Katarzyna Kolačkov
1, A–F, Krzysztof Tupikowski
2, A, C, E, F,
Grażyna Bednarek-Tupikowska
1, A C–FGenetic Aspects of Pheochromocytoma
Genetyczne aspekty guza chromochłonnego
1 Department of Endocrinology, Diabetology and Isotope Therapy, Wroclaw Medical University, Wroclaw,
Poland
2 Department of Urology and Urological Oncology, Wroclaw Medical University, Wroclaw, Poland
A – research concept and design; B – collection and/or assembly of data; C – data analysis and interpretation;
D – writing the article; E – critical revision of the article; F – final approval of article; G – other
Abstract
Pheochromocytomas are derived from chromaffin cells of the adrenal medulla which synthesize and secrete cate-cholamines, thus affecting the cardiovascular system and metabolic processes. Pheochromocytoma is a tumor of the following multicarcinoma hereditary syndromes: type 2 multiple endocrine neoplasia, von Hippel-Lindau disease, type 1 neurofibromatosis and the pheochromocytomas/paragangliomas syndrome. Pheochromocytomas are rela-tively rare, and because of non-specific manifestation of these tumors and the possible lack of signs and symptoms for extended periods of time, the diagnosis may be delayed, which may, in turn, lead to death. Pheochromocytomas may occur sporadically. However, due to the frequent incidence of hereditary forms of these cancers, the pres-ymptomatic genetic testing of family members with a positive family history is indicated, thus allowing for select-ing people with higher risk of cancer. Early detection of the syndrome and the coexistselect-ing tumors (which may be malignant) may lead to a correct diagnosis, regular surveillance, preventive examinations and implementation of appropriate early treatment. Recent examinations have shown significant involvement of RET, VHL, NF1, SDHB
and SDHD as well as the newly discovered KIF1Bβ, TMEM127 and MAX genes in pathogenesis of these tumors. The microarray-gene expression studies, based on the analysis of cellular pathways, have revealed two distinct clus-ters indicating two different routes of tumorgenesis. The genotype-phenotype correlations are still being studied and future research can give us clearer information about the function of these genes, which may prove crucial from the clinical point of view (Adv Clin Exp Med 2012, 21, 6, 821–829).
Key words: pheochromocytoma, paraganglioma, hereditary syndromes, genes.
Streszczenie
Guzy chromochłonne wywodzą się z komórek chromochłonnych rdzenia nadnerczy, które syntetyzują i wydzielają katecholaminy, przez co wpływają na układ krążenia i procesy metaboliczne. Guzy chromochłonne wchodzą w skład dziedzicznych zespołów nowotworowych, takich jak: zespół mnogiej gruczolakowatości wewnątrzwydzielniczej typu 2, choroba von Hippel-Lindau, nerwiakowłókniakowatość typu 1 oraz zespół guza chromochłonnego i przyzwoja-ków. Diagnoza guza chromochłonnego może być utrudniona ze względu na jego stosunkowo rzadkie występowa-nie, mało specyficzne objawy oraz możliwy ich brak przez dłuższy okres. Brak odpowiedniego rozpoznania może prowadzić nawet do śmierci pacjenta. Guzy chromochłonne mogą występować sporadycznie, jednak ze względu na częste występowanie rodzinnej formy tych nowotworów, jest wskazane przeprowadzanie przedobjawowych badań genetycznych w celu wczesnego wykrycia choroby, szczególnie wśród krewnych pierwszego stopnia. Diagnostyka genetyczna pozwala na objęcie chorych z grupy ryzyka odpowiednimi badaniami profilaktycznymi, których celem jest wczesne wykrycie zespołu i współistniejących nowotworów (niektóre z nich mogą być złośliwe), kontrolę stanu zdrowia pacjenta i wdrożenie odpowiedniego wczesnego leczenia. Ostatnie badania wykazały znaczący udział genów, takich jak: RET, VHL, NF1, SDHB i SDHD, jak również udział nowo odkrytych genów: KIF1Bβ, TMEM127 i MAX
w patogenezie tych nowotworów. Badania ekspresji genów (z wykorzystaniem mikromacierzy) na podstawie analizy szlaków komórkowych ujawniły dwa klastry wskazujące dwie różne drogi nowotworzenia. Korelacje genotyp-fenotyp są wciąż w fazie badań, a przyszłe doniesienia mogą dać więcej informacji na temat funkcji tych genów, co może być istotne z klinicznego punktu widzenia (Adv Clin Exp Med 2012, 21, 6, 821–829).
