HEALTH & HUMAN SERVICES - USA \MENT OF HUMANO
Published in final edited form as: Endocrinol Metab Clin North Am. 2017 June ; 46(2): 419-433. doi:10.1016/j.ecl.2017.01.007.
Genetics of Adrenocortical Development and Tumors
Maya Lodish, MD, MHSc
Pediatric Endocrinology Fellowship, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Building 10, Room 9D42, 10 Center Drive, MSC 1830, Bethesda, MD 20892-1830, USA
Keywords
Adrenal development; Adrenocortical carcinoma; Ontogenesis; Zonation; Signaling; Pathway; Genetic; Driver mutation
INTRODUCTION
This article links the understanding of the developmental physiology of the adrenal cortex to adrenocortical tumor formation. Many molecular mechanisms that lead to the formation of adrenocortical tumors have been discovered via next-generation sequencing approaches. The most frequently mutated genes in adrenocortical tumors are also factors in normal adrenal development and homeostasis, including those that alter the p53 and Wnt/B-catenin pathways. In addition, dysregulated protein kinase A (PKA) signaling and ARMC5 mutations have been identified as key mediators of adrenocortical tumorigenesis. The growing understanding of the genetic changes that orchestrate adrenocortical development and disease pave the way for potential targeted treatment strategies.
Adrenocortical carcinoma (ACC) has a bimodal age distribution with a peak in early childhood with a mean age of diagnosis at 3.2 years, and a peak in adulthood in the fourth and fifth decades.1, 2 ACC has an annual incidence of 0.7 to 2 per million.3, 4 The understanding of the pathophysiology of ACC is limited, and the disease carries a poor prognosis.5 Recent identification of genetic characteristics of ACC may lead to the development of novel therapeutic interventions. Several genes have been implicated as tumor drivers in sporadic ACC, including mutations in insulin-like growth factor 2 (IGF2), B-catenin (CTNNB1 or ZNRF3), and TP53.6, 7 Importantly, germline variants of some of the same genes identified to be drivers of sporadic ACC are also associated with familial tumor syndromes characterized by ACC, including Beckwith-Wiedemann syndrome (BWS), familial adenomatous polyposis (FAP), and Li-Fraumeni syndrome.
Elevated cAMP signaling is related to most benign cortisol-producing tumors of the adrenal gland. The first human disease that directly linked cAMP signaling to cortisol-producing lesions was with the discovery more than 25 years ago that activating mutations in GNAS1 caused adrenocortical tumors in infants with McCune-Albright syndrome (MAS). Mutations
in the regulatory subunit type 1 a (Rla) of the cAMPdependent protein kinase or PKA were then identified as the cause of another form of cortisol-producing hyperplasia, primary pigmented nodular adrenocortical disease (PPNAD). Inactivating mutations in inhibitors of the cAMP-signaling pathway (phosphodiesterases [PDEs]) were later identified as another cause of adrenocortical hyperplasia. Most recently, somatic activating mutations in the main catalytic subunit of PKA have been discovered in cortisol-producing adenomas. Put together, these findings provide convincing proof that increased cAMP signaling is key to adrenal tumor development. The implications of this finding lead to the search for targeted treatment strategies for adrenal tumors and hypercortisolism that act on the cAMP/PKA cascade.
A novel gene was recently identified that provides evidence that bilateral macronodular adrenal hyperplasia is frequently a genetic disorder. Germline mutations in the tumor suppressor gene ARMC-5 lead to the development of an autosomal dominantly inherited form of Cushing syndrome (CS). Because this type of CS may present in a cyclical manner that may take many years to diagnose, the potential to identify individuals at risk for the development of CS based on genetic findings has the potential to lead to more timely diagnosis of CS. Recent advances in the understanding of adrenocortical signaling have taught that cortisol secretion within the adrenal gland is more complex than previously thought. It is now known that paracrine signaling via intra-adrenal secretion of corticotrophin is a factor in adrenal hyperplasia.
