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1.
Proc Natl Acad Sci U S A ; 115(42): E9879-E9888, 2018 10 16.
Artigo em Inglês | MEDLINE | ID: mdl-30287485

RESUMO

Cancer genomics has enabled the exhaustive molecular characterization of tumors and exposed hepatocellular carcinoma (HCC) as among the most complex cancers. This complexity is paralleled by dozens of mouse models that generate histologically similar tumors but have not been systematically validated at the molecular level. Accurate models of the molecular pathogenesis of HCC are essential for biomedical progress; therefore we compared genomic and transcriptomic profiles of four separate mouse models [MUP transgenic, TAK1-knockout, carcinogen-driven diethylnitrosamine (DEN), and Stelic Animal Model (STAM)] with those of 987 HCC patients with distinct etiologies. These four models differed substantially in their mutational load, mutational signatures, affected genes and pathways, and transcriptomes. STAM tumors were most molecularly similar to human HCC, with frequent mutations in Ctnnb1, similar pathway alterations, and high transcriptomic similarity to high-grade, proliferative human tumors with poor prognosis. In contrast, TAK1 tumors better reflected the mutational signature of human HCC and were transcriptionally similar to low-grade human tumors. DEN tumors were least similar to human disease and almost universally carried the Braf V637E mutation, which is rarely found in human HCC. Immune analysis revealed that strain-specific MHC-I genotype can influence the molecular makeup of murine tumors. Thus, different mouse models of HCC recapitulate distinct aspects of HCC biology, and their use should be adapted to specific questions based on the molecular features provided here.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/genética , Perfilação da Expressão Gênica , Genômica/métodos , Neoplasias Hepáticas Experimentais/genética , Neoplasias Hepáticas/genética , Animais , Carcinoma Hepatocelular/patologia , Modelos Animais de Doenças , Humanos , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas Experimentais/patologia , Camundongos , Camundongos Endogâmicos C57BL , Transcriptoma
2.
Pac Symp Biocomput ; 24: 148-159, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30864318

RESUMO

Natural killer (NK) cells have increasingly become a target of interest for immunotherapies. NK cells express killer immunoglobulin-like receptors (KIRs), which play a vital role in immune response to tumors by detecting cellular abnormalities. The genomic region encoding the 16 KIR genes displays high polymorphic variability in human populations, making it difficult to resolve individual genotypes based on next generation sequencing data. As a result, the impact of polymorphic KIR variation on cancer phenotypes has been understudied. Currently, labor-intensive, experimental techniques are used to determine an individual's KIR gene copy number profile. Here, we develop an algorithm to determine the germline copy number of KIR genes from whole exome sequencing data and apply it to a cohort of nearly 5000 cancer patients. We use a k-mer based approach to capture sequences unique to specific genes, count their occurrences in the set of reads derived from an individual and compare the individual's k-mer distribution to that of the population. Copy number results demonstrate high concordance with population copy number expectations. Our method reveals that the burden of inhibitory KIR genes is associated with survival in two tumor types, highlighting the potential importance of KIR variation in understanding tumor development and response to immunotherapy.


Assuntos
Dosagem de Genes , Neoplasias/genética , Neoplasias/imunologia , Receptores KIR/genética , Algoritmos , Biologia Computacional/métodos , Bases de Dados Genéticas/estatística & dados numéricos , Feminino , Antígenos de Histocompatibilidade Classe I/metabolismo , Humanos , Estimativa de Kaplan-Meier , Células Matadoras Naturais/imunologia , Neoplasias/mortalidade , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/imunologia , Neoplasias do Colo do Útero/mortalidade , Neoplasias Uterinas/genética , Neoplasias Uterinas/imunologia , Neoplasias Uterinas/mortalidade , Sequenciamento do Exoma
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