Słowa kluczowe: guz chromochłonny, przyzwojaki, zespoły dziedziczne, geny, mutacje.
Adv Clin Exp Med 2012, 21, 6, 821–829 ISSN 1899–5276
REvIEWS
Pheochromocytomas (PHs) are rare, usually benign tumors that originate in the sympathetic nervous system. These hormonally active tumors derive from chromaffin cells of the adrenal medul-la. Chromaffin cells synthesize and secrete cate-cholamines, usually adrenaline and noradrenaline, which have a huge impact on the cardiovascular system and metabolic processes. Adrenaline and noradrenaline, transmitters in the nervous sys-tem, are released into the blood. Catecholamines are involved in the regulation of cardiac functions causing an increase in the contractility of the heart muscle as well as an increase in blood pressure. These hormones also affect the secretion of insulin and lipid metabolism stimulating a rise in glucose and free fatty acids in the blood. Catecholamines are secreted under stress, trauma and shock (to-gether with other hormones, such as cortisol, they mobilize the body’s defenses) as well as in fasting, hypoglycemia, and hypoxia [1].
Most of these tumors appear in the adrenal medulla. 10 to 20 per cent of catecholamine-pro-ducing tumors arise from extra-adrenal chromaf-fin tissue (called secreting paragangliomas PGL). The tumors may develop in the organ of Zucker-kandl (ZuckerZucker-kandl’s body), a vestigial chromaffin ganglion located at the root of the upper mesenter-ic artery, in the sympathetmesenter-ic plexus of the urinary bladder, the kidneys and heart, or in sympathetic ganglia in the mediastinum. These tumors may oc-cur in the head-and-neck non-chromaffin cells of the parasympathetic ganglia, most of them do not secrete catecholamines [2–4].
The clinical symptoms are associated with the increased secretion of catecholamines, especially adrenaline and noradrenaline which cause par-oxysmal hypertension and tachycardia, headaches (80%), increased blood sugar and leukocytosis, weight loss, pale skin, excess sweating (71%) and palpitations (64%) [1, 2, 4].
The incidence of pheochromocytomas is about 1 per 100,000 in the general population. The aver-age aver-age of diagnosis is between 40 and 50 years of age (sex does not affect the frequency) [1, 2, 5]. These tumors are relatively rare in humans; how-ever, the clinical signs and symptoms (especially paroxysmal hypertension and cardiac arrhyth-mias) have a significant impact on morbidity and even mortality. Many reviews indicate that ap-proximately 10% of these tumors occur bilaterally, about 10% of all cases of pheochromocytomas are found in the area of extra-adrenal chromaffin tis-sue and about 10% recur after removal [1, 2, 4, 5].
Pheochromocytomas are usually benign tu-mors. The rate of malignancy nears 10% and can be higher among patients with extra-adrenal sym-pathetic paraganglioma. Malignancy is defined
by the presence of distant metastases. Currently, there are no appropriate methods that evaluate aggressiveness with certainty; however, some bio-chemical or gene expression features might sug-gest malignancy. Presently, no effective therapy for malignant pheochromocytoma is available. In certain cases surgery, chemotherapy and ra-diotherapy are common beneficial practices [1, 3, 6]. Pheochromocytomas may occur sporadically; however, recent research of the genomics of fa-milial diseases has shown that even 30% of these tumors are inherited because of hereditary muta-tions and hereditary cancer syndromes [1, 4, 6, 7]. These multicarcinoma syndromes are transmitted in an autosomal dominant fashion; hence, early diagnosis and treatment is crucial.
The etiology of tumorgenesis of pheochromo-cytomas is not yet well-known, but a significant number of recent tests have demonstrated con-siderable involvement of genes in pathogenesis of these tumors.
Syndrome-Associated
Pheochromocytoma
Pheochromocytoma belongs to a group of syndromes including mainly: type 2 multiple en-docrine neoplasia (MEN 2), von Hippel-Lindau disease (vHL), type 1 neurofibromatosis (NF1) and pheochromocytomas/paragangliomas syn-drome (PH/PGL) [1, 4–7].