OVERVIEW OF ADRENOCORTICAL DEVELOPMENT
The adrenal cortex derives from components of the urogenital ridge, sharing a common origin with the kidney and gonads.8 The human adult adrenal cortex is separated into three distinct zones that may be characterized by their functionality and histology. The outermost layer, the zona glomerulosa, secretes aldosterone; the middle zona fasiculata secretes glucocorticoids; and the innermost zona reticularis produces sex steroid hormone precursors androstenedione and dehydroepiandrosterone (Fig. 1).
Adrenocortical cell precursors originate from the coelomic epithelium that, together with the gonadal cell precursors, forms the adrenogonadal primordium. The encapsulation of the adrenal primordium, creating the fetal adrenal gland, occurs by 9 weeks postconception.9, 10 By midgestation, the fetal adrenals are composed of two distinct cortical zones: the predominant fetal zone and the surrounding definitive zone. Shortly after birth, the adrenal cortex is remodeled and the fetal zone recedes. The establishment of the adrenal zona glomerulosa and zona fasiculata occurs in late fetal development; however, the zona reticularis is not completely established until adrenarche (Fig. 2). Corticotrophin is the primary regulator of development of the human fetal adrenal mediated through locally expressed growth factors including EGF, bFGF, and insulin-like growth factor (IGF)-I and - II.10 As the definitive cortex grows and the fetal cortex regresses, capsular cells give rise to steroid-producing adrenocortical cells.11
ADRENOCORTICAL TUMORS: OVERVIEW OF GENETIC BASIS
Current understanding of normal adrenocortical development sheds light on the molecular pathways that, when altered, may stimulate abnormal proliferation and drive adrenocortical tumor formation. Adrenal tumors may be functional and lead to syndromes of hormone excess, hypercortisolism (CS), hyperaldosteronism (Conn syndrome), hyperandrogenism (virilizing syndrome), or mixed. CS may be caused by over-secretion of cortisol from adrenocortical hyperplasia, tumors, or cancer. Most (75%- 90%) of these tumors are benign unilateral adenomas. ACC is infrequent, making up less than 5% of all ACTs. The remainder of the adrenal lesions (10%) are related to bilateral hyperplasia: PPNAD and primary bilateral macronodular adrenal disease (PBMAD). Knowledge of the molecular pathways involved in adrenocortical tumorigenesis arises from the genetic basis of inherited syndromes that include adrenocortical tumors (Table 1), and from next-generation sequencing approaches of tumor and germline DNA (Table 2).
Several paracrine and endocrine signals are key players in adrenocortical development. Steroidogenic factor-1 (SF-1, NR5A1) and nuclear receptor subfamily 0 group B member 1 (DAX-1, NR0B1) are key transcription factors critical for adrenocortical development.12 The sonic hedgehog pathway is central to adrenocortical development and has been implicated in ACC with up-regulation in adult ACCs, and downregulation in pediatric ACCs.13 The maintenance of the adrenal cortex involves the central migration of sonic hedgehog: positive progenitor cells where they differentiate into the cells making up the zona glomerulosa that later transition to zona fasiculata.14 The fibroblast growth factor (FGF) signaling pathway is integral to adrenal proliferation and differentiation. The four main signaling pathways downstream of FGF receptor activation are (1) Janus kinase/signal transducer and activator of transcription (Jak/ Stat), (2) phosphoinositide phospholipase C (PLCy), (3) phosphatidylinositol 3-kinase (PI3K), and (4) mitogen-activated protein kinase/ extracellular signal-regulated kinase (MAPK/Erk).15 FGFR1 and FGFR4 overexpression has been found in 65% of adrenocortical tumors and is associated with worse prognosis.16
INSULIN-LIKE GROWTH FACTOR SIGNALING PATHWAY
