Succinate Dehydrogenase Genes Research Articles

Age at Diagnosis of Pheochromocytoma Differs According to Catecholamine Phenotype and Tumor Location

Pheochromocytomas and paragangliomas (PPGLs) are diagnosed earlier in patients with hereditary than sporadic disease. Whether other factors influence age at diagnosis is unclear. We examined ages at which PPGLs were diagnosed according to different catecholamine phenotypes and locations of tumors. Retrospective multicenter study. Patients with PPGLs included 172 with and 183 without identified germline mutations or hereditary syndromes. BIOCHEMICAL MEASUREMENTS: Differences in plasma concentrations of metanephrine, a metabolite of epinephrine, were used to distinguish epinephrine-producing tumors from those lacking epinephrine production. Patients with epinephrine-producing tumors were diagnosed 11 yr later (P < 0.001) than those with tumors lacking appreciable epinephrine production. Among patients without evidence of a hereditary condition, those with and without epinephrine-producing tumors had respective mean ± se ages of 50 ± 2 and 42 ± 2 yr (P < 0.001) at diagnosis. Patients with multiple endocrine neoplasia type 2 and neurofibromatosis type 1, all with epinephrine-producing tumors, were similarly diagnosed with disease at a later age than patients with tumors that lacked appreciable epinephrine production secondary to mutations of von Hippel-Lindau and succinate dehydrogenase genes (40 ± 2 vs. 31 ± 1 yr, P < 0.001). Among the latter patients, those with multifocal tumors were diagnosed earlier than those with solitary tumors (19 ± 3 vs. 34 ± 2 yr, P < 0.001). The variations in ages at diagnosis associated with different tumor catecholamine phenotypes and locations suggest origins of PPGLs from different chromaffin progenitor cells with variable susceptibility to disease causing mutations. Different optimal age cut-offs for mutation testing are indicated for patients with and without epinephrine-producing tumors (44-49 vs. 30-35 yr, respectively).

Head and neck paragangliomas

The purpose of this study was to describe the natural history and optimal treatment for head and neck paragangliomas (PGs). Our methods were the review of the pertinent literature. PGs are rare tumors seen most commonly in the head and neck. Approximately 90% are sporadic; the remainder are familial and related to mutations of the succinate dehydrogenase (SDH) gene complex. Most PGs are benign and slow growing; 6% to 19% are malignant, as evidenced by the development of metastases. PGs may be treated by complete resection or moderate-dose radiotherapy with a ≥90% likelihood of cure. The optimal radiotherapy dose is approximately 45 Gy/25 fractions/5 weeks. The treatment modality selected depends on the risk of complications. Due to their rarity, the optimal treatment for malignant PGs is unclear. PGs may be treated by either complete resection or radiotherapy with a high likelihood of success. Treatment depends on the location and extent of the PG and the morbidity associated with treatment.

Catecholamine metabolomic and secretory phenotypes in phaeochromocytoma

Phaeochromocytomas and paragangliomas (PPGLs) are highly heterogeneous tumours with variable catecholamine biochemical phenotypes and diverse hereditary backgrounds. This analysis of 18 catecholamine-related plasma and urinary biomarkers in 365 patients with PPGLs and 846 subjects without PPGLs examined how catecholamine metabolomic profiles are impacted by hereditary background and relate to variable hormone secretion. Catecholamine secretion was assessed in a subgroup of 156 patients from whom tumour tissue was available for measurements of catecholamine contents. Among all analytes, the free catecholamine O-methylated metabolites measured in plasma showed the largest tumour-related increases relative to the reference group. Patients with tumours due to multiple endocrine neoplasia type 2 and neurofibromatosis type 1 (NF1) showed similar catecholamine metabolite and secretory profiles to patients with adrenaline-producing tumours and no evident hereditary background. Tumours from these three patient groups contained higher contents of catecholamines, but secreted the hormones at lower rates than tumours that did not contain appreciable adrenaline, the latter including PPGLs due to von Hippel-Lindau (VHL) and succinate dehydrogenase (SDH) gene mutations. Large increases of plasma dopamine and its metabolites additionally characterised patients with PPGLs due to the latter mutations, whereas patients with NF1 were characterised by large increases in plasma dihydroxyphenylglycol and dihydroxyphenylacetic acid, the deaminated metabolites of noradrenaline and dopamine. This analysis establishes the utility of comprehensive catecholamine metabolite profiling for characterising the distinct and highly diverse catecholamine metabolomic and secretory phenotypes among different groups of patients with PPGLs. The data further suggest developmental origins of PPGLs from different populations of chromaffin cell progenitors.

