Whole-exome sequencing identifies somatic ATRX mutations in pheochromocytomas and paragangliomas

Fishbein, Lauren; Khare, Sanika; Wubbenhorst, Bradley; DeSloover, Daniel; D’Andrea, Kurt; Merrill, Shana L.; Cho, Nam Woo; Greenberg, Roger A.; Else, Tobias; Montone, Kathleen T.; LiVolsi, Virginia A.; Fraker, Douglas L.; Daber, Robert; Cohen, Debbie L.; Nathanson, Katherine L.

doi:10.1038/ncomms7140

Cited by 161 publications

(150 citation statements)

References 44 publications

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“…The MET gene, previously known to cause hereditary papillary renal cancer 95 , was also found to be mutated in PPGLs 14,96 . Finally, somatic mutations in chromatin remodelling genes are recurrently detected in renal carcinomas and PPGLs 14,[96][97][98] .…”

Section: Discussionmentioning

confidence: 99%

Consensus Statement on next-generation-sequencing-based diagnostic testing of hereditary phaeochromocytomas and paragangliomas

et al. 2016

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Phaeochromocytomas and paragangliomas (PPGLs) are neural-crest-derived tumours of the sympathetic or parasympathetic nervous system that are often inherited and are genetically heterogeneous. Genetic testing is recommended for patients with these tumours and for family members of patients with hereditary forms of PPGLs. Due to the large number of susceptibility genes implicated in the diagnosis of inherited PPGLs, next-generation sequencing (NGS) technology is ideally suited for carrying out genetic screening of these individuals. This Consensus Statement, formulated by a study group comprised of experts in the field, proposes specific recommendations for the use of diagnostic NGS in hereditary PPGLs. In brief, the study group recommends target gene panels for screening of germ line DNA, technical adaptations to address different modes of disease transmission, orthogonal validation of NGS findings, standardized classification of variant pathogenicity and uniform reporting of the findings. The use of supplementary assays, to aid in the interpretation of the results, and sequencing of tumour DNA, for identification of somatic mutations, is encouraged. In addition, the study group launches an initiative to develop a gene-centric curated database of PPGL variants, with annual re-evaluation of variants of unknown significance by an expert group for purposes of reclassification and clinical guidance.

Funding Agencies|Cancer Prevention and Research Institute of Texas (CPRIT) [RP101202, RP57154]; Department of Defense [CDMRP W81XWH-12-1-0508]; Voelcker Fund; National Institutes of Health (NIH)s National Center for Research Resources; National Center for Advancing Translational Sciences [8UL1TR000149]; INSERM; French National Cancer Institute (INCA); Direction Generale de lOffre de Soins (DGOS); INCA [INCA-DGOS_8663]; European Union [633983]; Brazilian National Council for Scientific and Technological Development (CNPq); Cancer Research for PErsonalized Medicine (CARPEM); ERC Advanced Researcher Award

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Section: Discussionmentioning

confidence: 99%

Consensus Statement on next-generation-sequencing-based diagnostic testing of hereditary phaeochromocytomas and paragangliomas

et al. 2016

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“…Several genes have also been suggested to work as the disease modifiers of PCC and PGL. ATRX have been identified in a subset of malignant PCC and PGL having the alternative lengthening of telomeres phenotype (117). TERT promoter mutations have been identified to occur exclusively in succinate dehydrogenase deficient PGL (118,119).…”

Section: Pcc and Pglsmentioning

confidence: 99%

“…Somatic mutations in TSC2 occur frequently in pancreatic NETs (80). Overview of mutational burden in NETs merged from raw data in (80,85,86,87,98,99,100,104,117,120,121,122,128,136,137). Each dot represents a unique tumor, and the line shows the median number of mutations of each category.…”

