We conducted comprehensive integrative molecular analyses of the complete set of tumors in The Cancer Genome Atlas (TCGA), consisting of approximately 10,000 specimens and representing 33 types of cancer. We performed molecular clustering using data on chromosome-arm-level aneuploidy, DNA hypermethylation, mRNA, and miRNA expression levels and reverse-phase protein arrays, of which all, except for aneuploidy, revealed clustering primarily organized by histology, tissue type, or anatomic origin. The influence of cell type was evident in DNA-methylation-based clustering, even after excluding sites with known preexisting tissue-type-specific methylation. Integrative clustering further emphasized the dominant role of cell-of-origin patterns. Molecular similarities among histologically or anatomically related cancer types provide a basis for focused pan-cancer analyses, such as pan-gastrointestinal, pan-gynecological, pan-kidney, and pan-squamous cancers, and those related by stemness features, which in turn may inform strategies for future therapeutic development.
Approximately 20% of patients diagnosed with a phaeochromocytoma or paraganglioma carry a germline mutation in one of the succinate dehydrogenase (SDHx) genes (SDHA, SDHB, SDHC and SDHD), which encode the four subunits of the SDH enzyme. When a pathogenic SDHx mutation is identified in an affected patient, genetic counselling is proposed for first-degree relatives. Optimal initial evaluation and follow-up of people who are asymptomatic but might carry SDHx mutations have not yet been agreed. Thus, we established an international consensus algorithm of clinical, biochemical and imaging screening at diagnosis and during surveillance for both adults and children. An international panel of 29 experts from 12 countries was assembled, and the Delphi method was used to reach a consensus on 41 statements. This Consensus Statement covers a range of topics, including age of first genetic testing, appropriate biochemical and imaging tests for initial tumour screening and follow-up, screening for rare SDHx-related tumours and management of elderly people who have an SDHx mutation. This Consensus Statement focuses on the management of asymptomatic SDHx mutation carriers and provides clinicians with much-needed guidance. The standardization of practice will enable prospective studies in the near future.
Correspondence Pr. J. Bertherat´Service des Maladies Endocriniennes et MØtaboliques, Hôpital Cochin, Pavillon Cornil2 7, rue du Faubourg Saint−Jacques´75014, Paris´France´Phone: +33 (1) 58 41 18 95´Fax: +33 (1) 46 33 80 60É −Abstract Recent advances in the molecular genetic of adrenal tumors give new insights in the pathophysiology of these neoplasms in both hereditary and sporadic cases. The practice of genetic counsel− ling in patients with adrenal tumors have been recently changed by the identification and the understanding of new specific her− editary cancer susceptibility syndromes.In the case of sporadic adrenocortical tumors these progress also offer new prognosis predictors.The genetic predisposition to adrenocortical cancer in children has been well established in the Li−Fraumeni and Beckewith−Wiedeman syndromes due to germline p53 mutation located at 17p13 and dysregulation of the imprinted IGF−2 locus at 11p15, respectively. Adrenocortical tumors are also observed in Multiple Endocrine Neoplasia type I syndrome. Cushing's syn− drome due to primary pigmented nodular adrenocortical disease have been observed in patients with germline PRKAR1A inacti− vating mutations. Interestingly allelic loss at 17p13 and 11p15 have been observed in sporadic adrenocortical cancer and so− matic PRKAR1A mutations in secreting adrenocortical adeno− mas. The potential interest of these finding for the diagnosis of these tumors will be discussed. In the case of pheochromocyto− ma and paraganglioma, the demonstration that three genes en− coding three succinate dehydrogenase subunits (SDHD, SDHB, SDHC), belonging to the complex II of the respiratory chain in the mitochondria, are involved in the genetics of familial and especially in apparently sporadic phaeochromocytomas have dramatically modified our practice. Up to date, four diagnosis of familal disease (multiple endocrine neoplasia type II, von Hippel Lindau disease, neurofibromatosis type 1 and