Monitoring the survival of fish-pathogenic Francisella in water microcosms

In this report, the survival behaviour of fish pathogenic Francisella in water microcosms was investigated under laboratory conditions. Two isolates of Francisella noatunensis (NCIMB14265(T) and PQ 1106), from fish held in seawater and freshwater, were inoculated into natural (nonsterile) and sterile sea- and freshwater microcosms, respectively, and monitored under different temperature conditions (4, 8 and 12 °C) over a period of 60 days. The culturability of the strains was inversely related to the water temperature. Strain NCIMB14265(T) was found to survive longer in seawater than PQ 1106 held in freshwater at equivalent temperatures. The survival of both strains was higher in sterile than in nonsterile microcosms. These results were confirmed by quantitative PCR analysis targeting the succinate dehydrogenase (sdhA) gene. A cell viability assay coupled with FISH analyses showed that F. noatunensis cells enter a viable but not culturable (VBNC) state after a period in water. However, although metabolically active, the VBNC cells were not pathogenic to cod (Gadhus morhua) following an intraperitoneal challenge, under the conditions tested. The data presented contribute to a better understanding of the behaviour of F. noatunensis in natural seawater and freshwater environments, and show the need for further investigation of the role of VBNC cells in the environmental transmission of this pathogen.

Distribution and molecular characterization of Corynespora cassiicola isolates resistant to boscalid

A total of 618 isolates of corynespora leaf spot fungus (Corynespora cassiicola) collected from 24 commercial cucumber greenhouses in 12 cities in Ibaraki Prefecture, Japan, were tested for their sensitivity to boscalid. Boscalid‐resistant isolates were detected in 17 out of 19 greenhouses with a history of use of this fungicide and detection frequencies of the resistant isolates exceeded 47% in nine greenhouses. Frequencies of very highly resistant (VHR) isolates with 50% effective concentration (EC50) values of boscalid exceeding 30 μg mL−1 were higher than those of moderately resistant (MR) isolates with EC50 ranging from 2·0 to 5·9 μg mL−1 in 11 greenhouses. Additionally, highly resistant (HR) isolates with EC50 from 8·9 to 10·7 μg mL−1 were first detected. Furthermore, molecular characterization of genes encoding succinate dehydrogenase (SDH) subunits (SdhA, SdhB, SdhC and SdhD) was carried out to elucidate the amino acid substitution responsible for the resistance to boscalid. All 23 VHR isolates had the same mutation from CAC to TAC in the SdhB gene leading to the substitution of histidine with tyrosine at amino acid position 278 (B‐H278Y). At the same position, the substitution to arginine conferred by a mutation to CGC (B‐H278R) was detected in all four HR isolates. Some MR isolates showed a substitution from serine to proline at position 73 in SdhC (C‐S73P), from serine to proline or from glycine to valine at position 89 (D‐S89P) and 109 (D‐G109V), respectively, in SdhD. There was no common mutation in SDH genes of all MR isolates.