Type 2 multiple endocrine neoplasia is a herita-ble, autosomal dominant tumor syndrome associat-ed with tumors of endocrine system. The prevalence of the MEN 2 syndrome is estimated at approxi-mately 2.5 per 100,000 in the general population. Three types can be distinguished: MEN 2A, MEN 2B and FMTC – familial medullary thyroid carci-noma (55, 5–10 and 35–50% all cases respectively). Type 2A multiple endocrine neoplasia is charac-terized by medullary thyroid carcinomas, pheo-chromocytomas, and hyperplasia of the parathy-roid glands (respectively 95, 50, 15–30% of cases). Type 2B includes medullary thyroid carcinomas, pheochromocytomas (respectively 100 and 50% of cases), multiple mucosal neuromas and mar-fanoid habitus. Germline mutations in RET (the proto-oncogene gene encoding a receptor tyrosine kinase) underlie the molecular basis of the MEN 2 syndrome [1, 4–8].
cell carcinoma (no pheochromocytoma) and type 2 (7–20% of families), characterized by the pres-ence of pheochromocytoma, further subclassified as type 2A (pheochromocytoma, hemangioblas-toma with low risk of renal cell carcinoma), type 2B (pheochromocytoma, hemangioblastoma with high risk of renal cell carcinoma) and type 2C (on-ly pheochromocytoma) [9–11]. Pheochromocyto-ma is a component of the vHL disease in about 20% of cases and, in comparison with the sporadic form of this tumor, it more often occurs as mul-tiple and less malignant and is characterized by early onset. In approximately 30–50% of cases, PH or PGL is the first manifestation of the vHL dis-ease. Although the rate of prevalence of the vHL disease is quite small, 2–3 per 100,000 individuals, neurological complications from vascular tumors of the central nervous system and metastases from renal cell carcinoma are the most common causes of death [6, 9]. The function of the VHL gene (ge-netic base of the vHL syndrome) is construction and it is involved in several processes, including the regulation of hypoxia-inducible factor (HIF), angiogenesis and cell cycle control [4–7].
Neurofibromatosis type 1, known as the von Recklinghausen disease, is the most common in-herited disease associated with peripheral nervous system tumors, such as tumors of the parathyroid gland, neurofibromas, neurinomas of the hypo-thalamus and optic nerve, gliomas and, most of all, pheochromocytomas. NF 1, when diagnosed in early childhood, is usually characterized by café-au-lait pigmented spots, iris hamartomas, neuro-fibromas, skinfold freckling and pheochromocy-tomas. Neurofibromatosis is caused by mutations in the NF1 tumor suppressor gene which encodes a neurofibromin, a protein involved in the cell sig-naling [1, 4–7].
Pheochromocytomas are tumors of the ad-renal gland, whereas paragangliomas are derived from parasympathetic and from extra-adrenal sympathetic-associated chromaffin tissue. Pheo-chromocytomas/paragangliomas syndrome is strongly associated with the genes of succinate dehydrogenase (SDH) complex subunits, particu-larly SDHB and SDHD.
PH/PGL syndrome (defined also as familial PGL) can be divided into four types: PGL1, PGL2, PGL3 and PGL4 caused by mutations of the SD-HD, SDHAF2, SDHC, and SDHB genes respec-tively. Succinate dehydrogenase participates in the citric acid cycle and in the electron transfer chain. Mutation of the SDHD and SDHB genes may cause hypoxia and angiogenesis [1, 4, 6, 7].
Gene-Associated
Pheochromocytoma
Germline RET Mutation
in Pheochromocytoma
The MEN 2 syndrome is caused by proto-oncogene RET (identified in 1985), encoding ty-rosine transmembrane receptor, which consists of tree domains: extracellular, transmembrane and intercellular. The RET gene is involved in signal-ing within cells, therefore, development of several kinds of nerve cells is essential. The RET gene is expressed in several types of neuronal cells with C cell of the thyroid and adrenal medullary cells. Mutations of this gene can also cause Hirschsprung disease, characterized by lack of ganglion cells in the distal part of the colon. The RET gene, there-fore, plays an essential part in the development of the kidneys as well as the parasympathetic, sympa-thetic and enteric nervous systems. This proto-on-cogene is located on the long arm of chromosome 10 at position 11.2 (10q11.2) and is composed of 21 exons. More than 50 different point mutations associated with the MEN 2 syndrome were identi-fied in 7 of the 21 exons [6–8, 12].
