Diagnosis and Management of Hereditary Adrenal Cancer
Anna Angelousi, Mihail Zilbermint, Annabel Berthon, Stéphanie Espiard and Constantine A. Stratakis
Abstract
Benign adrenocortical tumours (ACT) are relatively frequent lesions; on the contrary, adrenocortical carcinoma (ACC) is a rare and aggressive malignancy with unfavourable prognosis. Recent advances in the molecular understanding of adrenal cancer offer promise for better therapies in the future. Many of these advances stem from the molecular elucidation of genetic conditions predisposing to the development of ACC. Six main clinical syndromes have been described to be associated with hereditary adrenal cancer. In these conditions, genetic counselling plays an important role for the early detection and follow-up of the patients and the affected family members.
A. Angelousi ☒ · M. Zilbermint · A. Berthon · S. Espiard · C.A. Stratakis ☒ Section on Endocrinology and Genetics, Program on Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA e-mail: a.angelousi@gmail.com
C.A. Stratakis e-mail: stratakc@mail.nih.gov
M. Zilbermint e-mail: mihail.zilbermint@nih.gov
A. Berthon
e-mail: annabel.berthon@nih.gov
S. Espiard e-mail: stephanie.espiard@live.fr
@ Springer International Publishing Switzerland 2016
G. Pichert and C. Jacobs (eds.), Rare Hereditary Cancers,
Recent Results in Cancer Research 205, DOI 10.1007/978-3-319-29998-3_8
Keywords
Protein Kinase A (PKA) · PRKAR1A gene · Li-Fraumeni syndrome · TP53 gene · Familial polyposis · APC gene
Contents
1 Introduction 126
2 Genetic Syndromes Associated with ACC
2.1 Li-Fraumeni Syndrome (LFS) 127
2.2 . LFS: Diagnostic Criteria 127
130
2.3 LFS: Genotype-Phenotype Correlations
131
2.4 LFS: Genetic Mutations and Genetic Testing
131
3 Beckwith-Wiedemann Syndrome (BWS)
132
3.2 BWS: Genotype-Phenotype Correlations
133
3.4 BWS: Genetic Counselling
134
4.1 MEN1: Diagnostic Criteria
135
4.2 MEN1: Genotype-Phenotype Correlations
135
4.3 MEN1: Genetic Mutations and Genetic Testing
135
4.4 MEN1: Genetic Counselling 136
5 Familial Adenomatous Polyposis (FAP) and Lynch Syndrome (LS) 137
5.1 FAP and LS: Diagnostic Criteria 137
5.2 FAP and LS: Genetic Mutations and Genetic Testing 137
5.3 FAP and LS: Genetic Counselling 138
6 Carney Complex (CNC)
138
6.1 CNC: Diagnostic Criteria
139
6.2 CNC: Genotype-Phenotype Correlations
6.3 CNC: Genetic Mutations and Genetic Testing 140
140
6.4 CNC: Genetic Counselling
141
7 Neurofibromatosis Type 1 (NF1)
141
7.1 NF1: Diagnostic Criteria
141
7.3 NF1: Genetic Mutations and Genetic Testing
142
7.4 NF1: Genetic Counselling 142
142
8 Conclusions
References 143
1 Introduction
Adrenocortical tumours (ACT) represent a group of lesions arising from cells of the adrenal cortex. The incidence of adrenal incidentalomas has been reported to be as high as 8.7 % in autopsy series and 4 % in radiological studies (Arnaldi and Boscaro 2012). However, adrenocortical carcinomas (ACCs) are rare neoplasms with an incidence of 0.5-2 million per year leading to 0.2 % of all cancer deaths in the USA. They are significantly more frequent in females in all ages. ACCs are
2.5 LFS: Genetic Counselling
132
3.1 1 BWS: Diagnostic Criteria
133 3.3 BWS: Genetic Mutations and Genetic Testing 132
4 Multiple Endocrine Neoplasia Type 1 (MEN1)
134
7.2 NF1: Genotype-Phenotype Correlations 141
usually aggressive tumours with poor prognosis and an only 16-44 % 5-year survival rate (Fassnacht and Allolio 2009). The median age of diagnosis is at approximately 46 years; an early peak of the disease between the ages of 5 and 7 years represents a clinically and molecularly different form of ACC. In childhood, ACCs are slightly more frequent compared to adults, representing as many as 1.3 % of the total number of cancers in children (Fassnacht and Allolio 2009; Icard et al. 2001).
The differential diagnosis between a benign ACT and an ACC can be chal- lenging given the frequency of the former and the rarity of the latter. In addition, about 60 % of ACC patients present with some hormone excess, but their detection remains elusive because the steroid hormone secretion is either subclinical or not typical of Cushing’s and Conn’s syndromes or hyperandrogenism (Arlt et al. 2011).
ACCs exhibit a complex pattern of genetic defects from many chromosomal aberrations to somatic mutations in a number of genes; they can also be caused by inherited mutations in specific cancer development-related genes (Lerario et al. 2014). Aside from genetic predisposition, no other risk factors have been estab- lished. High levels of oestrogens have been suggested to increase the incidence of ACC based on the observation of ACC development during pregnancy and the much higher frequency of ACC in females. Indeed, in vitro studies show growth-promoting effects of oestrogen on the ACC (Sirianni et al. 2012).