Succinate dehydrogenase gene mutations are strongly associated with paraganglioma of the organ of Zuckerkandl

Organ of Zuckerkandl paragangliomas (PGLs) are rare neuroendocrine tumors that are derived from chromaffin cells located around the origin of the inferior mesenteric artery extending to the level of the aortic bifurcation. Mutations in the genes encoding succinate dehydrogenase subunits (SDH) B, C, and D (SDHx) have been associated with PGLs, but their contribution to PGLs of the organ of Zuckerkandl PGLs is not known. We aimed to describe the clinical presentation of patients with PGLs of the organ of Zuckerkandl and investigate the prevalence of SDHx mutations and other genetic defects among them. The clinical characteristics of 14 patients with PGL of the organ of Zuckerkandl were analyzed retrospectively; their DNA was tested for SDHx mutations and deletions. Eleven out of 14 (79%) patients with PGLs of the organ of Zuckerkandl were found to have mutations in the SDHB (9) or SDHD (2) genes; one patient was found to have the Carney-Stratakis syndrome (CSS), and his PGL was discovered during surgery for gastrointestinal stromal tumor. Our results show that SDHx mutations are prevalent in pediatric and adult PGLs of the organ of Zuckerkandl. Patients with PGLs of the organ of Zuckerkandl should be screened for SDHx mutations and the CSS; in addition, asymptomatic carriers of an SDHx mutation among the relatives of affected patients may benefit from tumor screening for early PGL detection.

Bovine Mesenchymal Stem Cell의 지방분화를 이용한 지방대사관련 후보 유전자의 발현분석

본 실험은 지방대사에 영향을 주는 후보 유전자의 발현양상을 조사하기 위하여 bovine mesenchymal stem cell을 이용하여 체외에서 지방분화를 유도하였고, 지방분화 경과에 따른 지방관련 후보유전자의 발현양상을 분석 하였다. Oil red-O 염색법을 이용하여 지방 분화양상을 조사한 결과, 지방 분화 단계별(0, 2, 4 및 6일)로 붉게 염색된 지방적이 증가되었음을 확인하였고, 지방대사의 indicator인 PPAR<TEX>$\gamma$</TEX>와 FABP4 유전자는 지방분화 0일과 비교하여 6일에는 각각 3.11배와 3.11배가 증가하였다. 또한 지방대사와 관련이 있다고 추측되는 ICER, NOV, HSPB1 및 SDH 유전자의 발현양상을 조사한 결과, 지방분화 동안 ICER 유전자는 계속적으로 증가하여 6일은 0일에 비해 4.12배의 유의적인 증가를 보인 반면, NOV, HSPB1 및 SDH 유전자의 발현양은 0일 이후 계속적으로 감소하여, 6일에서 각각 2.89배, 3.18배 및 2.36배의 감소를 나타냈다. 본 실험에서, 등심조직에서 근내지방도에서 차이를 나타냈던 ICER, NOV, HSPB1 및 SDH 유전자를 보다 구체적이고 직접적으로 세포에서 지방분화를 통해 연관성을 조사했을 때, 지방분화와 직접적으로 관련되어 있는 것으로 나타났으며, 지방 대사를 조절하는 유전자로 추정된다. Adipogenesis has been one of the most intensely studied models of cellular differentiation. During adipogenesis, differential expression of many adipogenesis related genes lead to profound changes in cellular, morphological, and physiological characteristics of the differentiating cells. The aim of the present study was to examine the expression levels of adipogenic candidate genes, cAMP early repressor (ICER), nephroblastoma over-expressed protein (NOV), heat shock protein beta 1 (HSPB1) and succinate dehydrogenase (SDH), during adipogenesis of bovine mesenchymal stem cells (BMSC). The BMSC were cultured in DMEM / low glucose medium with adipogenic inducers for 6 days and the expression of various candidate genes which seemed related to adipogenesis were measured by real-time PCR. This study showed that the expression of peroxisome proliferator activated receptor <TEX>${\gamma}$</TEX>(PPAR<TEX>${\gamma}$</TEX>) and fatty acid binding protein 4 (FABP4) genes as adipogenic indicators were increased to 3.11 and 3.11 folds on day 6 than on day 0, respectively (p<0.05). To determine whether candidate genes were related to adipogenesis, the expression levels of ICER, NOV, HSPB1, and SDH genes were measured during adipogenesis in BMSC. Our results showed that the expression level of ICER gene was significantly increased to 4.12 folds (0.01729 vs. 0.07138; p<0.05), whereas NOV, HSPB1, and SDH genes were decreased to 2.89, 3.18 and 2.36 folds, respectively, on day 6 when compared to day 0. These results suggest that these candidate genes have stimulatory or inhibitory effects on adipogenesis in BMSC, indicating that these genes may be directly or indirectly related to the adipogenic event of adipose precursor cells.