The IGF signaling pathway is involved in differentiation and growth of the adrenal cortex. IGF-2 is highly expressed in human fetal adrenal glands. The chromosomal location of IGF-2 is within an imprinted locus on 11p15.5 that also includes the cyclin-dependent kinase inhibitor 1 C (CDKN1C) and H19. 17 The importance of IGF2 in adrenocortical development is illustrated by BWS, a pediatric overgrowth disorder with a predisposition to tumor development characterized by macroglossia and hemihypertrophy. BWS is caused by mutation, deletion, or hypermethylation of imprinted genes within the chromosome 11p15.5 region, encompassing CDKN1C, H19, IGF2, and P57. 18, 19 Adrenal cytomegaly with cysts is the predominant adrenal phenotype in BWS; however, ACC occurs with increased frequency in patients with BWS as ACC occurs in 7% of patients. 20, 21 Structural and functional abnormalities at 11p15 are also associated with sporadic adrenocortical tumors.22 Whole-genome, whole-exome, and/or transcriptome sequencing of 37 ACCs found that 91% show loss of heterozygosity of chromosome 11p; IGF2 on chromosome 11p was overexpressed in all tumors.23
WNT SIGNALING PATHWAY
The mammalian wingless-type MMTV integration site (Wnt) pathway is a central developmental regulator.24 In the absence of Wnt signaling, ß-catenin is in a complex with axin, APC, and GSK3-B. Within this complex, B-catenin is then phosphorylated and targeted for degradation. WhenWnt signaling is activated, B-catenin is uncoupled from the degradation complex and translocates to the nucleus, where it activates target genes.25 Constitutive activation of ß-catenin drives adrenocortical tumorigenesis. Defects in Wnt pathway activation, including genetic loss of APC or gain-of-function mutations in CTNNB1, are known driver mutations of ACC.7, 26 In fact, Wnt signaling has been found to be the most frequently mutated pathway in ACCs.27 CTNNB1 mediates cell-cell adhesion and anchors the actin cytoskeleton, thereby regulating cell growth.28 CCNE1 encodes cyclin E, a regulatory subunit of cyclin-dependent kinase. Cyclin E is a key regulator of the cell cycle and is overexpressed in many human tumors.29 Whole-exome sequencing of 41 matched ACC and normal tissues identified somatic mutations in CTNNB1 in 10% of tumors.27
The role of the Wnt/B-catenin pathway in adrenocortical tumors is illustrated in the autosomal dominantly inherited syndrome FAP. Germline inactivating mutations of the tumor suppressor gene APC characterize FAP, leading to multiple colonic polyps, colon cancer, and adrenocortical tumors caused by dysregulated Wnt/B-catenin signaling.26 Gain- of-function mutations in ß-catenin have been found in roughly 25% of benign and malignant adrenocortical tumors, highlighting the importance of activation of the Wnt signaling pathway.7 Exome sequencing of ACCs identified ZNRF3, encoding a cell surface E3 ubiquitin ligase, as a potential new tumor suppressor gene related to the ß-catenin and Wnt signaling pathway.30 A total of 19.3% of ACC samples out of 91 ACCs recently analyzed through the Cancer Genome Atlas were found to have alterations of ZNRF3.31, 32 Another large whole exome sequencing analysis of 41 tumors and matched normal samples found homozygous deletion at 22q12.1 including the Wnt repressors ZNRF3 and KREMEN1 in 9.8% and 7.3% of tumors, respectively.27
CELL CYCLE REGULATORS
The transcription factor p53 on chromosome 17p13 is a tumor suppressor that regulates cell cycle arrest, apoptosis, senescence, metabolism, and DNA repair. In many cancers, activity of p53 is lost.33 Whole-exome sequencing of 41 matched ACC and normal tissues identified somatic mutations in TP53 in 20% of ACC tumors.27 Pediatric ACC is exceedingly rare and carries a poor prognosis; the most common germline alteration in pediatric ACC is caused by p53. Whole-genome, whole-exome, and/or transcriptome sequencing of 37 ACCs found TP53 mutations and chromosome 17 loss of heterozygosity in 76% of pediatric ACCs.23 Li- Fraumeni syndrome is an autosomal-dominant cancer syndrome caused by heterozygous germline mutations in the p53 gene, and is associated with an increased risk of malignancies. Children with Li-Fraumeni syndrome are at an especially high risk of developing ACC.34 The median age of ACC diagnosis among TP53 mutation carriers is 4.8 years of age.35 Multiple endocrine neoplasia type 1 (MEN1) is another autosomal-dominant cancer syndrome involving dysregulation of the cell cycle. MEN1 is characterized by the
“three Ps” of primary hyperparathyroidism, pancreatic endocrine tumors, and pituitary adenomas; adrenal lesions may also occur. Loss of function mutations in MENIN disrupt cell cycle regulation and lead to cell proliferation. In approximately 20% to 40% of patients with MEN1, enlarged adrenals are found, with bilateral adrenal tumors in 1.3%.36 In two recent studies reporting exome sequencing in ACC, between 4% and 7% of tumors had inactivating mutations in MENIN.30 Finally, in the cell cycle during chromosome replication, telomeres are critical for maintaining genomic integrity. TERF2, a protein that plays a key role in the protective activity of telomeres, has also been found to be amplified in ACC.31, 37