Pheochromocytomas, a part of the multiple en-docrine neoplasia syndrome (type 2), are partially associated with RET gene mutations in codon 634 (exon 11, cysteine rich domain) and 918 (exon 16, tyrosine kinase domain). Mutation in codon 634 is strongly related to the type 2A MEN syndrome, whereas mutation in codon 918 is associated with MEN type 2B. Less common mutations in pheo-chromocytomas: codons 609, 611, 618, 620, are located in exon 10 and codons 791 and 804 are located in exon 15 [8].
The differential clinical expression of pheo-chromocytomas in the MEN 2 syndrome caused by RET mutations has been presented in a work by Frank J. Quayle et al. The studies underline the differences between rates of pheochromocytomas and mutations in codons of RET gene as evidence of the relationship between genes and clinical bi-ology. The different mutations in proto-oncogene RET are associated with varied, functional pen-etrance of pheochromocytoma in the MEN 2 syn-drome [13].
It has been shown that bilateral pheochromo-cytoma predominantly occurs in carriers with the
Substantial evidence exists for strong genotype– phenotype correlations in MEN 2 between a pa-tient’s phenotype and specific mutations in RET
gene.
In conclusion, patients with RET mutations are characterized by bilateral tumors, often recur-rent but usually with low risk of malignancy [6, 12, 14–17].
Mutations of VHL Gene
in Pheochromocytoma
The genetic basis of the von Hippel-Lindau syndrome underlies point mutations or deletions in the tumor suppressor gene, VHL (identified in 1993). The vHL syndrome is characterized by the presence of tumors in bilateral and multicentric forms. Approximately 40% of familial or bilateral pheochromocytomas are associated with germline mutation in the VHL gene [18].
According to Knudson’s two-hit hypothesis, in order to develop normal cells into tumor cells, inactivation of both copies of the gene is required. The most frequent mechanism of inactivation is the loss or hypermethylation of the wild type of
VHL – allele in a cell [19].
The VHL gene is located on the short arm of chromosome 3 (3p25) and comprises 3 exons. The gene encodes two different protein isoforms, pvHL, which are involved in different processes: inhibition of transcription elongation and regu-lation of hypoxia-inducible factor (HIF) activity. The VHL gene is widely expressed in normal hu-man tissue (both fetal and adult), as well as in or-gans not related to the vHL disease [10, 11, 18]. In about 20% of patients the disease is caused by mutations de novo in the VHL gene. Mutations in a patient with vHL type 1 are characterized mostly by loss of function mutation (large germ-line dele-tions, nonsense mutations and frameshifts) which causes a complete defect in the protein function, whereas vHL type 2 is associated with missense mutations in the VHL gene, affecting the protein-binding site of pvHL. The mechanism of tu-morgenesis with the involvement of the VHL gene is complex and might be different depending on the tumor type and the function of pvHL in HIF regulation [10, 19, 20].
The genotype-phenotype correlations are still being investigated and future research can con-tribute clearer information about the function of pvHL as well as provide answers to many remain-ing questions as to what may be crucial from the clinical point of view.
NF1
Pheochromocytoma-Associated Gene
Neurofibromatosis type 1 is a common hered-itary disease which predisposes to peripheral ner-vous system tumors. Pheochromocytoma may be a manifestation of neurofibromatosis type 1 (NF1), an autosomal-dominant genetic disorder. Even 50% of NF1 cases result from the spontaneous mutation of NF1 gene, the molecular basis for this disease (identified in 1990). The rate of prevalence of pheochromocytoma occurs between 0.1 and 5.7% [4, 5]. Approximately 9.6% of NF1 patients are characterized by bilateral pheochromocytoma and 6% are extra-adrenal [21]. Neurofibromato-sis is caused by an inactivating mutation in a NF1
tumor suppressor gene, which encodes a neuro-fibromin, a GTPase-activating protein (negative regulator of the RAS kinase pathway) that controls growth and cellular differentiation and is involved in the cell signaling. The NF1 gene is located on chromosome 17q11.2 and contains 60 exons. Be-cause of many different (mostly de novo) types of mutations (deletion, missense or nonsense muta-tions), that span the entire length along with the large size NF1 gene, mutational analysis is still very difficult [4–7, 22].