SDH-related pheochromocytoma and paraganglioma

Pheochromocytoma and paraganglioma are rare tumors of adrenals as well as the sympathetic and parasympathetic paraganglia. Clinical presentation of these tumors depends on localization, secretory profile and malignant potential. Four distinct syndromes--PGL1-4--are related to mutations in the succinate dehydrogenase gene--mitochondrial complex involved in electron transfer and Krebs cycle. Here we describe etiology, genetics, as well as clinical aspects of SDH-related tumors. We also describe recent discoveries in HIF-related pathway of tumorigenesis and mutations in new SDH-related genes that have improved our understanding of this disease.

Paraganglioma, neuroblastoma, and a SDHB mutation: Resolution of a 30‐year‐old mystery

Familial paraganglioma/pheochromocytoma (PGL/PCC) is genetically heterogenous with mutations in three of the four subunits of the heterotetrameric mitochondrial complex II enzyme succinate dehydrogenase (SDH) being causally responsible for the majority of cases. In addition to PGL/PCC an array of non-paraganglial tumors have been described in affected individuals. We present a 30-year follow-up on the family of a deceased patient who synchronously developed malignant neuroblastoma (NBL), PCC, and renal cell carcinoma (RCC). Other family members with late onset disease have come to our attention, and molecular study revealed a mutation in the SDHB gene. Despite the embryologic relationship, NBL has been seen in only two previous patients with familial PGL/PCC, both with deletions of the SDHB gene. Review of the literature suggests the lack of a reported association between NBL and familial PGL/PCC may be an ascertainment bias. We further suggest that study of the SDH genes in NBL survivors who develop secondary solid tumors, particularly RCC, may correct this bias, and provide for more effective and comprehensive tumor screening in this patient population.

Role of Hfq in iron-dependent and -independent gene regulation in Neisseria meningitidis

In Neisseria meningitidis, iron-responsive gene regulation is mediated primarily by the ferric uptake regulator (Fur) protein. When complexed with iron, Fur represses gene expression by preventing transcription initiation. Fur can also indirectly activate gene expression via the repression of regulatory small RNAs (sRNA). One such Fur- and iron-regulated sRNA, NrrF, was previously identified in N. meningitidis and shown to repress expression of the sdhA and sdhC genes encoding subunits of the succinate dehydrogenase complex. In the majority of Gram-negative bacteria, sRNA-mediated regulation requires a cofactor RNA-binding protein (Hfq) for proper gene regulation and stabilization. In this study, we examined the role of Hfq in NrrF-mediated regulation of the succinate dehydrogenase genes in N. meningitidis and the effect of an hfq mutation on iron-responsive gene regulation more broadly. We first demonstrated that the stability of NrrF, as well as the regulation of sdhC and sdhA in vivo, was unaltered in the hfq mutant. Secondly, we established that iron-responsive gene regulation of the Fur-regulated sodB gene was dependent on Hfq. Finally, we demonstrated that in N. meningitidis, Hfq functions in a global manner to control expression of many ORFs and intergenic regions via iron-independent mechanisms. Collectively these studies demonstrate that in N. meningitidis, iron- and NrrF-mediated regulation of sdhC and sdhA can occur independently of Hfq, although Hfq functions more globally to control regulation of other N. meningitidis genes primarily by iron-independent mechanisms.