CAMP-DEPENDENT PROTEIN KINASE PATHWAY
The cAMP-dependent PKA pathway plays a central role in controlling the development, function, and proliferation of adrenocortical cells. Breaking down the components of the cAMP/PKA pathway, first corticotrophin binds the MC2R G protein-coupled receptor, leading to the stimulation of adenylyl cyclase and release of cyclic-AMP. Next, cAMP activates PKA, a heterotetramer of two regulatory and two catalytic subunits; the PKA catalytic subunit (a serine-threonine kinase) then goes on to phosphorylate several targets, including those leading to cortisol synthesis. Four different genes encode four distinct isoforms of the regulatory subunits (Rla, R16, R2a, and R2B).38 In addition, four unique catalytic subunits of PKA are known (Ca, CB, Cy, and PRKX). Following the binding of cAMP to PKA, the catalytic subunits dissociate from the regulatory subunits, allowing for the phosphorylation of PKA targets in the cytoplasm and the nucleus. Modifications in specific subunits of PKA, including, PRKARla and PRKACa, play a major role in adrenal physiology and pathophysiology (Fig. 3).39, 40
MAS is the first disorder identified to connect cAMP/PKA pathway alterations to the growth of adrenal tumors. MAS is caused by postzygotic gain-of-function mutations in the alpha subunit of the gene for the stimulatory guanine-nucleotide-binding protein (Gsa) leading to constitutive activation of adenylate cyclase.40-42 Clinically, patients present with the classic triad of fibrous dysplasia, cafe-au-lait skin pigmentation, and precocious puberty. CS is present in a subset of patients with MAS caused by activating mutations of Gsa.43, 44 Multiple nodules that develop from adrenocortical cells with fetal features characterize the adrenals in MAS affected by CS. In a small number of sporadic cortisol-producing adenomas, somatic mutations of GNAS have been identified.3
Carney complex is an autosomal-dominant MEN syndrome, including myxomas, endocrine tumors, and endocrine gland involvement.45, 46 Endocrine tumors associated with CNC include testicular large cell, calcifying Sertoli cell tumors, growth hormone-producing pituitary adenomas, thyroid nodules, and PPNAD. Germline inactivating mutations of the PRKAR1A gene coding for the regulatory 1-a (Rla) subunit of PKA are the cause of for CNC in most patients. 47, 48 PPNAD is found in 60% of patients with CNC.49, 50 A series of 212 patients with PPNAD found that in 20% of the cases adrenal tumors were isolated without any other manifestations of CNC, with a preponderance of females.49 Somatic mutations in PRKAR1A and chromosomal loss of the region encompassing PRKAR1A have been identified in sporadic cortisol-secreting adenomas. One study of 44 sporadic
adrenocortical tumors found somatic 17q22 to 24 losses were seen in 23% of adenomas and 53% of adrenal cancers. In three tumors, somatic, PRKAR1A-inactivating mutations were identified, leading to protein truncation.51, 52 More recently, in whole exome sequencing from 84 ACCs, seven (8%) cases were found to have inactivating PRKAR1A mutations, and three additional cases had homozygous deletions of PRKAR1A, increasing the role of PKA signaling in ACC.31 In addition, this finding leads to a potential relationship between benign and malignant adrenocortical tumors.53 PPNAD and micronodular adrenocortical hyperplasia have both been associated with genetic defects in cAMP-binding PDEs. The role of PDEs is to lower cAMP levels after stimulation of the cAMP/PKA pathway; inactivating mutations of PDE cause buildup of cAMP and stimulation of the PKA signaling cascade. PDE11 A and PDE8B mutations have been found in patients with PPNAD and iMAD, and PDE8B have also been shown to be associated with predisposition to iMAD.47, 54, 55 Constitutive activation of the catalytic subunit of PKA, PRKACA, has been found to be a common cause of CS.40, 56-59 PRKACA-activating mutations are responsible for 42% of sporadic CS.40, 56-59 Activating PRKACA mutations obstruct the interaction of the regulatory subunit with the catalytic subunit, leading to constitutive activation of PKA, increased cortisol production, and altered tumor growth.59 Genetic copy number gains encompassing PRKACA on chromosome 19p13.2p13.12 locus are another described cause of CS related to activation of the PKA pathway.40, 60 Most recently, ACC has been found to be associated with somatic mutations of PRKAR1A.31 All of these findings have led to a search for novel targeted treatment strategies with PRKACA inhibitors for management of adrenocortical tumors.56, 58