2 Genetic Syndromes Associated with ACC
The genetic defects and the manifested clinical syndromes associated with ACC are also briefly described and summarized in Table 1.
2.1 Li-Fraumeni Syndrome (LFS)
LFS is a cancer predisposition syndrome first described in 1969; cancer predis- position in this condition is inherited in an autosomal dominant manner. Half of the patients with LFS develop at least one LFS-associated cancer by age 30; 90 % of the patients develop a tumour by 60 years of age (Gonzalez et al. 2009; Sorrell et al. 2013). While many types of tumours can be seen in patients with LFS, the most frequent include breast cancer, sarcoma and brain tumours.
Breast cancer accounts for 25-30 % of all LFS-associated tumours (Sorrell et al. 2013), sarcomas for 25-30 % (Gonzalez et al. 2009; Olivier et al. 2003) and brain tumours for 9-16 % (Gonzalez et al. 2009; Olivier et al. 2003; Palmero et al. 2010). ACC is a less frequent manifestation accounting for 10-14 % of cancers within the context of LFS (Palmero et al. 2010). The next most frequently associated cancers are leukaemia, lung, colorectal, skin, gastric and ovarian cancers (Sorrell et al. 2013; Olivier et al. 2003). As in other cancer predisposition syndromes, all cancers in LFS are diagnosed at much younger ages than their sporadic counterparts.
| Clinical syndromes | Inheritance | Locus | Gene(s) involved | Mutations | Prevalence of ACC | Genetic tests | Genetic counselling |
|---|---|---|---|---|---|---|---|
| LFS | AD | 17p13 | TP53 (oncosuppressor) | Germline- and somatic missense-inactivating mutations | - 10-14% (adults)- 50-80% (children) | - Sanger sequencing - MLPA | TP53 germline test should be considered in all ACC patients |
| BWS | AD | 11p15.5 | - IGF-2 - CDKNIC (oncosuppressor) - KCNQ10T1 - H19 | - Loss of methylation of IC2 or gain of methylation of IC1 on the maternal chromosome - Mutation of the maternal CDKN1C - UDP of 11p15.5 - Duplication, inversion or translocation of the 11p15.5 | <1% (mainly children) | - CGH - MLPA - Sequence analysis of CDKNIC - Testing for microdeletions/microduplications of the CDKN1C by other methods | No specific screening recommendation for ACC patients |
| MEN1 | AD | 11q13 | Menin (oncosuppressor) | Germline-inactivating mutation and somatic missense mutation or deletion leading to LOH | 1-2% of adults (13% if tumour > 1 cm) | - Testing for partial or whole-gene deletion - Haplotype analysis - MLPA | No regular monitoring for ACC. If pre-existing adrenal lesions, annual or biennial imaging is proposed |
| FAP | AD | 5q12-22 | - APC (oncosuppressor) - CTNNB1 | Germline-inactivating mutations: - Nucleotide substitution - Frameshift mutations APC promoter methylation | Rare: < 1% | - Sanger sequencing - Large rearrangement analysis - MLPA | No recommendation for routine screening in patients with ACC |
| LS | AD | - 3p22.2 (MLH1) -2p21 (MSH2) - 2p16.3 (MSH6) - 7p22.1 (PMS2) | - MSH2 - MSH6 - MLH1 - PMS2 | Inactivating mutations | 3% of adults | - sequencing - Large rearrangement analysis - Immunochemistry - Microsatellite instability analysis - MLPA | Routine screening in ACC tumours by immunochemistry of the 4 genes regardless of the family history |
(continued)
| Clinical syndromes | Inheritance | Locus | Gene(s) involved | Mutations | Prevalence of ACC | Genetic tests | Genetic counselling |
|---|---|---|---|---|---|---|---|
| CNC | AD | – 17q22.24 - 2p16 | PRKAR1A (oncosuppressor) | - Germline-inactivating mutations: single-nucleotide base substitutions or exonic insertions or deletions (LOH) - c.439A > G (p.S147G)ª | Rare (only case reports) | - Sanger sequencing - Array-based analysis - MLPA | No routine screening |
| NF1 | AD | – 17q11.2 | NF1 (oncosuppressor) | Loss-of-function mutation or deletion (LOH) | Rare <1% | - dHPLC - FISH - MLPA - CGH - Sanger sequencing | No routine screening |
ACC adrenocortical carcinoma, LFS Li-Fraumeni syndrome, WBS Beckwith-Wiedemann syndrome, MEN1 multiple endocrine hyperplasia type 1, FAP familial adenomatous polyposis, LS Lynch syndrome, CNC Carney complex syndrome, NF1 neurofibromatosis type 1, AD autosomal dominant, TP53 tumour protein 53, MLPA multiplex ligation-dependent probe amplification analysis, WGS whole-genome sequencing, WES whole-exome sequencing, IGF-2 insulin growth factor 2 gene, CDKNIK1 cyclin-dependent kinase inhibitor 1C, KCNQ10T1 potassium channel, voltage-gated KQT-like subfamily Q, member 1, IC1/2 imprinting centre 1/2, UDP uniparental disomy, LOH loss of heterozygosity, APC adenomatous polyposis coli, CTNNB1 catenin-beta 1, MLH1 MutL homolog, MSH1-6 MutS protein homolog 2-6, PMS2 postmeiotic segregation increased 2, PRKAR1A protein kinase regulatory subunit type 1 alpha gene, dHPLC denaturing high-performance liquid chromatography, FISH fluorescence in situ hybridization, CGH array comparative genomic hybridization, MLPA Multiple ligation-dependent probe amplification ªMutation associated with ACCs in members of a family with CNC
2.2 LFS: Diagnostic Criteria
