83 research outputs found
Evolution of DNA methylome from precancerous lesions to invasive lung adenocarcinomas
The evolution of DNA methylome and methylation intra-tumor heterogeneity (ITH) during early carcinogenesis of lung adenocarcinoma has not been systematically studied. We perform reduced representation bisulfite sequencing of invasive lung adenocarcinoma and its precursors, atypical adenomatous hyperplasia, adenocarcinoma in situ and minimally invasive adenocarcinoma. We observe gradual increase of methylation aberrations and significantly higher level of methylation ITH in later-stage lesions. The phylogenetic patterns inferred from methylation aberrations resemble those based on somatic mutations suggesting parallel methylation and genetic evolution. De-convolution reveal higher ratio of T regulatory cells (Tregs) versus CD8 + T cells in later-stage diseases, implying progressive immunosuppression with neoplastic progression. Furthermore, increased global hypomethylation is associated with higher mutation burden, copy number variation burden and AI burden as well as higher Treg/CD8 ratio, highlighting the potential impact of methylation on chromosomal instability, mutagenesis and tumor immune microenvironment during early carcinogenesis of lung adenocarcinomas
Immune evolution from preneoplasia to invasive lung adenocarcinomas and underlying molecular features
The mechanism by which anti-cancer immunity shapes early carcinogenesis of lung adenocarcinoma (ADC) is unknown. In this study, we characterize the immune contexture of invasive lung ADC and its precursors by transcriptomic immune profiling, T cell receptor (TCR) sequencing and multiplex immunofluorescence (mIF). Our results demonstrate that anti-tumor immunity evolved as a continuum from lung preneoplasia, to preinvasive ADC, minimally-invasive ADC and frankly invasive lung ADC with a gradually less effective and more intensively regulated immune response including down-regulation of immune-activation pathways, up-regulation of immunosuppressive pathways, lower infiltration of cytotoxic T cells (CTLs) and anti-tumor helper T cells (Th), higher infiltration of regulatory T cells (Tregs), decreased T cell clonality, and lower frequencies of top T cell clones in later-stages. Driver mutations, chromosomal copy number aberrations (CNAs) and aberrant DNA methylation may collectively impinge host immune responses and facilitate immune evasion, promoting the outgrowth of fit subclones in preneoplasia into dominant clones in invasive ADC
Multi-region exome sequencing reveals genomic evolution from preneoplasia to lung adenocarcinoma
There has been a dramatic increase in the detection of lung nodules, many of which are
preneoplasia atypical adenomatous hyperplasia (AAH), adenocarcinoma in situ (AIS), minimally
invasive adenocarcinoma (MIA) or invasive adenocarcinoma (ADC). The molecular landscape
and the evolutionary trajectory of lung preneoplasia have not been well defined. Here, we
perform multi-region exome sequencing of 116 resected lung nodules including AAH (n = 22),
AIS (n = 27), MIA (n = 54) and synchronous ADC (n = 13). Comparing AAH to AIS, MIA and
ADC, we observe progressive genomic evolution at the single nucleotide level and demarcated
evolution at the chromosomal level supporting the early lung carcinogenesis model from AAH
to AIS, MIA and ADC. Subclonal analyses reveal a higher proportion of clonal mutations in
AIS/MIA/ADC than AAH suggesting neoplastic transformation of lung preneoplasia is
predominantly associated with a selective sweep of unfit subclones. Analysis of multifocal
pulmonary nodules from the same patients reveal evidence of convergent evolution
Genome-wide association analysis identified splicing single nucleotide polymorphism in CFLAR predictive of triptolide chemo-sensitivity
COllege math: a blue print for choosing the best school for you
This book is intended for use as a workbook and guide in the process of choosing a college. This book inclides thirteen worksheet, each building on the preceding on
Advanced Data Analytics for Clinical Research Part II: Application to Cardiothoracic Surgery
- …