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PubMed2026

Fault Lines in the Genome: Somatic DNA Mutations in Aging and Neurodegeneration.

The human genome is both fragile and resilient: prone to alteration yet protected by extensive repair mechanisms. With age, individuals accumulate genetic damage from environmental factors and cell-intrinsic processes, with effects ranging from benign nucleotide shifts to disease-driving mutations. Such alterations to the genetic code outside the germline are described as somatic mutations and display striking heterogeneity across cell types. Recently, somatic mutations have emerged as a hallmark feature of aging in the body's longest-lived tissue: the central nervous system (CNS). The distinctively long lifespan, high metabolism, electrochemical activity, and unique epigenome of CNS cells may render them especially vulnerable to mutational accumulation. The CNS therefore provides a model for understanding how somatic mutations drive cellular dysfunction beyond an established role in cancer. Here, we review the somatic mutations that arise in the brain across lifespan, the mechanisms that lead to their formation, and their potential contributions to aging and age-related disease.

Journal Article↗
PubMed1997

The immunodominant antigen of an ultraviolet-induced regressor tumor is generated by a somatic point mutation in the DEAD box helicase p68.

The genetic origins of CD8+ T cell-recognized unique antigens to which mice respond when immunized with syngeneic tumor cells are unknown. The ultraviolet light-induced murine tumor 8101 expresses an H-2Kb-restricted immunodominant antigen, A, that induces cytolytic CD8+ T cells in vivo A+ 8101 cells are rejected by naive mice while A- 8101 tumor cells grow. To identify the antigen H-2Kb molecules were immunoprecipitated from A+ 8101 cells and peptides were eluted by acid. The sensitizing peptide was isolated by sequential reverse-phase HPLC and sequenced using microcapillary HPLC-triple quadruple mass spectrometry. The peptide, SNFVFAGI, matched the sequence of the DEAD box protein p68 RNA helicase except for a single amino acid substitution, caused by a single nucleotide change. This mutation was somatic since fibroblasts from the mouse of tumor origin expressed the wild-type sequence. The amino acid substitution created an anchor for binding of the mutant peptide to H-2Kb. Our results are consistent with mutant p68 being responsible for rejection of the tumor. Several functions of p68, which include nucleolar assembly and inhibition of DNA unwinding, may be mediated through its IQ domain, which was altered by the mutation. This is the first description of a somatic tumor-specific mutation in the coding region of a nucleic acid helicase.

Amino Acid Sequence↗
PubMed1997

Somatic cell mutations in cancer epidemiology.

Somatic cell mutations arising in vivo in reporter genes and in cancer-associated genes may now be measured in humans. Background mutation levels and mutational responses following various mutagen exposures are reviewed in this chapter. The detection methods are compared for similarities and differences based on the underlying biology of the systems. Currently available data on molecular mutational spectra are reviewed and the utility of such information is discussed in terms of mutagen exposure characterization and for defining the mutagenic basis of carcinogenesis. In addition to the reporter gene assays, recently developed assays for mutation in cancer-associated genes are considered. The strengths and limitations of using somatic cell mutations for cancer epidemiology and areas for future research are discussed.

Animals↗
PubMed1980

Drug-resistant lymphocytes in man as indicators of somatic cell mutation.