The diagnostic criteria of LFS are presented in Table 2. The initial classical criteria of LFS were developed in 1998 (Li et al. 1988) with a low sensitivity of 40 % and a better specificity of 91 % (Gonzalez et al. 2009). Later, new diagnostic efforts led to the adoption of the Birch and Eeles criteria that were developed for the inclusion of families that had genetic defects leading to LFS but did not meet the criteria established in 1998. The term ‘Li-Fraumeni-like syndrome’ (LFLS) is used for these patients and families; the Birch criteria have a diagnostic sensitivity of 96 % and a specificity of 38 % (Birch et al. 1994; Gonzalez et al. 2009), whereas the Eeles criteria have a sensitivity of 97 % and a specificity of 16 % (Eeles 1995). In 2001, Chompret et al. (2000, 2001) proposed new criteria with a better sensitivity (95 %), but with a lower specificity (52 %) (Gonzalez et al. 2009). The Chompret criteria were most recently updated in 2009 to better identify families with milder phenotypes (Gonzalez et al. 2009; Tinat et al. 2009; Bougeard et al. 2008).
| Classification scheme | Description of the criteria |
|---|---|
| Classic LFS (Li et al. 1988) | - Proband diagnosed with sarcoma before 45 years of age, and - A first-degree relative with cancer before 45 years of age, and - Another first- or second-degree relative with any cancer diagnosed under 45 years of age or with sarcoma at any age |
| Birch (Birch et al. 1994; Gonzalez et al. 2009) | Among families that do not conform to classic LFS: - Proband with any childhood cancer or sarcoma, brain tumour or adrenocortical carcinoma diagnosed under 45 years of age, and - A first- or second-degree relative with a typical LFS-related cancer (sarcoma, breast cancer, brain tumour, leukaemia or adrenocortical carcinoma) diagnosed at any age, and - A first- or second-degree relative in the same genetic lineage with any cancer diagnosed under the age of 60 years |
| Eeles Eeles (1995) | Among families that do not conform to classic LFS: - Two different tumours that are part of extended LFS in first- or second-degree relatives at any age (sarcoma, breast cancer, brain tumour, leukaemia, adrenocortical tumour, melanoma, prostate cancer and pancreatic cancer) |
| Chompret Chompret et al. (2000, 2001) | Proband with sarcoma, brain tumour, breast cancer or adrenocortical carcinoma before the age of 36 years, and - At least one first- or second-degree relative with cancer (other than breast cancer if the proband has breast cancer) under the age of 46 years or a relative with multiple primaries at any age, or a proband with multiple primary tumours, two of which are sarcoma, brain tumour, breast cancer and/or adrenocortical carcinoma, with the initial cancer occurring before the age of 36 years, regardless of the family history, or a proband with adrenocortical carcinoma at any age of onset, regardless of the family history |
LFS Li-Fraumeni syndrome
2.3 LFS: Genotype-Phenotype Correlations
TP53 germline mutations are the cause of LFS. The TP53 genotype in LFS is predictive of age of tumour onset and overall tumour risk (Olivier et al. 2006; Palmero et al. 2010). Mutations in the DNA-binding portion of the gene cause highly penetrant disease with early onset cancers; mutations outside the core DNA-binding domain are associated with slower rates of tumour development (Varley et al. 1999). According to clinical studies, TP53-mutant ACCs are larger and associated with a more advanced stage of tumour progression and shorter disease-free survival compared to cases without TP53 mutations; this is similar to non-LFS-associated ACC that carries somatic TP53 defects (Libe et al. 2007). Furthermore, LFS-associated ACCs and ACCs with somatic TP53 mutations show greater resistance to chemotherapy and radiation and overall higher rates of relapse (Tabori et al. 2010; Fernandez-Cuesta et al. 2012).
2.4 LFS: Genetic Mutations and Genetic Testing
Germline mutations of the tumour suppressor TP53 gene are found in 70 % of cases with LFS (Bachinski et al. 2005). The prevalence of germline TP53 mutations in sporadic ACTs is 3-6 % in the adult population (Herrmann et al. 2012; Raymond et al. 2013a) and significantly higher, approaching 50-80 %, in children (Varley et al. 1999; Libe et al. 2007). TP53 inactivation in the somatic step is a late step in tumorigenesis (Hollstein et al. 1991), but somatic mutations of the TP53 gene are frequent in sporadic, non-LFS-associated ACC (Ohgaki et al. 1993).
Most TP53 mutations are missense alterations that render the gene inactive; however, some reports have shown gain-of-function, oncogenic effects of some TP53 mutations. A specific germline TP53 mutation (R337H) of the p53 protein was identified in more than 80 % of children with ACT in Southern Brazil where the incidence of ACT is 15 times higher than that in the rest of the world. The R337H mutation is also seen in 13.5 % of Brazilian adults with ACT (Giacomazzi et al. 2013; Petitjean et al. 2007).