SDHx-Related
Pheochromocytoma Genes
In about 30% cases the pheochromocytomas/ paragangliomas syndrome is inherited. The he-reditary PH/PGL syndrome is strongly associ-ated with germline mutations in genes encoding two mitochondrial complex II subunit proteins (SDH): succinate dehydrogenase D (SDHD) and succinate dehydrogenase B (SDHB). Inactivation of succinate dehydrogenase (a mitochondrial en-zyme) can imitate chronic hypoxia leading to cel-lular proliferation. This enzyme participates in the Krebs cycle (converts succinate to fumarate) and is involved in the electron-transport chain. The SDH enzyme complex consists of four subunits encod-ed by the SDHA, SDHB, SDHC and SDHD genes. The SDHB, SDHC and SDHD genes are strongly associated with the pheochromocytomas/paragan-gliomas syndrome, whereas the SDHB and SDHD
genes in particular are involved in the pathogen-esis of pheochromocytomas [6, 7, 22, 23].
pheochromocy-tomas (with the Pro81Leu as the most frequent missense mutation). SDHD is located on chromo-some 11 at position 11.23 and consists of 4 exons. Because of a very high rate of prevalence of pheo-chromocytomas and paragangliomas (especially hand-and-neck paragangliomas not secreting catecholamines) among patients with SDHD gene mutations, carriers of these gene mutations should be regularly screened for PH/PGL-associated tu-mors [5–7, 23].
The PGL 4 syndrome is characterized by in-activating the SDHB suppressor gene mutations.
SDHB is located on chromosome 1p35-36 and consist of 8 exons. The SDHB gene is highly as-sociated with extra-adrenal pheochromocytomas with high risk of malignancy (50% patients carry
SDHB mutations). Mutations in this gene are the most common cause of the malignant pheochro-mocytomas/paragangliomas syndrome. Conse-quently, all patients with metastasis, especially from paraganglioma, should be tested for SDHB
gene mutation [6, 7, 22, 25, 26].
The genetic testing for SDHD/SDHB mutations is recommended for all patients with pheochro-mocytomas/paragangliomas syndrome, because of high participation rates of these gene mutations in tumor pathogenesis: 100%, in syndromic cases, 90% in patients with positive familial history and 27% in non-syndromic cases [22].
Although most research indicates that the
SDHD and SDHB genes are mainly responsible for pathogenesis of pheochromocytoma in the pheochromocytomas/paragangliomas syndrome, reports on participation of the SDHA and SDHC
gene are also available; due to the small group of respondents; however, the reports should be veri-fied [6, 7, 27, 28].
Novel Genetic Discoveries
The list of pheochromocytoma-susceptibil-ity genes is quite long and still open. Recent re-search has demonstrated significant progress in our knowledge of the genetic background of cate-cholamine-producing tumors, confirmed as newly discovered genes KIF1Bβ (Kinesis Family Member 1B), TMEM127 (encoding transmembrane protein 127) and MAX involved in signaling pathways in pheochromocytomas [6, 7, 29].
The KIF1Bβ gene consists of about 50 ex-ons and is located on chromosome 1p26.22. The
KIF1Bβ gene is associated with amino acid me-tabolism and oxidative stress responses. KIF1Bβ
as a suppressor gene is involved in controlling neuronal apoptosis; the gene’s function loss may promote tumor growth. There are only a few
pub-lished reports describing mutations in KIF1Bβ so far [6, 7, 29].
TMEM127, a tumor suppressor gene, contains four exons and is located on 2q11.2 chromosome. It is known that TMEM127 encodes a three span-ner transmembrane protein involved in mTOR signaling; however, the function of this gene is not yet well-known.Thus far, TMEM127 gene muta-tions have been identified in 2% of all casesof PH/ PGL [6, 7, 29, 30].
Another tumor suppressor gene, MAX, con-sists of five exons and is located on 14q23.3 chro-mosome. The MAX gene encodes the MAX pro-tein, a transcription factor, which is a cofactor of the MYC proto-oncogene and plays an important role in the regulation of cell proliferation, differen-tiation and death. MAX mutations are associated with a high risk of malignancy [6, 7, 29].