Direct in vivo tests of somatic mutation in man may provide realism in assessing the genetic risks of potential environmental mutagens. The autoradiographic determination of purine analogue (8-azaguanine; 6-thioguanine) resistant (AGr; TGr) peripheral blood lymphocytes (PBLs) arising in vivo in man is proposed as a candidate test. PBLs bearing the naturally occurring Lesch-Nyhan (LN) mutation are prototype mutant cells. LN PBLs are AGr and TGr, whereas normal PBLs are AG and TG sensitive. When judged by the inhibition of phytohemagglutinin (PHA) stimulated 3H-thymidine incorporation in vitro, analogue-resistant LN PBLs may be distinguished from analogue-sensitive normal PBLs by several methods. Early studies quantitating PHA stimulation by scintillation spectrometry detected down to 1% of LN PBLs in artificial mixtures with normal PBLs. Although LN heterozygous females could be identified on the basis of lymphocyte mosaicism, scintillation spectrometry was too insensitive to detect rare "LN-like" PBLs in non-LN individuals. Autoradiography, however, detected rare TGr PBLs in normal non-LN individuals. Their frequencies did not increase with age. With this method, TGr PBL frequencies in LN heterozygous females were found to range from 1 x 10(-3) to 5 x 10(-2), whereas blood samples from LN males showed from 23% to 100% TGr cells. Rare LN PBLs could be detected in artificial mixtures with normal cells. Studies in human patients undergoing various potential mutagenic therapies assessed the effects of these therapies on the TGr PBL variant frequencies (Vf) of non-LN individuals. Group TGr PBL Vf values were higher in treated patient groups than in controls. However, some untreated patient groups (cancer and psoriasis) also had elevated values, suggesting that disease itself may affect TGr PBL frequencies. Nonetheless, one patient group (vitiligo) showed elevated Vf values in treated (8-methoxypsoralen and long-range UV light = PUVA) but not in untreated patients, suggesting that treatment was responsible for the TGr PBL elevations. Longitudinal studies over time in cancer patients receiving X-irradiation therapy demonstrated that such exposures also are associated with TGr PBL frequency rises and suggested that longitudinal studies may be necessary to relate TGr PBL Vf elevations to specific environmental influences. Variant TGr PBLs were found at frequencies comparable to those in man in the peripheral blood of rats. They increased in a single study following treatment of the animals with a clinical alkylating agent. Characterization of the TGr PBLs suggests that some of these cells are mutants. Presumably the mutant cells arise in vivo by somatic cell mutation.

Animals↗
PubMed2003

The characterization of somatic APC mutations in colonic adenomas and carcinomas in Ashkenazi Jews with the APC I1307K variant using linkage disequilibrium.

Mutations of the adenomatous polyposis coli (APC) gene play a critical role in the development of colorectal neoplasms. A novel mechanism involves a germline variant, at codon 1307 of the APC gene. The mutation is thought to create an unstable segment of DNA, which facilitates the development of somatic mutations. I1307K has been shown to be ancestral in Middle Eastern populations. The aim of the present study was to confirm this observation for a Western population and to utilize this information in the characterization of the somatic changes in colorectal neoplasia in carriers of I1307K. DNA from 182 US Ashkenazim was screened for the I1307K variant, which was found in 22 (12.1%), and the ancestral nature of this variant was confirmed in this population by showing that all of those with the I1307K variant carried a specific allele at the D5S346 locus, while the majority shared a D5S1385 allele. Subsequently, 79 neoplasms were analysed from 15 I1307K carriers for loss of heterozygosity (LOH) at the D5S346 locus. LOH was detected in 18 neoplasms (23%). Of these 18, four neoplasms showed loss of the I1307K-associated allele, while 14 neoplasms had retained the I1307K-associated allele and, by implication, the I1307K variant. PCR products were also cloned into a plasmid vector to isolate individual APC alleles. For those neoplasms with LOH, 13 of the 18 neoplasms (72%) had a somatic mutation, of which 12 involved the I307K-bearing chromosome. This study is consistent with two previous studies in showing that additional somatic mutations close to codon 1307 are almost always on the I1307K-bearing chromosome, but either allele may demonstrate LOH. Further evidence for the interpretation of the action of I1307K as producing DNA instability is provided by analysing multiple neoplasms from the same person and by showing that these neoplasms have differing patterns of LOH and associated somatic mutations.

Adenoma↗
PubMed1991

Flow cytometric measurements of somatic cell mutations in Thorotrast patients.

Exposure to ionizing radiation has long been well-recognized as a risk factor for cancer development. Since ionizing radiation can induce mutations, an accurate way of measuring somatic mutation frequencies could be a useful tool for evaluating cancer risks. In the present study, we have examined in vivo somatic mutation frequencies at the erythrocyte glycophorin A (GPA) and T-cell receptor (TCR) loci in 18 Thorotrast patients who have been continuously irradiated with alpha-particles emitted from the internal deposition of thorium dioxide and who thus have increased risks of certain malignant tumors. When compared with controls, the results showed a significantly higher frequency of mutants at the lymphocyte TCR loci but not at the erythrocyte GPA loci in the Thorotrast patients. The discrepancy between the results of the two assays is discussed.

Aged↗
PubMed2024

The Genetic Determinants and Genomic Consequences of Non-Leukemogenic Somatic Point Mutations.