TP53 genotyping is typically performed by DNA Sanger sequence analysis and multiplex ligation-dependent probe assay (MLPA) or other techniques in order to detect large rearrangements of portions of the gene. Molecular genetic testing for TP53 germline mutations was developed in 1990 by David Malkin and colleagues (Malkin et al. 1990) and was quickly used as a screening tool to identify patients with hereditary forms of cancer. Currently, the growing availability and use of whole-genome sequencing (WGS), whole-exome sequencing (WES), whole-genome arrays and multigene panels increase the likelihood of detecting unintentionally or unexpectedly TP53 mutation carriers. The National Compre- hensive Cancer Network (NCCN) guidelines recommend TP53 analysis for indi- viduals who meet either the classic LFS criteria, the Chompret criteria, or who were
diagnosed with breast cancer under age 30 and are negative for BRCA1 or BRCA2 gene mutations.
2.5 LFS: Genetic Counselling
Decisions regarding germline TP53 testing should be made by healthcare profes- sionals with training in clinical cancer genetics. Most germline TP53 mutations are inherited from a parent, and only few are de novo. After identifying a mutation, the proband’s parent with any pertinent cancer history or family history should be tested first; otherwise, both parents should be tested. Siblings and offspring of the proband should also be tested. If one of the proband’s parents carries the TP53 mutation, each sibling has a 50 % risk of having the mutation. If neither parent carries the mutation, the risk to siblings is low, but they should be tested due to the possibility of germline mosaicism. A family history can appear negative due to a limited family structure or incomplete penetrance of the mutation. The frequency of de novo mutations is not well established; however, based on two studies, the de novo rate has been estimated to be between 7 and 24 % (Chompret et al. 2000; Gonzalez et al. 2009).
LFS: Key point: Testing for all at risk for TP53 mutation should be considered due to emerging evidence showing reduction of morbidity and mortality from TP53-related malignancies when an early screening protocol was implemented (Evans et al. 2010).
3 Beckwith-Wiedemann Syndrome (BWS)
BWS is one of the most common paediatric overgrowth disorders with an estimated incidence of 1 in 13,700 neonates, affecting men and women with equal frequency (Shuman et al. 1993). BWS is associated with epigenetic/genetic alterations on chromosome 11p15 and usually occurs sporadically (85 %), although familial transmission can also occur in 15 % of the cases (Weksberg et al. 2010). The overall risk of tumour development in children with BWS has been estimated to 7.5 % (4-21 %) (Rump et al. 2005).
3.1 BWS: Diagnostic Criteria
No consensus diagnostic criteria for BWS have been established; however, the most frequent features are anterior abdominal wall defects (80 %), macroglossia (97 %) and overgrowth. Other features such as external ear cartilage abnormalities (76 %), birth weight or postnatal growth over the 90th centile (88 %), facial naevus flam- meus (62 %), neonatal hypoglycaemia, nephromegaly (59 %) and hemihypertrophy (24 %) have been also described (Mazzuco et al. 2012; Elliott et al. 1994), in
addition to tumours, including nephro- and hepatoblastoma and adrenal cancer. Thus, the diagnosis of BWS is usually made when there is (i) positive family history (a parent or a sibling with a clinical diagnosis or a history of BWS) and (ii) the following: macroglossia, overgrowth (traditionally defined as height and weight >97th centile), visceromegaly, renal abnormalities (nephrocalcinosis), ab- dominal wall defect (omphalocele), embryonal tumours (nephroblastoma, hepato- blastoma), foetal adrenocortical cytomegaly, hemihyperplasia, cleft lip/palate and bifid uvula. Conditions that have also been described in association with BWS and may be used in diagnosing the disease, are: prematurity, polyhydramnion, neonatal hypoglycaemia, facial naevi and specific facial features such as prominent eyes, mid-facial hypoplasia, prominent mandible (Weksberg et al. 2010; Shuman et al. 1993).
BWS can be suspected even in utero based on intrauterine findings such as exomphalos, macroglossia, pancreatic hyperplasia, placentomegaly, as well as substantially increased levels of beta-human chorionic gonadotropin (hCG) upon maternal testing (Kagan et al. 2015).
3.2 BWS: Genotype-Phenotype Correlations
Increased insulin growth factor-2 (IGF2) signalling is the main molecular cause of the phenotype associated with BWS. IGF2 overexpression has also been linked with the development and progression of sporadic ACCs. In addition, molecular partners of IGF2, such as IGF-2 binding protein, have also been correlated with tumour volume in sporadic ACC (Boulle et al. 2001). Somatic hemihyperplasia is associated with mosaicism for paternal disomy of 11p15 or molecular alterations at imprinting centre 2 (IC2) or imprinting centre 1 (IC1) regulating IGF2 expression (Ohta et al. 2013; Shuman et al. 1993; Enklaar et al. 2006). More recently, mutations in the cyclin-dependent kinase inhibitor 1C (CDKN1C) gene or mi- crodeletions at IC1 and rarely microduplication at IC2 were found to explain BWS in cases with germline defects (Hatada et al. 1997; Enklaar et al. 2006; Bliek et al. 2009). Uniparental disomy of 11p15 or gain of methylation at IC1 is associated with the highest risk for Wilms’ tumour and hepatoblastoma. Loss of methylation at IC2 is associated with a lower risk for tumour development.