Genetics of Primary Bilateral Macronodular Adrenal Disease
PBMAD may be seen in multiple tumor syndromes MEN-1 and FAP and also include hereditary leiomyomatosis and renal cell carcinoma (HLRCC, caused by fumarate hydratase gene [FH] mutations). In HLRCC, inactivating mutations of FH lead predominantly to hereditary leiomyomatosis and renal cancer; however, in approximately 8% of patients adrenal lesions are found.61 A single case of clinical CS associated with PBMAD in the context of HLRCC has been described, in which loss of heterozygosity for FH was found in the adrenal lesion.62
ARMC5 is another armadillo-containing protein with homology to ß-catenin and APC that is involved in adrenocortical pathophysiology. Inactivating ARMC5 mutations have been found in more than half of cases of primary bilateral macronodular adrenal hyperplasia. 42 Additional studies have confirmed the high frequency of ARMC5 mutations in this disorder.63-66 ARMC5 is a putative tumor suppressor that regulates apoptosis. ARMC5 has also been shown in vitro to directly interact with PKA subunits, linking ARMC5 to the PKA/cAMP pathway.67 Intra-adrenal corticotrophin secretion by clusters of adrenocortical cells is a paracrine signaling pathway found to occur in PBMAD.68 Abnormal G-protein- coupled receptors expressed by adrenocortical cells themselves, including receptors for vasopressin, catecholamines, luteinizing hormone, serotonin, and glucose-dependent insulinotropic peptide, may also serve to regulate cortisol secretion.69-72 Intra-adrenal production of corticotrophin may offer a potential therapeutic target for CS in certain types
of adrenal hyperplasia through the application of corticotrophin receptor inhibitors (melanocorticon type 2 receptor antagonists).73
Genetics of aldosterone producing adenomas
Aldosterone-producing adenomas may be caused by somatic mutations in genes that regulate intracellular calcium concentration. Somatic mutation of two ATPases, ATPA1A (encoding the alpha subunit of the sodium/potassium ATPase) and ATP2B3 (encoding the plasma membrane calcium-transporting ATPase3) have been found in aldosterone-producing adenomas.74 KCNJ5 mutations, a gene that encodes a potassium channel, have also been found in 40% of aldosterone-producing adenomas.75, 76 Mutations in KCNJ5 alter the channel’s permeability to potassium ultimately leading to activation of the calcium- calmodulin-dependent protein kinase II.77 Germline ARMC5 variants may also be associated with primary aldosteronism.78
SUMMARY AND FUTURE CONSIDERATIONS
The most frequently mutated genes in adrenocortical tumors are also factors involved in normal adrenal development and homeostasis. A better understanding is being gained of the molecular genetics of adrenocortical tumor development. The most common somatic alterations in ACC are mutations or deletions of TP53 and ZNRF3 or CTNNB1, altering either the p53 or the Wnt/B-catenin pathway. The PKA/cAMP signaling pathway plays a crucial role in adrenocortical physiology and pathophysiology; activating mutations of pathway regulators and inactivating mutations of pathway inhibitors both lead to cortisol excess. Germline mutations of PRKAR1A lead to PPNAD and CS in adolescence or early adulthood. Somatic PRKACA-activating, PRKAR1A-inactivating, or GNAS-activating mutations may cause cortisol-secreting adenomas. Recently, whole-genome expression profile of normal adrenals was compared with PRKAR1A and GNAS-mutant adrenal glands, and it was shown that although activation of certain oncogenic signals were shared between these two lesions, others including Wnt signaling were differentially expressed depending on the lesion.79 These discoveries offer the possibility to target molecular alterations in this pathway with novel mechanisms to treat cortisol excess in CS, and highlight the importance of genetic testing in adrenocortical tumors.