Clonal hematopoiesis (CH) is defined by the expansion of a lineage of genetically identical cells in blood. Genetic lesions that confer a fitness advantage, such as point mutations or mosaic chromosomal alterations (mCAs) in genes associated with hematologic malignancy, are frequent mediators of CH. However, recent analyses of both single cell-derived colonies of hematopoietic cells and population sequencing cohorts have revealed CH frequently occurs in the absence of known driver genetic lesions. To characterize CH without known driver genetic lesions, we used 51,399 deeply sequenced whole genomes from the NHLBI TOPMed sequencing initiative to perform simultaneous germline and somatic mutation analyses among individuals without leukemogenic point mutations (LPM), which we term CH-LPMneg. We quantified CH by estimating the total mutation burden. Because estimating somatic mutation burden without a paired-tissue sample is challenging, we developed a novel statistical method, the Genomic and Epigenomic informed Mutation (GEM) rate, that uses external genomic and epigenomic data sources to distinguish artifactual signals from true somatic mutations. We performed a genome-wide association study of GEM to discover the germline determinants of CH-LPMneg. After fine-mapping and variant-to-gene analyses, we identified seven genes associated with CH-LPMneg (TCL1A, TERT, SMC4, NRIP1, PRDM16, MSRA, SCARB1), and one locus associated with a sex-associated mutation pathway (SRGAP2C). We performed a secondary analysis excluding individuals with mCAs, finding that the genetic architecture was largely unaffected by their inclusion. Functional analyses of SMC4 and NRIP1 implicated altered HSC self-renewal and proliferation as the primary mediator of mutation burden in blood. We then performed comprehensive multi-tissue transcriptomic analyses, finding that the expression levels of 404 genes are associated with GEM. Finally, we performed phenotypic association meta-analyses across four cohorts, finding that GEM is associated with increased white blood cell count and increased risk for incident peripheral artery disease, but is not significantly associated with incident stroke or coronary disease events. Overall, we develop GEM for quantifying mutation burden from WGS without a paired-tissue sample and use GEM to discover the genetic, genomic, and phenotypic correlates of CH-LPMneg.

Journal Article↗
PubMed2005

Adhesiveness of beta5 integrin variant lacking FNK767-769 is similar to that of the prototype containing FNKFNK764-769.

Little is known about the functions of two different beta5 integrins: repeated-FNK (FNKFNK764-769) and single-FNK (FNK764-766) amino acid sequences in the cytoplasmic domain. We examined whether they occurred as germ line mutations or somatic mutations associated with neoplastic transformation, and whether there were functional alterations. Out of six cultured cell lines, only KATO-III cells had the single-FNK beta5 sequence. The single-FNK beta5 was found in 9 out of 79 patients with colon carcinoma, but no somatic mutations were detected in cancerous tissues. CHO cells were transformed with expression vectors containing single-FNK or repeated-FNK beta5 cDNA, which were derived from KATO-III cells. CHO cells transfected with single-FNK and repeated-FNK showed similar adhesiveness to, and proliferative activity on, vitronectin substrates.

Amino Acid Sequence↗
PubMed2003

Associations between hyperglycaemia and somatic transversion mutations in mitochondrial DNA of people with diabetes mellitus.

AIMS/HYPOTHESIS: Considering that increased oxidative stress induced by hyperglycaemia plays a possible role in the pathogenesis of diabetic complications and that mitochondrial DNA (mDNA) is thought to be more vulnerable than nuclear DNA, we investigated what somatic mutations actually occur in the mDNA of diabetic patients. We also studied the relations between those mutations and urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) which is known to increase considerably in people with diabetes. METHODS: We identified somatic mutations by subcloning and sequencing two segments of mDNA [control region (nt 15996-16401) and the segment encompassing t-RNA(Leu(UUR))(nt 3149-3404)] in the peripheral blood cells of six diabetic women and control subjects matched for age and sex. This was done in 20 colonies each. In each case we also assayed urinary 8-OHdG. RESULTS: No difference in the aggregate somatic mutational burden of mDNA was found between patients and control subjects. However, the incidence of somatic transversion mutations in mDNA was significantly higher in diabetic patients than in control subjects (13.93+/-4.57 x 10(-5) vs 1.27+/-1.27 x 10(-5) mutations per base pair; p=0.031, according to Mann-Whitney U-test). There was no significant difference in transition mutations. A correlation was found between the transversion mutational burden and HbA(1)c values, but not between it and 8-OHdG content in the urine. CONCLUSIONS/INTERPRETATION: We showed that somatic transversion point mutations of mDNA increase in diabetic patients. Such transversion mutations can become a new biomarker for mDNA damage associated with hyperglycaemia and possibly caused by oxidative stress but not reflected by urinary 8-OHdG.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed1997

[Tumor suppressor genes].

