Molecular characterization of novel germline deletions affecting SDHD and SDHC in pheochromocytoma and paraganglioma patients

Bayley, Jean Pierre; Weiss, Marjan M.; Grimbergen, Anneliese; Brussel, Bernadette T J van; Hes, Frederik J.; Jansen, Jeroen C.; Verhoef, Senno; Devilee, Peter; Corssmit, Eleonora P M; Vriends, Annette H. J. T.

doi:10.1677/erc-09-0084

Cited by 16 publications

(12 citation statements)

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“…Both MLPA [67] and similar multiplex PCR methods [68] have been applied in SDH deletion analysis, and have led to the recognition that deletions can represent up to 10% of all mutations [69]. …”

Section: New Strategies In Mutation Analysismentioning

confidence: 99%

Recent advances in the genetics of SDH-related paraganglioma and pheochromocytoma

Hensen

Bayley

2010

Familial Cancer

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The last 10 years have seen enormous progress in the field of paraganglioma and pheochromocytoma genetics. The identification of the first gene related to paraganglioma, SDHD, encoding a subunit of mitochondrial succinate dehydrogenase (SDH), was quickly followed by the identification of mutations in SDHC and SDHB. Very recently several new SDH-related genes have been discovered. The SDHAF2 gene encodes an SDH co-factor related to the function of the SDHA subunit, and is currently exclusively associated with head and neck paragangliomas. SDHA itself has now also been identified as a paraganglioma gene, with the recent identification of the first mutation in a patient with extra-adrenal paraganglioma. Another SDH-related co-factor, SDHAF1, is not currently known to be a tumor suppressor, but may shed some light on the mechanisms of tumorigenesis. An entirely novel gene associated with adrenal pheochromocytoma, TMEM127, suggests that other new paraganglioma susceptibility genes may await discovery. In addition to these recent discoveries, new techniques related to mutation analysis, including genetic analysis algorithms, SDHB immunohistochemistry, and deletion analysis by MLPA have improved the efficiency and accuracy of genetic analysis. However, many intriguing questions remain, such as the striking differences in the clinical phenotype of genes that encode proteins with an apparently very close functional relationship, and the lack of expression of SDHD and SDHAF2 mutations when inherited via the maternal line. Little is still known of the origins and causes of truly sporadic tumors, and the role of oxygen in the relationships between high-altitude, familial and truly sporadic paragangliomas remains to be elucidated.

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Section: New Strategies In Mutation Analysismentioning

confidence: 99%

Recent advances in the genetics of SDH-related paraganglioma and pheochromocytoma

Hensen

Bayley

2010

Familial Cancer

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“…In 2007, Pasini et al reported in some familial GIST patients, germline mutations in the succinate dehydrogenase subunits SDHB, SDHC, and SDHD [21]; SDH mutations had been previously reported in patients with familial paraganglioma [22]. SDH subunit A mutations have also recently been implicated in GIST [Pantaleo MA, JNCI 2011; Pantaleo MA, Am J Surg Pathol 2011][23].…”

Section: Introductionmentioning

confidence: 99%

Survival of gastrointestinal stromal tumor patients in the imatinib era: life raft group observational registry

et al. 2012

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Background Gastrointestinal stromal tumors (GIST), one of the most common mesenchymal tumors of the gastrointestinal tract, prior to routine immunohistochemical staining and the introduction of tyrosine kinase inhibitors, were often mistaken for neoplasms of smooth muscle origin such as leiomyomas, leiomyosarcomas or leiomyoblastomas. Since the advent of imatinib, GIST has been further delineated into adult- (KIT or PDGFRα mutations) and pediatric- (typified by wild-type GIST/succinate dehydrogenase deficiencies) types. Using varying gender ratios at age of diagnosis we sought to elucidate prognostic factors for each sub-type and their impact on overall survival. Methods This is a long-term retrospective analysis of a large observational study of an international open cohort of patients from a GIST research and patient advocacy's lifetime registry. Demographic and disease-specific data were voluntarily supplied by its members from May 2000-October 2010; the primary outcome was overall survival. Associations between survival and prognostic factors were evaluated by univariate Cox proportional hazard analyses, with backward selection at P < 0.05 used to identify independent factors. Results Inflections in gender ratios by age at diagnosis in years delineated two distinct groups: above and below age 35 at diagnosis. Closer analysis confirmed the above 35 age group as previously reported for adult-type GIST, typified by mixed primary tumor sites and gender, KIT or PDGFRα mutations, and shorter survival times. The pediatric group (< age 18 at diagnosis) was also as previously reported with predominantly stomach tumors, females, wild-type GIST or SDH mutations, and extended survival. "Young adults" however formed a third group aged 18-35 at diagnosis, and were a clear mix of these two previously reported distinct sub-types. Conclusions Pediatric- and adult-type GIST have been previously characterized in clinical settings and these observations confirm significant prognostic factors for each from a diverse real-world cohort. Additionally, these findings suggest that extra diligence be taken with "young adults" (aged 18-35 at diagnosis) as pediatric-type GIST may present well beyond adolescence, particularly as these distinct sub-types have different causes, and consequently respond differently to treatments.

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“…For example, MIRb is one of the enriched repeat elements. MIRb insertion was reported to be involved in paraganglioma and pheochromocytoma which are associated with germline mutation of the tumour suppressor genes [32]. …”

Section: Resultsmentioning

confidence: 99%

Genome-wide analysis of human hotspot intersected genes highlights the roles of meiotic recombination in evolution and disease

Zhou

et al. 2013

BMC Genomics

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BackgroundMeiotic recombination events are not randomly located, but rather cluster at hotspot regions. Recently, the fine-scale mapping of genome-wide human recombination hotspots was performed. Here, we systematically analyzed the evolutionary and disease-associated features of hotspots that overlapped with protein-coding genes.ResultsIn this study, we defined hotspot intersected genes as HI genes. We found that HI genes were prone to be located in the extracellular part and were functionally enriched in cell-to-cell communication. Tissue-specific genes and secreted protein encoding genes were overrepresented in HI genes, while housekeeping genes were underrepresented. Compared to slowly evolving housekeeping genes and random genes with lower recombination rates, HI genes evolved faster. The fact that brain and blood specific genes were overrepresented in HI genes indicates that they may be involved in the evolution of human intelligence and the immune system. We also found that genes related to disease were enriched in HI genes, especially genes with disease-associated chromosomal rearrangements. Hotspot sequence motifs were overrepresented in common sequences of HI genes and genes with disease-associated chromosomal rearrangements. We further listed repeat elements that were enriched both in hotspots and genes with disease-associated chromosomal rearrangements.ConclusionHI genes are evolving and may be involved in the generation of key features of human during evolution. Disease-associated genes may be by-products of meiotic recombination. In addition, hotspot sequence motifs and repeat elements showed the connection between meiotic recombination and genes with disease-associated chromosomal rearrangements at the sequence level. Our study will enable us to better understand the evolutionary and biological significance of human meiotic recombination.

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Molecular characterization of novel germline deletions affecting SDHD and SDHC in pheochromocytoma and paraganglioma patients

Cited by 16 publications

References 36 publications

Recent advances in the genetics of SDH-related paraganglioma and pheochromocytoma

Recent advances in the genetics of SDH-related paraganglioma and pheochromocytoma

Survival of gastrointestinal stromal tumor patients in the imatinib era: life raft group observational registry

Genome-wide analysis of human hotspot intersected genes highlights the roles of meiotic recombination in evolution and disease

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