RESUMO
The original version of this Article omitted a declaration from the competing interests statement, which should have included the following: 'K.P.W. is President of Tempus Lab, Inc., Chicago, IL, USA'. This has now been corrected in both the PDF and HTML versions of the Article.
RESUMO
The original version of this Article contained an error in the author affiliations. The affiliation of Kevin P. White with Tempus Labs, Inc., Chicago, IL, USA was inadvertently omitted.This has now been corrected in both the PDF and HTML versions of the Article.
RESUMO
Homozygous deletions are rare in cancers and often target tumour suppressor genes. Here, we build a compendium of 2218 primary tumours across 12 human cancer types and systematically screen for homozygous deletions, aiming to identify rare tumour suppressors. Our analysis defines 96 genomic regions recurrently targeted by homozygous deletions. These recurrent homozygous deletions occur either over tumour suppressors or over fragile sites, regions of increased genomic instability. We construct a statistical model that separates fragile sites from regions showing signatures of positive selection for homozygous deletions and identify candidate tumour suppressors within those regions. We find 16 established tumour suppressors and propose 27 candidate tumour suppressors. Several of these genes (including MGMT, RAD17, and USP44) show prior evidence of a tumour suppressive function. Other candidate tumour suppressors, such as MAFTRR, KIAA1551, and IGF2BP2, are novel. Our study demonstrates how rare tumour suppressors can be identified through copy number meta-analysis.
Assuntos
Deleção de Genes , Genes Supressores de Tumor , Neoplasias/genética , Alelos , Sítios Frágeis do Cromossomo/genética , Dosagem de Genes , Genoma Humano , Homozigoto , Humanos , Ploidias , Telômero/metabolismoRESUMO
Combined analyses of molecular data, such as DNA copy-number alteration, mRNA and protein expression, point to biological functions and molecular pathways being deregulated in multiple cancers. Genomic, metabolomic and clinical data from various solid cancers and model systems are emerging and can be used to identify novel patient subgroups for tailored therapy and monitoring. The integrative genomics methodologies that are used to interpret these data require expertise in different disciplines, such as biology, medicine, mathematics, statistics and bioinformatics, and they can seem daunting. The objectives, methods and computational tools of integrative genomics that are available to date are reviewed here, as is their implementation in cancer research.
Assuntos
Biologia Computacional/métodos , Genômica , Neoplasias/genética , Neoplasias/metabolismo , Teorema de Bayes , Análise por Conglomerados , Estudos de Coortes , Metilação de DNA , Dosagem de Genes , Humanos , MicroRNAs/metabolismo , Mutação , Proteômica/métodos , RNA Mensageiro/metabolismo , Fatores de Risco , Software , Biologia de SistemasRESUMO
Angiosarcoma is an aggressive malignancy that arises spontaneously or secondarily to ionizing radiation or chronic lymphoedema. Previous work has identified aberrant angiogenesis, including occasional somatic mutations in angiogenesis signaling genes, as a key driver of angiosarcoma. Here we employed whole-genome, whole-exome and targeted sequencing to study the somatic changes underpinning primary and secondary angiosarcoma. We identified recurrent mutations in two genes, PTPRB and PLCG1, which are intimately linked to angiogenesis. The endothelial phosphatase PTPRB, a negative regulator of vascular growth factor tyrosine kinases, harbored predominantly truncating mutations in 10 of 39 tumors (26%). PLCG1, a signal transducer of tyrosine kinases, encoded a recurrent, likely activating p.Arg707Gln missense variant in 3 of 34 cases (9%). Overall, 15 of 39 tumors (38%) harbored at least one driver mutation in angiogenesis signaling genes. Our findings inform and reinforce current therapeutic efforts to target angiogenesis signaling in angiosarcoma.