The main role of tumour suppressor genes is the inhibition of cell proliferation. Somatic mutations in these genes are found frequently in sporadic tumors. Germ line mutations in tumour suppressor genes are responsible for hereditary cancer syndromes. In a carrier of such a germ line mutation, a somatic mutation or loss of the remaining functional copy of the gene is sufficient for the complete loss of function of the tumour suppressor. Therefore the carriers of germ line mutations have a high risk of developing malignancies. Many tumour suppressor genes have been cloned and characterized recently and many others are intensively searched for. Protein products of these genes serve different cellular functions and many of them directly participate in the cell cycle control. The characterization of tumour suppressor genes is important both for the understanding of processes of carcinogenesis and for practical use in the diagnostics, prognostics and therapy of tumours.

Animals↗
PubMed2004

Analysis of somatic APC mutations in rare extracolonic tumors of patients with familial adenomatous polyposis coli.

Patients with familial adenomatous polyposis coli (FAP) carry heterozygous mutations of the APC gene. At a young age, these patients develop multiple colorectal adenomas that consistently display a second somatic mutation in the remaining APC wild-type allele. Inactivation of APC leads to impaired degradation of beta-catenin, thereby promoting continuous cell-cycle progression. The role of APC inactivation in rare extracolonic tumors of FAP patients has not been characterized sufficiently. Among tissue specimen from 174 patients with known APC germ-line mutations, we identified 8 tumors infrequently seen in FAP. To investigate the pathogenic role of APC pathway deregulation in these lesions, they were analyzed for second-hit somatic mutations in the mutational cluster region of the APC gene. Immunohistochemistry was performed to compare the expression pattern of beta-catenin to the mutational status of the APC gene. Exon 3 of the beta-catenin gene (CTNNB1) was analyzed for activating mutations to investigate alternative mechanisms of elevated beta-catenin concentration. Although CTNNB1 mutations were not observed, second somatic APC mutations were found in 4 of the 8 tumors: a uterine adenocarcinoma, a hepatocellular adenoma, an adrenocortical adenoma, and an epidermal cyst. These tumors showed an elevated concentration of beta-catenin. No APC mutations were seen in focal nodular hyperplasia of the liver, angiofibrolipoma, and seborrheic wart. This is the first study reporting second somatic APC mutations in FAP-associated uterine adenocarcinoma and epidermal cysts. Furthermore, our data strengthen a role for impaired APC function in the pathogenesis of adrenal and hepatic neoplasms in FAP patients.

Adaptor Proteins, Signal Transducing↗
PubMed2004

Novel germline hMSH2 genomic deletion and somatic hMSH2 mutations in a hereditary nonpolyposis colorectal cancer family.

Germline and somatic mutations of the hMSH2 gene were determined in a Japanese hereditary nonpolyposis colorectal cancer (HNPCC) family fulfilling the Amsterdam criteria. PCR-SSCP-sequencing of genomic DNA detected a somatic hMSH2 mutation of an A deletion at codon 227-229 in a duodenal carcinoma and a somatic hMSH2 mutation of an A insertion at codon 21 in a gastric carcinoma from affected family members, both carcinomas exhibiting high microsatellite instability. However, no germline hMSH2 mutation was detected by the PCR-SSCP-sequencing method. Genomic DNA was then analyzed by Southern blot hybridization using three hMSH2 cDNA probes (probe A involving exons 1-5, probe B involving exons 4-11 and probe C involving exons 9-16) after digestion by restriction enzymes, EcoRI, HindIII and NsiI. The NsiI digest of DNA from normal tissues of affected members exhibited an aberrant 8.6 kb restriction fragment, in addition to the normal 10.6 kb fragment, when hybridized to probes A and B. This suggested the presence of a heterozygous 2kb genomic deletion encompassing exon 4, 5 or 6. RT-PCR-sequencing revealed that the deleted region encompassed exon 5. This novel genomic deletion of the hMSH2 gene was confirmed to be pathogenic, and the Southern hybridization pattern was applied to the pre-symptomatic diagnosis.