The frequency of pheochromocytoma-asso-ciated germline mutations is likely to increase in further research identifying tumor susceptibility genes.
The microarray-gene expression studies, based on analysis of cellular pathways of tumorgenesis and different transcription profiles of PH/PGL, have revealed two distinct groups – clusters. Clus-ter 1 is associated with the Krebs cycle and hypoxia signaling and comprises mutations in VHL and complex of SDHx genes. Cluster 2, associated with RET, NF1 as well as TMEM127 and KIF1Bβ gene mutations, is associated with translation initiation, protein synthesis and kinase signaling. These clus-ters, indicating two different routes of tumorgen-esis, highlight the need for further investigation concerning the molecular basis of pathology in all such tumors, which could play a crucial role in potential targets of future therapeutic approaches and may indicate and contribute to the develop-ment of new appropriate modalities treatdevelop-ment[6, 29, 30].
Diagnosis of Malignant
Pheochromocytomas
Because of non-specific signs and symptoms, the possible lack of hypertension and other symp-toms (which may have a significant impact on mor-bidity and even mortality) for extended time peri-ods and rare occurrence of pheochromocytomas, diagnosis may be delayed. There is currently no ef-fective therapy for malignant pheochromocytoma and paraganglioma. The clinical and histopatho-logical diagnosis of PH and PGL malignancy is dif-ficult and controversial due to the lack of accurate diagnostic and prognostic markers.
most frequently used diagnostic method, is usu-ally based on determining plasma-free or urinary-fractionated O-methylated metabolites of cate-cholamine (metanephrine, normetanephrine and methoxytyramine). The release of these metabo-lites is sustained and, therefore, much more sensi-tive than the secretion of catecholamines into the bloodstream, which may be modest, absent or can occur episodically. However, applying this method carries the risk of overlooking tumors which se-crete a low concentration of catecholamines and their metabolites. On the other hand, drugs that increase the catecholamine level may lead to false positive results [3, 31, 32]. Biomarkers based on traditional biochemical tests do not distinguish between malignant and benign forms of PH/PGL. According to the current WHO (World Health Organization) definition, pheochromocytomas and paragangliomas are defined as malignant only by the presence of distant metastases. Most of pheochromocytomas are large and can be de-tected by computed tomography (CT), magnetic resonance imaging (MRI) or ultrasound scans. MIBG (metaiodobenzylguanidine) scintigraphy and positron emission tomography (PET) with [18F]-F-fluorodopamine and [18F]-F-dihydroxy-phenylalanine are reference methods, particularly useful in detecting small, multiple tumors (PH and PGL) and metastases [3, 32].
Based on biochemical measurements, imaging and histopathologic characteristics many authors are trying to find whether biomarkers, size and location of the primary tumor may help to distin-guish malignancy or different hereditary forms of pheochromocytoma [3, 31–35]. The best known histopathological scoring method for predicting metastatic potential – PASS (Pheochromocytoma of the Adrenal Gland Scaled Score), proposed by Thompson, has been deemed unreliable due to its limitations by poor interobserver concordance [33, 35]. Therefore, there is no histological feature that unquestionably defines malignant potential of pheochromocytoma.
Zielinka et al. showed that primary tumors in patients with malignant pheochromocytoma were diagnosed at a significantly younger age and were significantly larger (> 5 cm) compared to patients with benign forms of these tumors [33]. These findings show that the primary tumor size is the clinical risk factor for metastasis and have been confirmed by studies by Ayala-Ramirez M. et al. [34]. Zielinka et al. also took notice of the catecholamine level analysis. Patients with ma-lignant pheochromocytoma secreted significantly norepinephrine more often, while patients with benign pheochromocytoma were characterized by an increased level of epinephrine [33]. Another
re-search has been conducted to assess whether mea-surements of metabolites of catecholamines might help to distinguish a hereditary form of pheochro-mocytoma. Patients with MEN2 and NF1 were characterized by increased plasma concentrations of metanephrine, vHL patients have increased levels of normetanephrine, whereas increases in methoxytyramine were observed among patients with SDHB and SDHD mutations. Parallel to re-lated microarray studies, based on the presence or absence of epinephrine production we can dis-tinguish two cluster groups of different hereditary PH/PGL: cluster 1 with VHL and complex SDHx
genes, and cluster 2 with RET, NF1 and TMEM127
genes [31, 35].
