Genomic landscape of paediatric adrenocortical tumours

Pinto, Emília M.; Chen, Xiang; Easton, John; Finkelstein, David; Liu, Zhifa; Pounds, Stanley; Rodríguez‐Galindo, Carlos; Lund, Troy C.; Mardis, Elaine R.; Wilson, Richard K.; Boggs, Kristy; Yergeau, Donald; Cheng, Jinjun; Mulder, Heather L.; Manne, Jayanthi; Jenkins, Jesse J.; Mastellaro, Maria José; Figueiredo, Bonald C.; Dyer, Michael A.; Pappo, Alberto S.; Zhang, Jinghui; Downing, James R.; Ribeiro, Raul C.; Zambetti, Gerard P.

doi:10.1038/ncomms7302

Cited by 168 publications

(187 citation statements)

References 49 publications

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“…External data were downloaded from the European Genome-Phenome Archive (EGA; https://www.ebi.ac.uk/ega/home) using the accession numbers EGAD00001000085, EGAD00001000135, EGAD00001000159, EGAD00001000160, EGAD00001000161, EGAD00001000162, EGAD00001000163, EGAD00001000164, EGAD00001000165, EGAD00001000259, EGAD00001000260, EGAD00001000261, EGAD00001000268, and EGAD00001000269 [49][50][51][52][53][54][55][56][57][58][59][60][61][62] ; internal datasets are related to previous PMIDs 27748748, 27479119, 26923874, 25670083, 25253770, 24972766, 24553142, 25135868, 26632267, 26179511, 24651015, 28726821, 23817572, 25962120, 26294725 17,19,44,63-74 (Supplementary Note 1).…”

Section: Methodsmentioning

confidence: 99%

“…Ninety-five per cent of the patients were under 18 years of age (or age unspecified but confirmed age group paediatric), but available data were included for patients up to 25 years, as these were considered relevant for cancer types that typically peak at a young age. All centres have approved data access and informed consent had been obtained from all patients.External data were downloaded from the European Genome-Phenome Archive (EGA; https://www.ebi.ac.uk/ega/home) using the accession numbers EGAD00001000085, EGAD00001000135, EGAD00001000159, EGAD00001000160, EGAD00001000161, EGAD00001000162, EGAD00001000163, EGAD00001000164, EGAD00001000165, EGAD00001000259, EGAD00001000260, EGAD00001000261, EGAD00001000268, and EGAD00001000269 [49][50][51][52][53][54][55][56][57][58][59][60][61][62] ; internal datasets are related to previous PMIDs 27748748, 27479119, 26923874, 25670083, 25253770, 24972766, 24553142, 25135868, 26632267, 26179511, 24651015, 28726821, 23817572, 25962120, 26294725 17,19,44,63-74 (Supplementary Note 1).The final cohort included 914 individual patients of no more than 25 years of age including primary tumours for 879 patients with 47 matched relapsed tumours, and an additional 35 independent relapsed tumours ( Supplementary Tables 1, 2). Deep-sequencing (~ 30× ) whole-genome data (WGS) were available for 547 samples with matched control, whole-exome sequencing (WES) for 414, and low-coverage whole-genome sequencing (lcWGS) for an additional 54 germline and 186 tumour samples.…”

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confidence: 99%

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The landscape of genomic alterations across childhood cancers