Acknowledgments
Figure design was performed by Jeremy Swan and Nicole Jonas.
Funding: This work was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health.
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52. Gaujoux S, Tissier F, Groussin L, et al. Wnt/beta-catenin and 3’,5’-cyclic adenosine 5’- monophosphate/protein kinase A signaling pathways alterations and somatic beta-catenin gene mutations in the progression of adrenocortical tumors. J Clin Endocrinol Metab. 2008; 93(10): 4135-4140. [PubMed: 18647815]
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54. Rothenbuhler A, Horvath A, Libe R, et al. Identification of novel genetic variants in phosphodiesterase 8B (PDE8B), a cAMP-specific phosphodiesterase highly expressed in the adrenal cortex, in a cohort of patients with adrenal tumours. Clin Endocrinol. 2012; 77(2):195- 199.
55. Horvath A, Giatzakis C, Tsang K, et al. A cAMP-specific phosphodiesterase (PDE8B) that is mutated in adrenal hyperplasia is expressed widely in human and mouse tissues: a novel PDE8B isoform in human adrenal cortex. Eur J Hum Genet. 2008; 16(10):1245-1253. [PubMed: 18431404]
56. Cao Y, He M, Gao Z, et al. Activating hotspot L205R mutation in PRKACA and adrenal Cushing’s syndrome. Science. 2014; 344(6186):913-917. [PubMed: 24700472]
57. Goh G, Scholl UI, Healy JM, et al. Recurrent activating mutation in PRKACA in cortisol- producing adrenal tumors. Nat Genet. 2014; 46(6):613-617. [PubMed: 24747643]
58. Sato Y, Maekawa S, Ishii R, et al. Recurrent somatic mutations underlie corticotropin-independent Cushing’s syndrome. Science. 2014; 344(6186):917-920. [PubMed: 24855271]
59. Di Dalmazi G, Kisker C, Calebiro D, et al. Novel somatic mutations in the catalytic subunit of the protein kinase A as a cause of adrenal Cushing’s syndrome: a European multicentric study. J Clin Endocrinol Metab. 2014; 99(10):E2093-E2100. [PubMed: 25057884]
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KEY POINTS
· Current understanding of normal adrenocortical development sheds light on the molecular pathways that, when altered, may stimulate abnormal proliferation and drive adrenocortical tumor formation.
· Knowledge obtained from inherited syndromes that are characterized by adrenocortical tumors and next-generation sequencing of adrenocortical tumors have helped find causative mutations for these lesions.
· Recent studies have identified cyclic AMP-dependent protein kinase A (PKA) signaling as a key mediator of cortisol secretion by the normal adrenal cortex. It therefore follows that mutations in genes that involve dysregulated cAMP/PKA pathway components are implicated in adrenocortical pathology.
· ARMC5 is a recently discovered gene that is associated with bilateral macronodular adrenocortical hyperplasia.