This type of research may lead to distinguish-ing between malignant and benign forms of can-cer and to identifying hereditary mutations which cause tumors and associated syndromes.
Appropriate methods of distinguishing be-nign from malignant pheochromocytoma remains a relentless purpose of many studies. The scarcity of effective malignant pheochromocytoma treat-ments indicates the need to identify biomarkers of metastatic disease and new therapeutic targets.
Many interesting and beneficial studies have demonstrated the genetic predispositions and mo-lecular mechanisms involved in the development of malignancy in pheochromocytomas.
Carriers of VHL mutations are characterized by multiple and bilateral tumors, patients with
RET mutations show bilateral, often recurrent tumors with a low risk of malignancy, whereas mutations in the SDHB gene are associated with extra adrenal pheochromocytoma with a high risk of malignancy (about 50% patients with metastatic disease carry SDHB mutation).
Using microarray analysis techniques can re-veal differential gene expression profiling of ma-lignant and benign tumors [6, 29, 30, 36–38].
Thus far, numerous studies have confirmed a substantial contribution of genes in the patho-genesis of pheochromocytoma. As previously mentioned, pheochromocytomas usually occur as sporadic; however, genetic screenings have recently revealed that even 30% of these tumors are inherited because of hereditary mutations and hereditary cancer syndromes. Future studies may reveal an even greater involvement of genes in the pathogenesis of pheochromocytoma, so frequency is likely to increase [1, 4, 6, 7].
there-fore, genetic screening of family members has al-lowed us to select people with an increased risk of cancer. Genomic screens may not only predict the aggressiveness of pheochromocytomas but also provide appropriate medical treatment.
These multicarcinoma syndromes are inher-ited in an autosomal dominant fashion, so early diagnosis and treatment is crucial, especially in cases of malignant, multiple tumors or a young age of onset.
For the genetic diagnosis of pheochromocyto-ma pheochromocyto-many studies propose an algorithm to detect the inherited syndromes considering nonsyndromic pheochromocytomas, malignant phenotype, bilat-eral and extra-adrenal tumors as well as to reduce the cost and delay of genetic analysis [6, 7, 39–41].
Summary
There has been significant progress in our understanding of the genetic background in the pathogenesis of the adrenal medulla tumors in-cluding pheochromocytomas. In about 68% of cases pheochromocytomas occur as a sporadic form of cancer. Pheochromocytomas are also as-sociated with hereditary syndromes such as type 2 multiple endocrine neoplasia caused by the RET
gene mutations, von Hippel-Lindau disease asso-ciated with germline mutation of VHL gene, the neurofibromatosis type 1 syndrome with the par-ticipation of NF1 gene and pheochromocytomas/
paragangliomas syndrome strongly related to the
SDHD and SDHB genes. Contribution of suscep-tibility genes in hereditary pheochromocytoma is: 13% VHL gene, 5% RET gene, 4% NF1 gene, and 6 and 4% SDHB and SDHD genes respectively [27]. Recent examinations have shown newly discov-ered KIF1Bβ, TMEM127 and MAX genes involved in pathogenesis of pheochromocytoma.
Microarray studies, based on analysis of cel-lular pathways, reveal two groups of different he-reditary PH/PGL: cluster 1 with VHL and com-plex SDHx genes, and cluster 2 with RET, NF1 and
TMEM127 genes.
This type of research may lead to distinguish-ing between malignant and benign forms of can-cer and to identifying hereditary mutations which cause tumors and accompanying syndromes. The scarcity of effective treatments of malignant pheo-chromocytoma indicates the need to identify bio-markers of metastatic disease and new therapeutic targets.
The genetic diagnosis in the development of pheochromocytomas and specific manage-ment of family members with a positive history play an important role in preventive medicine. The familial syndromes are associated with oth-er tumors (which may be malignant) and early detection of the syndromes may lead to correct diagnosis, regular surveillance, preventive exami-nations and implementation of early and appro-priate treatment.
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Address for correspondence:
Katarzyna Kolačkov
Department of Endocrinology, Diabetology and Isotope Therapy Wroclaw Medical University
Pasteura 4 50-367 Wrocław Poland
Tel.: +48 71 784 25 58
E-mail: [email protected]
Conflict of interest: None declared