Advantage of Upregulation of Succinate Dehydrogenase in Staphylococcus aureus Biofilms

Previous studies have demonstrated that various tricarboxylic acid (TCA) cycle genes, particularly the succinate dehydrogenase genes (sdhCAB), are upregulated in Staphylococcus aureus biofilms. To better study the role of this enzyme complex, an sdhCAB deletion mutant (Deltasdh) was constructed. Compared to the wild type (wt) the mutant was impaired in planktonic growth under aerobic conditions, excreted acetic acid could not be reused and accumulated continuously, succinate was excreted and found in the culture supernatant, and metabolome analysis with cells grown in chemically defined medium revealed reduced uptake/metabolism of some amino acids from the growth medium. Moreover, the mutant was able to counteract the steadily decreasing extracellular pH by increased urease activity. The addition of fumarate to the growth medium restored the wt phenotype. The mutant showed a small-colony variant (SCV)-like phenotype, a slight increase in resistance to various aminoglycoside antibiotics, and decreased pigmentation. The decreased growth under aerobic conditions is due to the interruption of the TCA cycle (indicated by the accumulation of succinate and acetic acid) with the consequence that many fewer reduction equivalents (NADH and FADH2) can fuel the respiratory chain. The results indicate that the TCA cycle is required for acetate and amino acid catabolism; its upregulation under biofilm conditions is advantageous under such nutrient- and oxygen-limited conditions.

Relevance of germline mutation screening in both familial and sporadic head and neck paraganglioma for early diagnosis and clinical management.

Background: Head and neck paraganglioma (PGL) are benign tumors that can cause important direct or surgery induced morbidity. Almost all familial and 11–29% of sporadic PGL are caused by inactivating germline mutations in succinate dehydrogenase (SDH) genes. Our aim was to screen for such mutations and to evaluate clinical parameters as predictors of germline mutation. Methods: Seventy-four PGL patients were analyzed for germline mutations and large deletions in SDH genes, VHL and RET. Results were correlated to clinical characteristics including gender, age, tumor localization and multifocality. The surgical approach was evaluated in terms of tumor origin, sequelae and subsequent evolution. Results: Mutations in SDHB and SDHD were identified in equal proportion in 13/13 (100%) of familial and in 15/61 (25%) of sporadic cases. Familiarity, age ≤50 years and male gender were predictors of any germline mutation, while multifocality and carotid/vagal localization were indicative of SDHD mutation in particular. Conclusions: In contrast to other series, this cohort of Spanish patients showed many SDHB mutations. Sporadic cases with germline mutation are frequent and underline the importance of mutational screening of all PGL patients, allowing the identification of relatives at risk and the early diagnosis of the disease, reducing or avoiding morbidity.

Relevance of Germline Mutation Screening in Both Familial and Sporadic Head and Neck Paraganglioma for Early Diagnosis and Clinical Management

Background: Head and neck paraganglioma (PGL) are benign tumors that can cause important direct or surgery induced morbidity. Almost all familial and 11–29% of sporadic PGL are caused by inactivating germline mutations in succinate dehydrogenase (SDH) genes. Our aim was to screen for such mutations and to evaluate clinical parameters as predictors of germline mutation.Methods: Seventy-four PGL patients were analyzed for germline mutations and large deletions in SDH genes, VHL and RET. Results were correlated to clinical characteristics including gender, age, tumor localization and multifocality. The surgical approach was evaluated in terms of tumor origin, sequelae and subsequent evolution.Results: Mutations in SDHB and SDHD were identified in equal proportion in 13/13 (100%) of familial and in 15/61 (25%) of sporadic cases. Familiarity, age ≤50 years and male gender were predictors of any germline mutation, while multifocality and carotid/vagal localization were indicative of SDHD mutation in particular.Conclusions: In contrast to other series, this cohort of Spanish patients showed many SDHB mutations. Sporadic cases with germline mutation are frequent and underline the importance of mutational screening of all PGL patients, allowing the identification of relatives at risk and the early diagnosis of the disease, reducing or avoiding morbidity.