3.3 BWS: Genetic Mutations and Genetic Testing
BWS is associated with abnormal regulation of gene transcription in the imprinted domain on chromosome 11p15.5. Normally, IGF2 gene is maternally imprinted; therefore, only the paternal allele is expressed. On the other hand, the paternal alleles of CDKN1C and H19 are silenced by imprinting; thus, only the maternal alleles are expressed (Weksberg et al. 2010). It has been shown that the BWS-associated defects on chromosome 11p15.5 result in the expression of the
otherwise repressed maternal copy of the IGF2 gene, and in some cases, this is accompanied by repression and DNA methylation of the maternal (otherwise active) copy of the neighbouring H19 gene. Thus, in BWS, the more common molecular genetic defects are as follows: (Weksberg et al. 2003, 2005): (1) loss of methylation of the IC2 on the maternal chromosome leading to an increased activity of the KCNQ1OT1 (opposite strand/antisense transcript 1) gene, (2) gain of methylation of the IC1 on the maternal chromosome, (3) mutation of the maternal CDKN1C allele, (4) paternal uniparental disomy of 11p15.5 and (5) duplication, inversion or translocation of the 11p15.5.
The genetic tests that can detect more than 80 % of individuals with BWS are the following: (1) molecular cytogenetic analysis of chromosome 11p and/or (2) methylation studies of IC1 and IC2. Methylation-specific (MS) multiplex ligation-dependent probe amplification (MLPA) is the most recently developed robust testing methodology for these defects. Sequence analysis of CDKN1C should be undertaken in familial cases, in individuals with BWS and cleft palate, or in those who meet diagnostic criteria for BWS but have no detectable molecular cytogenetic abnormalities of chromosome 11p, or methylation abnormalities. Chromosome 11p-specific molecular cytogenetic analysis for the detection of microdeletions or duplications may be undertaken in familial cases in which a CDKN1C mutation has not been detected and conventional cytogenetics are normal (Niemitz et al. 2004; Prawitt et al. 2005).
3.4 BWS: Genetic Counselling
Prenatal diagnosis for at-risk pregnancies in families with heritable forms of BWS requires prior identification of the disease-causing defect in the family. Most individuals with BWS are reported to have normal chromosome studies or kary- otypes. Approximately 85 % of individuals with BWS have no family history of BWS, while about 15 % have a family history consistent with autosomal dominant transmission of BWS (Shuman et al. 1993). Specific prenatal testing is possible by cytogenetic analysis for families with an inherited chromosome abnormality or by molecular genetic testing for families in which the molecular mechanism of BWS has been defined.
Key point: Due to the low incidence of ACC in BWS, no specific screening recommendations for ACC exist (Else et al. 2014). Patients with BWS should be monitored for the development of tumours, including ACC.
4 Multiple Endocrine Neoplasia Type 1 (MEN1)
MEN1 is a tumour syndrome that is caused by defects of the menin gene on chromosome 11q13 and in most cases is inherited in an autosomal dominant manner. Parathyroid tumours, resulting in primary hyperparathyroidism, are the
most common feature (95 %), followed by pancreatic neuroendocrine tumours (45 %), anterior pituitary tumours (40 %), thymic carcinoids, thyroid adenomas and ACT. Adrenal involvement in MEN1 has been reported in 20-40 % of cases; however, endoscopic ultrasound detected adrenal lesions in up to 73 % of MEN1 patients (Schaefer et al. 2008). ACCs is rare; less than 1 % of patients with MEN1 develop ACC, but the incidence increases to approximately 13 % among patients with MEN1 and adrenal tumours larger than 1 cm (Gatta-Cherifi et al. 2012).
Most patients with MEN1 have bilateral adrenocortical hyperplasia (40 %) that is usually non-functional and benign. Less than 10 % of patients with enlarged adrenal glands have hormonal hypersecretion, and among these, primary aldos- teronism and ACTH-independent Cushing’s syndrome are the most commonly encountered conditions; hyperandrogenemia has been associated with MEN1-associated ACCs (Gatta-Cherifi et al. 2012).
4.1 MEN1: Diagnostic Criteria
The diagnosis of the MEN1 syndrome is based on the presence of one of the three following criteria:
i. A patient with 2 or more MEN1-associated endocrine tumours;
ii. A patient with MEN1-associated tumours and a first-degree relative with MEN1;
iii. An individual who has a MEN1 mutation without clinical or biochemical manifestations of MEN1 (Newey and Thakker 2011).
4.2 MEN1: Genotype-Phenotype Correlations
No correlation between the MEN1 genotype and phenotype has yet been clearly identified. A study suggested that adrenal lesions usually develop in patients with mutations in the exons 2 and 10 (Newey and Thakker 2011). Various clinical manifestations may be caused by tissue-dependent factors such as epigenetics, as it is found in parathyroid tumours associated with tissue-specific methylation.