Adolescent↗
PubMed2005

Somatic PTPN11 mutations in childhood acute myeloid leukaemia.

Somatic mutations in PTPN11, the gene encoding the transducer SHP-2, have emerged as a novel class of lesions that upregulate RAS signalling and contribute to leukaemogenesis. In a recent study of 69 children and adolescents with de novo acute myeloid leukaemia (AML), we documented a non-random distribution of PTPN11 mutations among French-American-British (FAB) subtypes. Lesions were restricted to FAB-M5 cases, where they were relatively common (four of 12 cases). Here, we report on the results of a molecular screening performed on 181 additional unselected patients, enrolled in participating institutions of the Associazione Italiana Ematologia Oncologia Pediatrica-AML Study Group, to provide a more accurate picture of the prevalence, spectrum and distribution of PTPN11 mutations in childhood AML and to investigate their clinical relevance. We concluded that PTPN11 defects do not represent a frequent event in this heterogeneous group of malignancies (4.4%), although they recur in a considerable percentage of patients with FAB-M5 (18%). PTPN11 lesions rarely occur in other subtypes. Within the FAB-M5 group no clear association of PTPN11 mutations with any clinical variable was evident. Nearly two third of the patients with this subtype were found to harbour an activating mutation in PTPN11, NRAS, KRAS2 or FLT3.

Acute Disease↗
PubMed1997

Somatic hypermutation: mutations 3' of rabbit VDJ H-chain genes.

VDJ genes of rabbit B cells are diversified by a somatic gene conversion-like mechanism in which V(H) gene segments 5' of the VDJ gene serve as donors. To assess whether somatic mutation also contributes to Ab diversification in the rabbit, we searched for mutations 3' of VDJ genes because mutations in this region presumably result from somatic mutation rather than gene conversion. We PCR-amplified and cloned the region extending 534 bp 3' of VDJ genes from splenic DNA of young and adult rabbits. Results of nucleotide sequence analysis of the clones revealed a high mutation frequency (2.4%) within the first 120 bp downstream of VDJ genes. This frequency decreased rapidly with increasing distance 3' of the VDJ genes. The mutations demonstrated both strand bias and dinucleotide preferences characteristic of somatic hypermutation. We conclude that Ab diversity in rabbit is generated not only by somatic gene conversion but also by somatic hypermutation.

Amino Acid Sequence↗
PubMed2006

Germinal center-independent affinity maturation in tumor necrosis factor receptor 1-deficient mice.

Germinal centers (GCs) have been identified as site at which the somatic mutation of immunoglobulins occurs.However, somatic mutations in immunoglobulins have also been observed in animals that normally do not harbor germinal centers. This clearly indicates that somatic mutations can occur in the absence of germinal centers. We therefore attempted to determine whether or not GCs exist in TNFR1-deficient mice, and are essential for the somatic mutation of immunoglobulins, using (4-hydroxy-3-nitropheny)acetyl-ovalbumin (NP-OVA). Both wild-type and TNFR1-deficient mice were immunized with NPOVA, and then examined with regard to the existence of GCs. No typical B-cell follicles were detected in the TNFR1-deficient mice. Cell proliferation was detected throughout all splenic tissue types, and no in vivo immunecomplex retention was observed in the TNFR1-deficient mice. All of these data strongly suggest that no GCs were formed in the TNFR1-deficient mice. Although TNFR1-deficient mice are unable to form GCs, serological analyses indicated that affinity maturation had been achieved in both the wild-type and TNFR1-deficient mice. We therefore isolated and sequenced several DNA clones from wild-type and the TNFR1-deficient mice. Eight out of 12 wild-type clones, and 11 out of 14 clones of the TNFR-1-deficient mice contained mutations at the CDR1 site. Thus, the wild-type and TNFR1-deficient mice were not extremely different with regard to types and rates of somatic mutation. Also, high-affinity antibodies were detected in both types of mice. Collectively, our data appear to show that affinity maturation may occur in TNFR1-deficient mice, which completely lack GCs.

Animals↗
PubMed1995

MDM2 overexpression is rare in ovarian carcinoma irrespective of TP53 mutation status.

