A network-based, integrative study to identify core biological pathways that drive breast cancer clinical subtypes.

BACKGROUND: The rapid collection of diverse genome-scale data raises the urgent need to integrate and utilise these resources for biological discovery or biomedical applications. For example, diverse transcriptomic and gene copy number variation data are currently collected for various cancers, but relatively few current methods are capable to utilise the emerging information. METHODS: We developed and tested a data-integration method to identify gene networks that drive the biology of breast cancer clinical subtypes. The method simultaneously overlays gene expression and gene copy number data on protein-protein interaction, transcriptional-regulatory and signalling networks by identifying coincident genomic and transcriptional disturbances in local network neighborhoods. RESULTS: We identified distinct driver-networks for each of the three common clinical breast cancer subtypes: oestrogen receptor (ER)+, human epidermal growth factor receptor 2 (HER2)+, and triple receptor-negative breast cancers (TNBC) from patient and cell line data sets. Driver-networks inferred from independent datasets were significantly reproducible. We also confirmed the functional relevance of a subset of randomly selected driver-network members for TNBC in gene knockdown experiments in vitro. We found that TNBC driver-network members genes have increased functional specificity to TNBC cell lines and higher functional sensitivity compared with genes selected by differential expression alone. CONCLUSION: Clinical subtype-specific driver-networks identified through data integration are reproducible and functionally important.

Pulmonary periarterial inflammation in fatal asthma.

BACKGROUND: To date, little information has been available about pulmonary artery pathology in asthma. The pulmonary artery supplies the distal parts of the lungs and likely represents a site of immunological reaction in allergic inflammation. The objective of this study was to describe the inflammatory cell phenotype of pulmonary artery adventitial inflammation in lung tissue from patients who died of asthma. METHODS: We quantified the different inflammatory cell types in the periarterial region of small pulmonary arteries in lung tissue from 22 patients who died of asthma [fatal asthma (FA)] and 10 control subjects. Using immunohistochemistry and image analysis, we quantified the cell density for T lymphocytes (CD3, CD4, CD8), B lymphocytes (CD20), eosinophils, mast cells (chymase and tryptase), and neutrophils in the adventitial layer of pulmonary arteries with a diameter smaller than 500 microm. RESULTS: Our data (median/interquartile range) demonstrated increased cell density of mast cells [FA=271.8 (148.7) cells/mm2; controls=177.0 (130.3) cells/mm2, P=0.026], eosinophils [FA=23.1 (58.6) cells/mm2; controls=0.0 (2.3) cells/mm2, P=0.012], and neutrophils [FA=50.4 (85.5) cells/mm2; controls=2.9 (30.5) cells/mm2, P=0.009] in the periarterial space in FA. No significant differences were found for B and T lymphocytes or CD4+ or CD8+ subsets. Chymase/tryptase positive (MCCT) mast cells predominated over tryptase (MCT) mast cells in the perivascular arterial space in both asthma patients and controls [MCCT/(MCCT+MCT)=0.91 (0-1) in FA and 0.75 (0-1) in controls, P=0.86]. CONCLUSIONS: Our results show that the adventitial layer of the pulmonary artery participates in the inflammatory process in FA, demonstrating increased infiltration of mast cells, eosinophils, and neutrophils, but not of T and B lymphocytes.

Curative resection of colorectal adenocarcinoma: multivariate analysis of 5-year follow-up.

The purpose of this study was to evaluate the influence of clinicopathologic factors on colorectal cancer, especially the age factor. From 1986 to 1992 a total of 2082 cases of colorectal cancers underwent operation in our institution. After exclusion of familial adenomatous polyposis, multiple cancer, Dukes' D stage, and nonadenocarcinoma patients, there were 1124 patients with single colorectal adenocarcinoma who had undergone curative operation; 1110 cases were included in the study after exclusion of surgical mortalities (14 cases, 1.2%). Age distribution ranged from 19 to 91 years (mean 58 years). The patients were divided into three age groups: < 40 years (grade 1), 40-69 years (grade 2), >/= 70 years (grade 3); other clinicopathologic factors including gender, tumor gross type, location, pathology, and stage were also evaluated in the study. The colonic/rectal cancer ratio was 1.00:1.74, and that of the male/female distribution was 1.00:0.84. The overall 5-year cancer-free rate was 69.9% after curative resection. The young age (< 40 years) patients comprised more women (53.6%) and had a colon location in 41%. Although they had a higher percentage of scirrhous type lesions (1.8%), worse histology (17%), and more advanced stage (49.1%) than the older groups, their survival rate was only slightly lower than the other two groups (67% vs. 70% and 72%, respectively), which was not statistically significant (p = 0.83). By univariate analysis, the factors that influenced the 5-year cancer-free rate were gender (p = 0.031), tumor location (p = 0.003), gross type (p = 0.000), pathology (p = 0.000), and stage (p = 0.001). The independent factors determined for the 5-year cancer-free rate after multivariate analysis were similar to those assessed by univariate analysis. There 5-year survival of colorectal adenocarcinoma was not poorer in young patients. Poor survival factors were male gender, rectal location, scirrhous type, poor and mucinous histology, and advanced stage (Dukes' C) found at curative resection for colorectal adenocarcinoma.