4.3 MEN1: Genetic Mutations and Genetic Testing
MEN1 is caused by (typically) germline mutations of menin (MEN1 gene), a tu- mour suppressor gene that predisposes to the development of endocrine and non-endocrine tumours with variable penetrance. Menin is the major regulator of transcription interacting with many molecules and signalling pathways (Wu and Hua 2008; Marini et al. 2009). More than 1133 germline and 203 somatic mutations of the MEN1 have been reported (Lemos and Thakker 2008). A number of MEN1
polymorphisms have been identified and should be differentiated from pathogenic mutations during genetic analysis (Lemos and Thakker 2008). Loss of heterozy- gosity (LOH) involving the MEN1 locus on chromosome 11q13 has also been observed in 5-50 % of sporadic endocrine tumours (Thakker et al. 2012), but somatic MEN1 mutations are relatively rare in tumours compared to other tumour suppressor genes. If MEN1 coding region mutations are not identified, then testing for partial or whole-gene deletion or haplotype analysis of the MEN1 locus should be considered.
More than 10 % of MEN1 germline mutations are found de novo and may be transmitted to subsequent generations. Five to Twenty five percentage of patients with MEN1 may not harbour germline mutations and these individuals may have partial or whole-gene deletions, or mutations in the promoter or untranslated regions (Newey and Thakker 2011; Thakker et al. 2012). In these cases, MLPA for the detection of exonic deletions is recommended (Tham et al. 2007).
A few patients with MEN1 may have mutations in others genes, mostly p27 (CDK1NB); however, it is not known if these patients are at risk for ACC.
4.4 MEN1: Genetic Counselling
Relatives of a patient with a known MEN1 mutation should be offered MEN1 germline mutational analysis before any biochemical or radiological screening tests for the detection of MEN1 tumours (Thakker et al. 2012).
Briefly, MEN1 mutational analysis should be undertaken in (i) patients with two or more MEN1-associated endocrine tumours (Newey and Thakker 2011). Such mutational analysis may be undertaken in (i) children within the first decade of life; (ii) asymptomatic first-degree relative of a known MEN1 mutation carrier; and (iii) patients with suspicious or atypical MEN1, which includes individuals with parathyroid adenomas occurring before the age of 30 years; or multigland parathyroid disease, gastrinoma and multiple pancreatic neuroendocrine tumour (NET) at any age; or individuals who have two or more MEN1-associated tumours that are not part of the classical triad of parathyroid, pancreatic islet and anterior pituitary tumours.
Individuals with MEN1 mutations undergo biochemical screening at least once per year and also have baseline pituitary and abdominal imaging. Screening begins in early childhood because the disease has developed in some individuals by the age of 5 years, and it should be repeated throughout life, since in some individuals tumour may not develop until they are elderly (Thakker et al. 2012).
Key point: No regular monitoring for ACC is recommended in patients with MEN1. However, because of the increased risk of malignant transformation of pre-existing adrenal lesions, MEN1 patients should be monitored for possible ACC as other patients with radiologically detectable ACTs.
5 Familial Adenomatous Polyposis (FAP) and Lynch Syndrome (LS)
FAP is a disorder inherited in an autosomal dominant manner and is primarily associated with the early development of multiple colonic adenomatous polyps and an increased risk of colorectal cancer; the prevalence of adrenal tumours in patients with FAP varies from 7.4 to 13 %. LS is a disorder inherited in an autosomal dominant manner that is also associated with an increased risk for colorectal cancer as well as other malignancies such as carcinomas of endometrium, ovary, small bowel, hepatobiliary system, central nervous system, lung adenocarcinoma, sar- coma, melanoma and ACCs (Raymond et al. 2013b). Patients with FAP carry a germline-inactivating mutation in the adenomatous polyposis coli (APC) gene, whereas patients with LS carry germline mutations of genes important for DNA mismatch repair. Recent studies showed that the prevalence of LS in patients with ACC was 3 % comparable to their prevalence of colorectal and endometrial cancer estimated at 2-5 % (Raymond et al. 2013b; Liu et al. 2014).
5.1 FAP and LS: Diagnostic Criteria
Diagnosis of LS is based on Amsterdam I and II criteria as well the most recently revised Bethesda criteria which include also histological findings (Liu et al., 2014). The revised Bethesda criteria include the following:
i. Colorectal cancer diagnosed in a patient who is less than 50 years of age;
ii. Presence of synchronous or metachronous colorectal or LS associated tumours;
iii. Colorectal cancer with the microsatellite instability-high histology diagnosed in a patient who is less than 60 years of age;
iv. Colorectal cancer or LS-associated tumour diagnosed under the age of 50 years in at least one first-degree relative;
v. Colorectal cancer or LS-associated tumour diagnosed at any age in two first- or second-degree relatives.