Section: Tuberous Sclerosis Complexmentioning

confidence: 99%

GEP- NETS UPDATE: Genetics of neuroendocrine tumors

Crona

Skogseid

2016

European Journal of Endocrinology

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Neuroendocrine tumors (NETs) are a heterogeneous group of neoplasms, arising from neuroendocrine cells that are dispersed throughout the body. Around 20% of NETs occur in the context of a genetic syndrome. Today there are at least ten recognized NET syndromes. This includes the classical syndromes: multiple endocrine neoplasias types 1 and 2, and von Hippel-Lindau and neurofibromatosis type 1. Additional susceptibility genes associated with a smaller fraction of NETs have also been identified. Recognizing genetic susceptibility has proved essential both to provide genetic counseling and to give the best preventive care. In this review we will also discuss the knowledge of somatic genetic alterations in NETs. At least 24 genes have been implicated as drivers of neuroendocrine tumorigenesis, and the overall rates of genomic instability are relatively low. Genetic intra-tumoral, as well as inter-tumoral heterogeneity in the same patient, have also been identified. Together these data point towards the common pathways in NET evolution, separating early from late disease drivers. Although knowledge of specific mutations in NETs has limited impact on actual patient management, we predict that in the near future genomic profiling of tumors will be included in the clinical arsenal for diagnostics, prognostics and therapeutic decisions.

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“…Subsequent studies have reported frequent ATRX loss (but not DAXX loss) in astrocytoma, leiomyosarcoma, dedifferentiated liposarcoma and other tumor types, and the loss of ATRX has been highly correlated with the alternative lengthening of telomeres phenotype. 6,12,13,[17][18][19][20][21] However, knockdown of ATRX or DAXX has not led to alternative lengthening of telomeres, and patients with germline ATRX mutations do not appear to be cancer prone. 18,22 In addition, although loss of either ATRX or DAXX is perfectly associated with alternative lengthening of telomeres in pancreatic neuroendocrine tumors, the situation is more complex in sarcomas.…”

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confidence: 99%

Comprehensive screening of alternative lengthening of telomeres phenotype and loss of ATRX expression in sarcomas

et al. 2015

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According to cytogenetic aberrations, sarcomas can be categorized as complex or simple karyotype tumors. Alternative lengthening of telomeres is a telomere-maintenance mechanism common in sarcomas. Recently, this mechanism was found to be associated with loss of either α-thalassemia/mental retardation syndrome X-linked (ATRX) or death domain-associated (DAXX) protein. We previously reported that alternative lengthening of telomeres and loss of ATRX expression were common in leiomyosarcoma, angiosarcoma, pleomorphic liposarcoma, and dedifferentiated liposarcoma. In the present study, we screened an additional 245 sarcomas of other types to determine the prevalence of alternative lengthening of telomeres, loss of ATRX/DAXX expression, and their relationship. Undifferentiated pleomorphic sarcomas were frequently alternative lengthening of telomeres positive (65%) and loss of ATRX was seen in approximately half of the alternative lengthening of telomeres-positive tumors. Nineteen of 25 myxofibrosarcomas were alternative lengthening of telomerespositive, but only one was ATRX deficient. Three of 15 radiation-associated sarcomas were alternative lengthening of telomeres positive, but none of them was ATRX deficient. Alternative lengthening of telomeres and/or loss of ATRX were uncommon in malignant peripheral nerve sheath tumors, gastrointestinal stromal tumors, and embryonal rhabdomyosarcomas. By contrast, none of the 71 gene fusion-associated sarcomas was ATRX deficient or alternative lengthening of telomeres positive. All tumors exhibited preserved DAXX expression. Combining our previous studies and this study, a total of 384 sarcomas with complex karyotypes were examined, 83 of which were ATRX deficient (22%). By telomere-specific fluorescence in situ hybridization, 45% (138/308) were alternative lengthening of telomeres positive, 55% (76/138) of which were ATRX deficient. Loss of ATRX was highly associated with alternative lengthening of telomeres (Po 0.001). We conclude that alternative lengthening of telomeres is a frequent telomere-maintenance mechanism in cytogenetically complex sarcomas. Loss of ATRX is highly associated with this feature.

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Whole-exome sequencing identifies somatic ATRX mutations in pheochromocytomas and paragangliomas

Cited by 161 publications

References 44 publications

Consensus Statement on next-generation-sequencing-based diagnostic testing of hereditary phaeochromocytomas and paragangliomas

Consensus Statement on next-generation-sequencing-based diagnostic testing of hereditary phaeochromocytomas and paragangliomas

GEP- NETS UPDATE: Genetics of neuroendocrine tumors

Comprehensive screening of alternative lengthening of telomeres phenotype and loss of ATRX expression in sarcomas

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