Compound heterozygous mutation with a novel splice donor region DNA sequence variant in the succinate dehydrogenase subunit B gene in malignant paraganglioma

Pheochromocytoma and paraganglioma (PGL) are rare neuroendocrine tumors in children. Apparently sporadic cases of PGL may harbor germline mutations in the succinate dehydrogenase (SDHx) gene. SDHB mutations are associated with malignant disease. We report a 13-year-old African American boy with diffusely metastatic PGL and compound heterozygous mutation leading to a novel splice donor region DNA sequence variant in the SDHB gene. Family history was positive for non-classical congenital adrenal hyperplasia and pituitary adenoma. After surgical resection of the primary PGL and chemotherapy, he was treated with metaiodobenzy lguanidine (MIBG) combined with arsenic trioxide. At 3-year follow-up, he had stable disease.

Isocitrate Dehydrogenase Mutations Are Rare in Pheochromocytomas and Paragangliomas

Paragangliomas and pheochromocytomas are neuroendocrine tumors that occur sporadically and in the context of inherited tumor syndromes including hereditary paraganglioma-pheochromocytoma syndrome and von Hippel-Lindau disease (VHL). The paraganglioma-pheochromocytoma syndrome is caused by germline-inactivating mutations in the mitochondrial succinate dehydrogenase (SDH) genes SDHB, SDHC, SDHD, or SDHAF2, and VHL is the result of inactivating VHL gene mutations. In SDH- and VHL-related paraganglioma and pheochromocytoma, hypoxia-inducible factor (HIF) stabilization has been described as the causal oncogenic event. Recently, HIF activation has also been found in glioblastoma multiforme, as the result of somatic mutational inactivation of the isocitrate dehydrogenase (IDH) type 1 or type 2 enzymes. These findings suggest that inactivating IDH1 and IDH2 mutations might also play a role in paraganglioma and pheochromocytoma tumorigenesis, especially in non-SDH- or non-VHL-related tumors. We investigated 365 pheochromocytomas and paragangliomas, including 269 sporadic tumors without SDH or VHL gene mutations, for mutations in IDH1 and IDH2. Only codons 132 and 172 were screened because these are the ones exclusively involved. In one of 131 paragangliomas, a somatic heterozygous IDH1 p.Arg132Cys mutation was detected in a sporadic carotid paraganglioma diagnosed in a 61-yr-old woman. No mutations were found in 234 pheochromocytomas. IDH mutations are very rare in paragangliomas and pheochromocytomas and do not appear to play an important role in oncogenic HIF activation known to be present in these tumors.

A role for succinate dehydrogenase genes in low chemoresponsiveness to hypoxia?

The detection of hypoxia by the carotid bodies elicits a ventilatory response of utmost importance for tolerance to high altitude. Germline mutations in three genes encoding subunit B, C and D of succinate dehydrogenase (SDHB, SDHC and SDHD) have been associated with paragangliomas of the carotid body. We hypothesized that SDH dysfunction within the carotid body could result in low chemoresponsiveness and intolerance to high altitude. The frequency of polymorphisms of SDHs, hypoxia-inducible factor type 1 (HIF1alpha) and angiotensin converting enzyme (ACE) genes was compared between 40 subjects with intolerance to high altitude and a low hypoxic ventilatory response at exercise (HVRe < or = 0.5 ml min(-1) kg(-1); HVR- group) and 41 subjects without intolerance to high altitude and a high HVRe (> or = 0.80 ml min(-1) kg(-1); HVR+). We found no significant association between low or high HVRe and (1) the allele frequencies for nine single nucleotide polymorphisms (SNPs) in the SDHD and SDHB genes, (2) the ACE insertion/deletion polymorphism and (3) four SNPs in the HIF1alpha gene. However, a marginal significant association was found between the synonymous polymorphism c.18A>C of the SDHB gene and chemoresponsiveness: 8/40 (20%) in the HVR- group and 3/41 (7%) in the HVR+ group (p = 0.12). A principal component analysis showed that no subject carrying the 18C allele had both high ventilatory and cardiac response to hypoxia. In conclusion, no clear association was found between gene variants involved in oxygen sensing and chemoresponsiveness, although some mutations in the SDHB and SDHD genes deserve further investigations in a larger population.