5.2 FAP and LS: Genetic Mutations and Genetic Testing
APC-inactivating mutations result in constitutive activation of ß-catenin and ele- vated levels of ß-catenin/TCF (T cell factor) target genes. Activation of this path- way may play an important role in adrenocortical tumourigenesis through activating mutations of the ß-catenin gene (CTNNB1) in ACC. APC is a downstream regulator of the Drosophila melanogaster wingless (Wnt) molecular signalling pathway. Abnormal, constitutive Wnt activation is thought to be oncogenic (Karim et al. 2004). The majority of APC mutations are nucleotide substitutions and frameshift
mutations that result in inactive APC and consequently overactive Wnt signalling. APC promoter methylation may also result in suppressed APC activity (Raymond et al. 2013b). Patients with LS have mutations of genes involved in DNA mismatch repair such as MLH1, MSH2, MSH6 and PMS2 (Karamurzin et al. 2012). ACC patients with a family history suggestive of LS should be considered for genetic risk assessment. Immunohistochemical screening in all ACCs may be an effective strategy for identifying these patients (Raymond et al. 2013b). This includes immunochemistry for the 4 gene products as well as microsatellite instability analysis. Full germline genetic testing for LS should include DNA sequencing and large rearrangement analysis. Patients with multiple colorectal adenomas (>10) should be considered for germline genetic testing of APC. Similarly, full germline genetic testing for FAP should include DNA sequencing and large rearrangement analysis (Stoffel et al. 2015).
5.3 FAP and LS: Genetic Counselling
Genetic counselling in patients with FAP or LS is necessary for follow-up and therapeutic decisions. For example, in families with classic FAP, sigmoidoscopy or colonoscopy should be carried out every 1-2 years starting at the age of 10- 11 years and continued lifelong in mutation carriers. Surgery is indicated if there are large numbers of adenomas or adenomas with high degree of dysplasia. Generally, screening for extracolonic tumours should be considered when colorectal polyposis is diagnosed before the age of 25-30 years.
Key point: Routine screening for LS in ACC tumours by immunochemistry for the protein products of the four responsible genes (MLH1, MSH2, MSH6 and PMS2) is recommended regardless of the family history (Birch et al. 1994; Else et al. 2014).
6 Carney Complex (CNC)
Carney complex is multiple tumour syndrome inherited in an autosomal dominant disorder. The main endocrine manifestation of CNC is primary pigmented nodular adrenocortical hyperplasia (PPNAD), a rare form of bilateral adrenocortical hyperplasia featuring small to normal-sized adrenal glands that contain multiple small and pigmented, cortical nodules with internodular atrophy (Stratakis et al. 2001). ACCs are extremely rare in this syndrome, and only two cases of ACC in CNC have been reported.
6.1 CNC: Diagnostic Criteria
The diagnosis of CNC is based on the presence of two or more major diagnostic criteria or on the presence of just one major if the patient is a carrier of a known inactivating mutation of the protein kinase regulatory subunit type 1 alpha gene (PRKAR1A) (Bossis et al. 2004). The major diagnostic criteria for CNC include the following:
i. Spotty skin pigmentation with typical distribution (lips, conjunctiva and inner or outer canthi, vaginal and penile mucosal (Fig. 1));
ii. Cutaneous myxoma;
iii. Cardiac myxoma;
iv. Breast myxomatosis;
v. PPNAD or paradoxical positive response of urinary glucocorticosteroid excretion to dexamethasone administration during Liddle’s test;
vi. Acromegaly due to GH-producing adenoma;
vii. Large cell calcifying Sertoli cell tumours (LCCSCT) or characteristic cal- cifications on testicular ultrasound;
viii. Thyroid carcinoma or multiple, hypoechoic nodules on thyroid ultrasound in a young patient;
ix. Psammomatous melanotic schwannomas;
x. Blue naevus, epithelioid blue naevus;
xi. Breast ductal adenoma;
xii. Osteochondromyxomas. Supplementary criteria include (Rodriguez et al. 2012; Boikos and Stratakis 2006): (i) affected first-degree relative and (ii) inactivating mutation of the PRKAR1A gene.
6.2 CNC: Genotype-Phenotype Correlations
There seems to be no direct and consistent correlation between PRKAR1A muta- tions described to date and the various CNC phenotypes. Only recently, certain associations between specific mutations and particular sets of CNC manifestations have emerged (Bertherat et al. 2009). Phosphodiesterases type 11A (PDE11A) and type 8b (PDE8B) mutations have also been found in isolated micronodular adrenocortical disease, a condition that is similar to PPNAD but distinct from CNC. Interestingly, among CNC patients, germline protein-truncating mutations of PDE11A predispose to a variety of endocrine tumours. A higher frequency of PDE11A variants was found in cases with PPNAD and testicular tumours (LCCSCTs). A base substitution (c.439A > G/p.S147G) in PRKAR1A identified to a large family was found to cause a large spectrum of adrenal diseases that ranged from lack of significant manifestations to ACC (Anselmo et al. 2012). Cases with this mutation did not present myxomas, schwannomas or any other tumours associated with CNC.
6.3 CNC: Genetic Mutations and Genetic Testing
Genetic linkage analysis identified two independent loci for CNC, one on chro- mosome 17p22-24 and the other on chromosome 2p16. Most of the cases of CNC are caused by inactivating mutations in the PRKARIA gene located at 17q22-24 which encodes the most widely expressed of the protein kinase A (PKA) regulatory subunits. Germline heterozygous PRKAR1A mutation most often create a premature stop codon, and the resulting RNA is degraded by a mechanism of nonsense-mediated mRNA decay, inactivating fully the mutant allele. More than 125 pathogenic mutations of the PRKAR1A gene in CNC patients have been reported to date, but only approximately 70 % of CNC patients are found by Sanger sequencing to carry PRKAR1A defects; a significant number (21.6 %) of patients with CNC who are negative by currently available testing may have PRKAR1A haploinsufficiency due to genomic defects that are not detected by Sanger sequencing (Salpea et al. 2014). Array-based studies are necessary for diagnostic confirmation of these defects and should be done in patients with unusual and/or severe CNC phenotypes who are PRKAR1A mutation negative.
