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1.
Proc Natl Acad Sci U S A ; 112(49): 15148-53, 2015 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-26575630

RESUMO

Aberrant transcription of the pericentromeric human satellite II (HSATII) repeat is present in a wide variety of epithelial cancers. In deriving experimental systems to study its deregulation, we observed that HSATII expression is induced in colon cancer cells cultured as xenografts or under nonadherent conditions in vitro, but it is rapidly lost in standard 2D cultures. Unexpectedly, physiological induction of endogenous HSATII RNA, as well as introduction of synthetic HSATII transcripts, generated cDNA intermediates in the form of DNA/RNA hybrids. Single molecule sequencing of tumor xenografts showed that HSATII RNA-derived DNA (rdDNA) molecules are stably incorporated within pericentromeric loci. Suppression of RT activity using small molecule inhibitors reduced HSATII copy gain. Analysis of whole-genome sequencing data revealed that HSATII copy number gain is a common feature in primary human colon tumors and is associated with a lower overall survival. Together, our observations suggest that cancer-associated derepression of specific repetitive sequences can promote their RNA-driven genomic expansion, with potential implications on pericentromeric architecture.


Assuntos
Centrômero/genética , DNA Satélite/genética , Neoplasias/genética , Sequências Repetitivas de Ácido Nucleico , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Humanos , Hibridização de Ácido Nucleico , RNA/genética
2.
Proc Natl Acad Sci U S A ; 111(43): 15544-9, 2014 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-25313082

RESUMO

Previous studies have established that a subset of head and neck tumors contains human papillomavirus (HPV) sequences and that HPV-driven head and neck cancers display distinct biological and clinical features. HPV is known to drive cancer by the actions of the E6 and E7 oncoproteins, but the molecular architecture of HPV infection and its interaction with the host genome in head and neck cancers have not been comprehensively described. We profiled a cohort of 279 head and neck cancers with next generation RNA and DNA sequencing and show that 35 (12.5%) tumors displayed evidence of high-risk HPV types 16, 33, or 35. Twenty-five cases had integration of the viral genome into one or more locations in the human genome with statistical enrichment for genic regions. Integrations had a marked impact on the human genome and were associated with alterations in DNA copy number, mRNA transcript abundance and splicing, and both inter- and intrachromosomal rearrangements. Many of these events involved genes with documented roles in cancer. Cancers with integrated vs. nonintegrated HPV displayed different patterns of DNA methylation and both human and viral gene expressions. Together, these data provide insight into the mechanisms by which HPV interacts with the human genome beyond expression of viral oncoproteins and suggest that specific integration events are an integral component of viral oncogenesis.


Assuntos
Genoma Humano/genética , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/virologia , Interações Hospedeiro-Patógeno/genética , Papillomaviridae/fisiologia , Sequência de Bases , Metilação de DNA/genética , Regulação Neoplásica da Expressão Gênica , Genes Neoplásicos , Humanos , Dados de Sequência Molecular , Integração Viral/genética
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