroendocrine tumors, and VHL-associated tumors is currently underway (NCT04924075). In addition, mTOR complex 1 inhibitors for kinase signaling PPGL, such as everolimus, or other TKIs, such as cabozantinib, are promising agents [73]. Selective RET TKIs are also promising for treating patients with RET mutations. Regarding PPGL, Mweempwa et al. reported a patient with RET-SEPTIN9 fusion who responded to the selec- tive RET inhibitor selpercatinib upon treatment [74]. Pseudohypoxia-related PPGL and the mechanisms of action of the corresponding HIF-2a inhibitors are shown in Fig. 2 [73, 75].
Conclusions and future prospects
In this manuscript, we reviewed representative genetic predisposition syndromes associated with adrenal tumors (ACC and PPGL) and discussed their surveil- lance and therapeutic interventions. In particular, the genotype-phenotype relationship and clinical develop- ment of molecular-targeted agents based on genomic information were highlighted. A genotype-phenotype relationship indicated that ACC was associated with LFS, whereas PPGL was associated with MEN2 or VHL. Overall, the clinical behavior and biological features of ACC and PPGL are different, although both diseases develop from the adrenal gland. Our retrospective single-institution analysis suggested a significant dif- ference in overall survival (OS) between patients with ACC who received mitotane-based regimens and those with PPGL who received the CVD regimen (median OS, 7.2 months vs. 4.4 years) [76, 77].
Several topics should be addressed in future research. First, it remains unknown whether clinical characteris- tics, including prognosis, differ between cases derived from genetic predisposition syndromes and sporadic cases. Second, whether the surveillance strategy should be changed depending on the genetic background
Oxaloacetate
Malate
Citrate
Isocitrate
FH
Krebs cycle
IDH
Fumarate 1
a-ketoglutarate
SDHx
Succinate 1
Succinyl-CoA
Nucleus
Stabilization
Proteasome
PHD1/2
HIF2a
Degradation
HIF2a
HIF target genes
VHL
HIF1B
HIF2a inhibitor
or whether it should be uniform has not been deter- mined. As shown in Table 1, the age at onset of adre- nal tumors is heterogeneous among genetic syndromes; hence, the surveillance strategy will be affected. In the context of novel PPGL treatments, the PFS benefit of sunitinib is valuable in advancing the clinical develop- ment of this rare malignancy. Treatment stratification based on molecular profiles, such as HIF-2a inhibitors, is also expected. However, available molecular informa- tion does not affect the clinical development of ACC. Close cooperation among medical genomics experts, endocrinologists, oncologists, and early investigators is indispensable for improving the clinical management of patients with these multifaceted diseases.
Abbreviations
| ACC | adrenocortical carcinoma |
| PPGL | pheochromocytoma/paraganglioma |
| IGF2 | insulin-like growth factor 2 |
| HIF2a | hypoxia-inducible factor 2-alpha |
| mTORC1 | mammalian target of rapamycin complex1 |
Acknowledgments
We would like to thank Editage for the English language editing.
Authors’ contributions
A.O. wrote the main manuscript text and A.O. and N.H. prepared Figs. 1-2. N.H., S.T. and A.U. revised the manuscript. All authors reviewed the manuscript.
Funding
This study received no grants from any funding agencies.
Availability of data and materials Not applicable.
Declarations
Ethics approval and consent to participate Not applicable.
Competing interests
The authors declare no competing interests.
Received: 27 August 2023 Accepted: 14 March 2024 Published online: 26 March 2024
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