hereditary para− ganglioma) should be discussed and causative mutations in six different phaechomocytoma susceptibility genes (RET, VHL, NF1, SDHB, SDHD, SDHC) could be identified. In this review, we will perform an update compiling these new clinical, genetic and functional data recently published. We will suggest guidelines for the practice of the phaeochomocytoma genetic testing in the patients and their families, and for an early detection of tumors in the patients or in individuals determined to be at−risk of dis− ease by the presymptomatic genetic testing Key wordsAdrenocortical tumor´Li−Fraumeni syndrome´Beckwith−Wie− demann syndrome´Multiple endocrine neoplasia type 1´Carney complex´Paraganglioma´Pheochromocytoma
Purpose To evaluate genotype-phenotype associations in individuals carrying germline variants of TMEM127, a poorly known gene that confers susceptibility to pheochromocytoma (PHEO) and paraganglioma (PGL) Design Data collected from a registry of probands with TMEM127 variants, published reports and public databases Main outcome analysis clinical, genetic and functional associations Results The cohort comprised 110 index patients (111 variants) with a mean age of 45 (range, 21-84 years). Females were predominant (76 vs. 34, P<0.001). Most patients had PHEO (n=94; 85.5%), although PGL (n=10; 9%) and renal cell carcinoma (RCC, n=6; 5.4%) were also detected, either alone or in combination with PHEO. One-third of the cases had multiple tumors and known family history was reported in 15.4%. Metastatic PHEO/PGL was rare (2.8%). Epinephrine alone, or combined with norepinephrine, accounted for 82% of the catecholamine profiles of PHEO/PGLs. Most variants (n=63) occurred only once and 13 were recurrent (2-12 times). Although non-truncating variants were less frequent than truncating changes overall, they were predominant in non-PHEO clinical presentations (36% PHEOs vs. 69% other, P<0.0001) and clustered disproportionately within transmembrane regions (P<0.01), underscoring the relevance of these domains for TMEM127 function. Integration of clinical and previous experimental data supported classification of variants into four groups based on mutation type, localization and predicted disruption. Conclusions Patients with TMEM127 variants often resemble sporadic nonmetastatic PHEOs. PGL and RCC may also co-occur, although their causal link requires further evaluation. We propose a new classification to predict variant pathogenicity and assist with carrier surveillance.
BackgroundsThe incidence of germline mutations in the newly discovered cryptic exon (E1’) of VHL gene in patients with von Hippel-Lindau (VHL) disease and in patients with paraganglioma or pheochromocytoma (PPGL) is not currently known.MethodsWe studied a large international multicentre cohort of 1167 patients with a previous negative genetic testing. Germline DNA from 75 patients with a single tumour of the VHL spectrum (‘Single VHL tumour’ cohort), 70 patients with multiple tumours of the VHL spectrum (‘Multiple VHL tumours’ cohort), 76 patients with a VHL disease as described in the literature (‘VHL-like’ cohort) and 946 patients with a PPGL were screened for E1’ genetic variants.ResultsSix different genetic variants in E1' were detected in 12 patients. Two were classified as pathogenic, 3 as variants of unknown significance and 1 as benign. The rs139622356 was found in seven unrelated patients but described in only 16 patients out of the 31 390 of the Genome Aggregation Database (p<0.0001) suggesting that this variant might be either a recurrent mutation or a modifier mutation conferring a risk for the development of tumours and cancers of the VHL spectrum.ConclusionsVHL E1’ cryptic exon mutations contribute to 1.32% (1/76) of ‘VHL-like’ cohort and to 0.11% (1/946) of PPGL cohort and should be screened in patients with clinical suspicion of VHL, and added to panels for Next Generation Sequencing (NGS) diagnostic testing of hereditary PPGL. Our data highlight the importance of studying variants identified in deep intronic sequences, which would have been missed by examining only coding sequences of genes/exomes. These variants will likely be more frequently detected and studied with the upcoming implementation of whole-genome sequencing into clinical practice.
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