Somatic mutations in TP53 are seen in many human cancers. In addition, the protein product of the wild-type TP53 can be sequestered by the protein MDM2 (murine double minute 2). This protein is commonly overexpressed in human sarcomas and gliomas, usually as a result of gene amplification. In this study, 43 ovarian carcinomas (OCs) were analysed for aberrations in the TP53 gene by immunohistochemistry (IHC), loss of heterozygosity (LOH) or mutation analysis. The MDM2 gene and its product was studied by Southern blotting and IHC. Over 50% of the OCs studied showed mutations in TP53 by either direct sequencing (19/36, 53%), positive IHC (23,43, 53%) or both, whereas 0/32 had amplification of MDM2 and only 1/37 tumours had positive IHC using the anti-MDM2 antibody IF-2. The solitary example of positive IHC in this series was seen in a mixed müllerian tumour with sarcomatous differentiation and was not accompanied by MDM2 DNA amplification. These results support previous data showing that around 50% of OCs have mutations in TP53 and in addition, suggest that MDM2 is not amplified in OC, but the presence of sarcomatous features in mixed müllerian tumours may result in positive immunohistochemistry with IF-2.

Chromosome Deletion↗
PubMed2006

A hypermutation phenotype and somatic MSH6 mutations in recurrent human malignant gliomas after alkylator chemotherapy.

Malignant gliomas have a very poor prognosis. The current standard of care for these cancers consists of extended adjuvant treatment with the alkylating agent temozolomide after surgical resection and radiotherapy. Although a statistically significant increase in survival has been reported with this regimen, nearly all gliomas recur and become insensitive to further treatment with this class of agents. We sequenced 500 kb of genomic DNA corresponding to the kinase domains of 518 protein kinases in each of nine gliomas. Large numbers of somatic mutations were observed in two gliomas recurrent after alkylating agent treatment. The pattern of mutations in these cases showed strong similarity to that induced by alkylating agents in experimental systems. Further investigation revealed inactivating somatic mutations of the mismatch repair gene MSH6 in each case. We propose that inactivating somatic mutations of MSH6 confer resistance to alkylating agents in gliomas in vivo and concurrently unleash accelerated mutagenesis in resistant clones as a consequence of continued exposure to alkylating agents in the presence of defective mismatch repair. The evidence therefore suggests that when MSH6 is inactivated in gliomas, alkylating agents convert from induction of tumor cell death to promotion of neoplastic progression. These observations highlight the potential of large scale sequencing for revealing and elucidating mutagenic processes operative in individual human cancers.

Aged↗
PubMed2003

Novel succinate dehydrogenase subunit B (SDHB) mutations in familial phaeochromocytomas and paragangliomas, but an absence of somatic SDHB mutations in sporadic phaeochromocytomas.

Phaeochromocytomas arising in adrenal or extra-adrenal sites and paragangliomas of the head and neck, in particular of the carotid bodies, occur sporadically and also in a familial setting. In addition to mutations in RET and VHL in familial disease, germline mutations in SDHD and SDHB genes that encode subunits of mitochondrial complex II have also been associated with the development of familial phaeochromocytomas. To further investigate the role of SDHD and SDHB in the development of these tumours we determined the occurrence of germline SDHD and SDHB mutations in four patients with a family history of phaeochromocytoma with associated head and neck paraganglioma, one patient with a family history of phaeochromocytoma only and two patients with apparently sporadic extra-adrenal phaeochromocytoma, one of whom had early onset disease. Secondly, we investigated whether somatic SDHB mutations correlated with loss of heterozygosity at 1p36 in a subgroup of 11 sporadic and three MEN 2-associated RET-mutation-positive phaeochromocytomas. Novel SDHB mutations were identified in the probands from four families and two apparently sporadic cases (six of seven probands studied), including two missense mutations, a single nonsense and frameshift mutation, as well as two splice site mutations, one of which was shown to have partial penetrance resulting in 'leaky' splicing. Further, five intronic polymorphisms in SDHB were found. No SDHD mutations were identified. In addition, no somatic SDHB mutations were found in the remaining allele of the 11 sporadic adrenal phaeochromocytomas with allelic loss at 1p36 or the three MEN 2-associated RET-mutation-positive phaeochromocytomas. Therefore, we conclude that SDHB has a major role in the pathogenesis of familial phaeochromocytomas, but the possible role of SDHB in sporadic tumours showing allelic loss at 1p36 has yet to be ascertained.

Adolescent↗