We conducted comprehensive integrative molecular analyses of the complete set of tumors in The Cancer Genome Atlas (TCGA), consisting of approximately 10,000 specimens and representing 33 types of cancer. We performed molecular clustering using data on chromosome-arm-level aneuploidy, DNA hypermethylation, mRNA, and miRNA expression levels and reverse-phase protein arrays, of which all, except for aneuploidy, revealed clustering primarily organized by histology, tissue type, or anatomic origin. The influence of cell type was evident in DNA-methylation-based clustering, even after excluding sites with known preexisting tissue-type-specific methylation. Integrative clustering further emphasized the dominant role of cell-of-origin patterns. Molecular similarities among histologically or anatomically related cancer types provide a basis for focused pan-cancer analyses, such as pan-gastrointestinal, pan-gynecological, pan-kidney, and pan-squamous cancers, and those related by stemness features, which in turn may inform strategies for future therapeutic development.
Summary We report a comprehensive analysis of 412 muscle-invasive bladder cancers characterized by multiple TCGA analytical platforms. Fifty-eight genes were significantly mutated, and the overall mutational load was associated with APOBEC-signature mutagenesis. Clustering by mutation signature identified a high-mutation subset with 75% 5-year survival. mRNA expression clustering refined prior clustering analyses and identified a poor-survival ‘neuronal’ subtype in which the majority of tumors lacked small cell or neuroendocrine histology. Clustering by mRNA, lncRNA, and miRNA expression converged to identify subsets with differential epithelial-mesenchymal transition status, carcinoma-in-situ scores, histologic features, and survival. Our analyses identified 5 expression subtypes that may stratify response to different treatments.
Cholangiocarcinoma (CCA) is a hepatobiliary malignancy exhibiting high incidence in countries with endemic liver-fluke infection. We analysed 489 CCAs from 10 countries, combining whole-genome (71 cases), targeted/exome, copy-number, gene expression, and DNA methylation information. Integrative clustering defined four CCA clusters – Fluke-Positive CCAs (Clusters 1/2) are enriched in ERBB2 amplifications and TP53 mutations, conversely Fluke-Negative CCAs (Clusters 3/4) exhibit high copy-number alterations and PD-1/PD-L2 expression, or epigenetic mutations (IDH1/2, BAP1) and FGFR/PRKA-related gene rearrangements. Whole-genome analysis highlighted FGFR2 3′UTR deletion as a mechanism of FGFR2 upregulation. Integration of non-coding promoter mutations with protein-DNA binding profiles demonstrates pervasive modulation of H3K27me3-associated sites in CCA. Clusters 1 and 4 exhibit distinct DNA hypermethylation patterns targeting either CpG islands or shores – mutation signature and subclonality analysis suggests that these reflect different mutational pathways. Our results exemplify how genetics, epigenetics and environmental carcinogens can interplay across different geographies to generate distinct molecular subtypes of cancer.
Despite recent advances in the diagnosis and treatment of head and neck cancer, there has been little evidence of improvement in 5-year survival rates over the last few decades. To determine more accurate trends in site-specific outcomes as opposed to a more general overview of head and neck cancer patients, we analyzed the site-specific data collected in the Surveillance, Epidemiology, Population-based cancer statistics in the United States (US) for 2004 is expected to yield 28,260 new cases of oral cavity and pharynx cancer and 20,260 new cases of larynx cancer, with a mortality of 7,230 and 3,830 deaths per year, respectively. 1 Despite improvements in diagnosis and treatment, in the last 3 decades there have been no changes in the 5-year survival rate for larynx cancer patients and only a slight but significant improvement for oral cavity and pharynx cancer patients when comparing patients treated during 1973-1977 (5-year survival rate of 53%) to patients treated during 1993-1997 (5-year survival rate of 56%) according to results based on data from the Surveillance, Epidemiology, and End Results (SEER) program of the National Cancer Institute. 2 This slight change in survival was first noted in the 2002 publication, 2 but these data can still be interpreted as indicating that "there is no change in prognosis for the last 2 decades" for head and neck cancer (HNC). However, during the last 2 decades many articles have consistently demonstrated advances in treatment, most notably the use of combination therapy (adjuvant radiotherapy after surgery, concurrent chemotherapy and radiotherapy) with improvements in survival rates.  In addition, improvements in radiotherapy and perioperative care, as well as prevention of chemotherapy-related complications, have resulted in increased quality of life and decreased treatment-related mortality. 6 Another important factor that may influence survival includes lead-time bias. New technologies such as fiberoptic laryngoscopy, more widespread dental professional screening for oral cancer and higher-resolution radiological techniques may result in earlier stage diagnosis for some tumors, as well as more accurate staging. 7-9 Such improvements in diagnosis may also occur in a site-specific manner.In addition, treatment for head and neck cancer has evolved and become site-specific with treatment modalities individualized for specific anatomic sites and stages. 4,6 Therefore, analysis of head and neck cancer as a group may obscure important differences in survival trends for site-specific tumors that are dependent upon site-specific treatment advances.For all historical periods, specific head and neck cancer sites have had very different treatment approaches and more importantly, different 5-year survival rates. For example, lip cancer has a 5-year survival rate over 80%, while hypopharynx cancer survival rates reach only about 30%. 4 It is also possible that the stage and site distribution of cancer cases has changed over time. Unfortunately, conventional methods of ...
Recapitulation of lung development from human pluripotent stem cells (hPSCs) in three dimensions (3D) would allow deeper insight into human development, as well as the development of innovative strategies for disease modeling, drug discovery and regenerative medicine1. We report here the generation from hPSCs of lung bud organoids (LBOs) that contain mesoderm and pulmonary endoderm and develop into branching airway and early alveolar structures after xenotransplantation and in Matrigel 3D culture. Expression analysis and structural features indicated that the branching structures reached the second trimester of human gestation. Infection in vitro with respiratory syncytial virus, which causes small airway obstruction and bronchiolitis in infants2, led to swelling, detachment and shedding of infected cells into the organoid lumens, similar to what has been observed in human lungs3. Introduction of mutation in HPS1, which causes an early-onset form of intractable pulmonary fibrosis4,5, led to accumulation of extracellular matrix and mesenchymal cells, suggesting the potential use of this model to recapitulate fibrotic lung disease in vitro. LBOs therefore recapitulate lung development and may provide a useful tool to model lung disease.
SUMMARY Renal cell carcinoma (RCC) is not a single disease, but several histologically defined cancers with different genetic drivers, clinical courses, and therapeutic responses. The current study evaluated 843 RCC from the three major histologic subtypes, including 488 clear cell RCC, 274 papillary RCC, and 81 chromophobe RCC. Comprehensive genomic and phenotypic analysis of the RCC subtypes reveals distinctive features of each subtype that provide the foundation for the development of subtype-specific therapeutic and management strategies for patients affected with these cancers. Somatic alteration of BAP1, PBRM1, and PTEN and altered metabolic pathways correlated with subtype-specific decreased survival, while CDKN2A alteration, increased DNA hypermethylation, and increases in the immune-related Th2 gene expression signature correlated with decreased survival within all major histologic subtypes. CIMP-RCC demonstrated an increased immune signature, and a uniform and distinct metabolic expression pattern identified a subset of metabolically divergent (MD) ChRCC that associated with extremely poor survival.
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