Gröbner¹,

Worst²,

Weischenfeldt³

et al. 2018

Nature

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The landscape of genomic alterations across childhood cancers a list of authors and affiliations appears at the end of the paper. OPENPan-cancer analyses that examine commonalities and differences among various cancer types have emerged as a powerful way to obtain novel insights into cancer biology. Here we present a comprehensive analysis of genetic alterations in a pan-cancer cohort including 961 tumours from children, adolescents, and young adults, comprising 24 distinct molecular types of cancer. Using a standardized workflow, we identified marked differences in terms of mutation frequency and significantly mutated genes in comparison to previously analysed adult cancers. Genetic alterations in 149 putative cancer driver genes separate the tumours into two classes: small mutation and structural/copy-number variant (correlating with germline variants). Structural variants, hyperdiploidy, and chromothripsis are linked to TP53 mutation status and mutational signatures. Our data suggest that 7-8% of the children in this cohort carry an unambiguous predisposing germline variant and that nearly 50% of paediatric neoplasms harbour a potentially druggable event, which is highly relevant for the design of future clinical trials.Cure rates for childhood cancers have increased to about 80% in recent decades, but cancer is still the leading cause of death by disease in the developed world among children over one year of age 1,2 . Furthermore, many children who survive cancer suffer from long-term sequelae of surgery, cytotoxic chemotherapy, and radiotherapy, including mental disabilities, organ toxicities, and secondary cancers 3 . A crucial step in developing more specific and less damaging therapies is the unravelling of the complete genetic repertoire of paediatric malignancies, which differ from adult malignancies in terms of their histopathological entities and molecular subtypes 4 . Over the past few years, many entityspecific sequencing efforts have been launched, but the few paediatric pan-cancer studies thus far have focused only on mutation frequencies, germline predisposition, and alterations in epigenetic regulators [4][5][6] .We have carried out a broad exploration of cancers in children, adolescents, and young adults, by incorporating small mutations and copy-number or structural variants on somatic and germline levels, and by identifying putative cancer genes and comparing them to those previously reported in adult cancers by The Cancer Genome Atlas (TCGA) 7 . We have also examined mutational signatures and potential drug targets. The compendium of genetic alterations presented here is available to the scientific community at http://www.pedpancan.com.This integrative analysis includes 24 types of cancer and covers all major childhood cancer entities, many of which occur exclusively in children 8 (Fig. 1, Supplementary Table 1). Ninety-five per cent of the patients in this study were diagnosed during childhood or adolescence (aged 18 years or younger) and 5% as young adults (up to 25 years) (Extended Data ...

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Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

The landscape of genomic alterations across childhood cancers

Gröbner¹,

Worst²,

Weischenfeldt³

et al. 2018

Nature

Self Cite

1,175

1,156

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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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“…Among HLA class II antigens, HLA-DPA1 expression was most significantly associated with DFS after adjustment for tumor weight and stage (Pinto et al 2016). Integrative analysis of genomic alterations of pediatric ACT identified a highrisk group characterized by concomitant TP53 and ATRX mutations, massive structural variations and frequent background mutations and higher expression of genes associated with chromosome instability and cell cycle (Pinto et al 2015). A recent study in pediatric ACT showed that an elevated KI67 LI and MKI67 overexpression are associated with reduced DFS.…”

Section: Markers Of Malignancy Are Different In Pediatric Act Comparementioning

confidence: 99%

The next step: mechanisms driving adrenocortical carcinoma metastasis

Lalli

Luconi²

2018

Endocrine-Related Cancer

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Endocrine tumors have the peculiarity to become clinically evident not only due to symptoms related to space occupation by the growing lesion, similarly to most other tumors, but also, and most often, because of their specific hormonal secretion, which significantly contributes to their pathological burden. Malignant endocrine tumors, in addition, have the ability to produce distant metastases. Here, we critically review the current knowledge about mechanisms and biomarkers characterizing the metastatic process in adrenocortical carcinoma (ACC), a rare endocrine malignancy with a high risk of relapse and metastatization even when the primary tumor is diagnosed and surgically removed at an early stage. We highlight perspectives of future research in the domain and possible new therapeutic avenues based on targeting factors having an important role in the metastatic process of ACC.

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Genomic landscape of paediatric adrenocortical tumours

Cited by 168 publications

References 49 publications

The landscape of genomic alterations across childhood cancers

The landscape of genomic alterations across childhood cancers

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

The next step: mechanisms driving adrenocortical carcinoma metastasis

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