6.4 CNC: Genetic Counselling
CNC-adrenal tumours are typically histologically benign lesions. However, two cases of ACC with CNC have been described (Anselmo et al. 2012; Morin et al. 2012). The rarity of CNC and ACC precludes statistical demonstration of their association.
Key point: ACCs are extremely rare in this syndrome, and therefore, genetic testing for PRKAR1A mutation in ACCs should be reserved in cases with other signs of Carney complex.
Neurofibromatosis Type 1 (NF1) 7
NF1 is an autosomal dominant disease with an incidence of one in 3-4000 cases. ACC in patients with NF1 is rare: six case reports are available in the public domain (Menon et al. 2014; Fienman and Yakovac 1970; Sorensen et al. 1986; Wagner et al. 2005; Gutmann et al. 1994; Fraumeni and Miller 1967). Yet, there has not been any clear evidence of a causal association between NF1 gene mutations and development of adrenocortical tumours.
7.1 NF1: Diagnostic Criteria
Two or more of the following clinical features are sufficient to establish a diagnosis of NF1:
i. Six or more café-au-lait macules (>0.5 cm at largest diameter in a prepubertal child or >1.5 cm in postpubertal individuals);
ii. Axillary freckling or freckling in inguinal regions;
iii. Two or more neurofibromas of any type or one or more plexiform neurofibromas;
iv. Two or more iris hamartomas (Lisch nodules);
v. Osseous lesion (sphenoid wing dysplasia, long-bone dysplasia);
vi. Optic pathway glioma;
vii. A first-degree relative with NF1 diagnosed by the above criteria.
7.2 NF1: Genotype-Phenotype Correlations
Patients with NF1 microdeletions tend to develop neurofibromas at an earlier age, have a lower mean IQ, manifest abnormal facial features and are at increased risk of developing malignant peripheral nerve sheath tumours (Menon et al. 2014). Patients are susceptible to a variety of malignant tumours, of which the most common are the sarcomas (leiomyosarcoma and neurofibrosarcoma), breast cancer and lung
cancers and cancers of the gastrointestinal tract. A novel germline frameshift mutation (c.5452_5453delAT) in exon 37 of the NF1 gene was recently associated with the ACC development (Menon et al. 2014).
7.3 NF1: Genetic Mutations and Genetic Testing
At present, the diagnosis of NF1 is made using established clinical criteria, reserving NF1 genetic testing for unusual presentations. NF1 results from a loss-of-function mutation or deletion in the NF1 gene. NF1 is a tumour suppressor gene encoding neurofibromin. This protein functions as a negative regulator of the Ras proto-oncogene, which is a key signalling molecule in the control of cell growth. About 50 % of individuals with NF1 have no family history of the disease, and the disease is due to de novo mutations. In patients with a heterozygous germline NF1 mutation, the loss of the other allele will lead to the complete loss of neurofibromin function and the development of tumours, according to the two-hit hypothesis. ACC development is linked to loss of heterozygosity of NF1 gene (Menon et al. 2014). The NF1 gene mutation is found in approximately 85-95 % of cases using a combination of molecular techniques, including denaturing high-performance liquid chromatography (dHPLC), direct sequencing, fluorescence in situ hybridization (FISH), MLPA and array comparative genomic hybridization (CGH) (Ferner et al. 2007). Prenatal testing is possible by direct mutation testing of foetal DNA extracted from chorionic villous sampling or amniocentesis.
7.4 NF1: Genetic Counselling
Genetic counselling is advised for patients with NF1, as neurofibromas often start to develop in late adolescence. An individual with NF1 has a 50 % risk of passing on the condition to an offspring, but the clinical manifestation cannot be predicted, even within families. It is imperative to examine the parents for cutaneous stigmata or for Lisch nodules. Genetic counselling prior to conception is advised in all NF1 individuals.
Key point: There are no recommendations for NF1 gene mutation screening in patients with ACCs because of the rare cases described up to date in the literature and the lack of a clear evidence of linking NF1 to ACCs (Ferner et al. 2007).
8 Conclusions
Every patient with ACC should receive a basic physical examination aimed at finding clues of hereditary diseases. A detailed family history and a search for malignancies even in second- and third-degree relatives should be obtained. If the clinical history points to a specific disease, corresponding genes should be
sequenced. Germline TP53 mutations have to be considered, since it is the underlying genetic cause in the 50-80 % of all ACC cases in childhood. The possibility of a TP53 mutation should not be dismissed because of a negative family history as up to 25 % can occur de novo. However, next-generation sequencing now allows sequencing of a panel of genes at the same time. This systematic screening should be performed in the absence of family history. The design of the arrays should include TP53, IGF-2, CDKN1C, KCNQ10T1, APC, MSH genes, PRKAR1A, Menin and NF-1. The use of next-generation sequencing will be especially helpful in permitting guided potential target therapy options.
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