Cortex
Medulla
Capsule ZG
ZF
ZR
Medulla
Adrenogonadal Primordii
ZG
ZG
Definitive zone
Definitive zone
ZF
ZF
Fetal zone
Transitional zone
Medulla
Fetal zone
ZR
Medulla
Medulla
Medulla
8 wk adrenogonadal primordium
9 wk fetal adrenal
24-28 wk
T Birth
6 mo
6 y Adrenarche
A
B
ACH
ACH
XXXXENE
XXX
Y
als
AC
Y
Os
AC
₿
₿
PDE
P
ATP
CAMP
AMP
ATP
CAMP
AMP
PKA
R
R
PKA
R
R
C
R
R
C
C
R
R
R
R
C
C
C
C
C
C
C
C
C
C
C
C
C
C
PCREB
PCREB
CREB
cre
CREB
cre
cre
cre
| Syndrome | Gene | Locus | Function of the WT Protein | Associated Manifestations |
|---|---|---|---|---|
| Primary bilateral macronodular adrenocortical disease | ARMCS | 16p11 | Potential role in regulation of apoptosis and steroidogenesis | Meningioma? |
| Multiple endocrine neoplasia type 1 | Menin | 11q13 | Regulator of gene transcription, cell proliferation, apoptosis, and genome stability | Multiple endocrine neoplasia type 1 hyperparathyroidism, pituitary adenomas, pancreatic neuroendocrine tumors |
| Hereditary leiomyomatosis and renal cell cancer | FH | 1q42 | Krebs cycle, amino acid metabolism | Hereditary leiomyomatosis and renal cell carcinoma |
| Li-Fraumeni syndrome | TP53 | 17p13.1 | Cell cycle regulator | Breast cancer and soft tissue sarcomas, brain tumors, osteosarcoma, leukemia, and adrenocortical carcinoma |
| McCune-Albright syndrome | GNAS1 | 20q13 | Stimulation of adenyl cyclase, activation of the cAMP/protein kinase A pathway | Fibrous bone dysplasia, cafe-au-lait spots, precocious puberty, acromegaly, toxic multinodular goiter |
| Gardner syndrome | APC | 5q12-22 | Prevent b-catenin accumulation, inhibition of the Wnt/B-catenin pathway | Familial adenomatous polyposis: colon adenomas and carcinomas, pigmented retinal lesions, desmoid tumors, other malignant tumors as adrenocortical carcinomas |
| Beckwith-Wiedemann syndrome | IGF2 | 11p15 imprinting | Growth factor | Hemihypertrophy, macroglossia, ear pits, hypoglycemia, aisceromegaly, abdominal wall defects, Wilms tumor, hepatoblastoma, adrenocortical carcinoma |
| Carney complex | PRKAR1A | 17q22-24 | Activation of the cAMP/ protein kinase A pathway | Lentigines, pituitary adenomas, cardiac myxomas |
| Gene | Cytogenetic Location | Gene Name | OMIM |
|---|---|---|---|
| TERF2 | 16q22.1 | TELOMERIC REPEAT-BINDING FACTOR 2 | 602027 |
| ZNRF3 | 22q12.1 | ZINC FINGER AND RING FINGER PROTEIN 3 | 612062 |
| TP53 | 17p13.1 | TUMOR PROTEIN p53 | 191170 |
| CTNNB1 | 3p22.1 | CATENIN, BETA-1 | 116806 |
| PRKAR1A | 17q24.2 | PROTEIN KINASE, cAMP-DEPENDENT, REGULATORY, TYPE 1, ALPHA | 188830 |
| CCNE1 | 19q12 | CYCLIN E1 | 123837 |
| IGF2 | 11p15.5 | INSULIN-LIKE GROWTH FACTOR II | 147470 |
| FGFR1 | 8p11.23 | FIBROBLAST GROWTH FACTOR RECEPTOR 1 | 136350 |
| FGFR4 | 5q35.2 | FIBROBLAST GROWTH FACTOR RECEPTOR 4 | 134935 |
| RB1 | 13q14.2 | RB1 GENE | 614041 |