American Association of Clinical Endocrinologists and American Association of Endocrine Surgeons Medical Guidelines for the Management of Adrenal Incidentalomas: Executive Summary of Recommendations

American Association of Clinical Endocrinologists and American Association of Endocrine Surgeons Medical Guidelines for the Management of Adrenal Incidentalomas: Executive Summary of Recommendations

American Association Of Clinical Endocrinologists And American Association Of Endocrine Surgeons Medical Guidelines For The Management Of Adrenal Incidentalomas

American Association Of Clinical Endocrinologists And American Association Of Endocrine Surgeons Medical Guidelines For The Management Of Adrenal Incidentalomas

SDH mutations in tumorigenesis and inherited endocrine tumours: lesson from the phaeochromocytoma–paraganglioma syndromes

A genetic predisposition for paragangliomas and adrenal or extra-adrenal phaeochromocytomas was recognized years ago. Beside the well-known syndromes associated with an increased risk of adrenal phaeochromocytoma, Von Hippel Lindau disease, multiple endocrine neoplasia type 2 and neurofibromatosis type 1, the study of inherited predisposition to head and neck paragangliomas led to the discovery of the novel 'paraganglioma-phaeochromocytoma syndrome' caused by germline mutations in three genes encoding subunits of the succinate dehydrogenase (SDH) enzyme (SDHB, SDHC and SDHD) thus opening an unexpected connection between mitochondrial tumour suppressor genes and neural crest-derived cancers. Germline mutations in SDH genes are responsible for 6% and 9% of sporadic paragangliomas and phaeochromocytomas, respectively, 29% of paediatric cases, 38% of malignant tumours and more than 80% of familial aggregations of paraganglioma and phaeochromocytoma. The disease is characterized by autosomal dominant inheritance with a peculiar parent-of-origin effect for SDHD mutations. Life-time tumour risk seems higher than 70% with variable clinical manifestantions depending on the mutated gene. In this review we summarize the most recent knowledge about the role of SDH deficiency in tumorigenesis, the spectrum and prevalence of SDH mutations derived from several series of cases, the related clinical manifestantions including rare phenotypes, such as the association of paragangliomas with gastrointestinal stromal tumours and kidney cancers, and the biological hypotheses attempting to explain genotype to phenotype correlation.

Mitochondrial and Nuclear Genes of Mitochondrial Components in Cancer

Although the observation of aerobic glycolysis of tumor cells by Otto v. Warburg had demonstrated abnormalities of mitochondrial energy metabolism in cancer decades ago, there was no clear evidence for a functional role of mutant mitochondrial proteins in cancer development until the early years of the 21st century. In the year 2000, a major breakthrough was achieved by the observation, that several genes coding for subunits of the respiratory chain (ETC) complex II, succinate dehydrogenase (SDH) are tumor suppressor genes in heritable paragangliomas, fulfilling Knudson’s classical two-hit hypothesis. A functional inactivation of both alleles by germline mutations and chromosomal losses in the tumor tissue was found in the patients. Later, SDH mutations were also identified in sporadic paragangliomas and pheochromocytomas. Genes of the mitochondrial ATP-synthase and of mitochondrial iron homeostasis have been implicated in cancer development at the level of cell culture and mouse experiments. In contrast to the well established role of some nuclear SDH genes, a functional impact of the mitochondrial genome itself (mtDNA) in cancer development remains unclear. Nevertheless, the extremely high frequency of mtDNA mutations in solid tumors raises the question, whether this small circular genome might be applicable to early cancer detection. This is a meaningful approach, especially in cancers, which tend to spread tumor cells early into bodily fluids or faeces, which can be screened by non-invasive methods.