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To address the biological heterogeneity of lung cancer, we studied 199 lung adenocarcinomas by integrating genome-wide data on copy number alterations and gene expression with full annotation for major known somatic mutations in this cancer. This showed non-random patterns of copy number alterations significantly linked to EGFR and KRAS mutation status and to distinct clinical outcomes, and led to the discovery of a striking association of EGFR mutations with underexpression of DUSP4, a gene within a broad region of frequent single-copy loss on 8p. DUSP4 is involved in negative feedback control of EGFR signaling, and we provide functional validation for its role as a growth suppressor in EGFR-mutant lung adenocarcinoma. DUSP4 loss also associates with p16/CDKN2A deletion and defines a distinct clinical subset of lung cancer patients. Another novel observation is that of a reciprocal relationship between EGFR and LKB1 mutations. These results highlight the power of integrated genomics to identify candidate driver genes within recurrent broad regions of copy number alteration and to delineate distinct oncogenetic pathways in genetically complex common epithelial cancers.Oncogene (2009) 28, 2773–2783; doi:10.1038/onc.2009.135; published online 15 June 2009 [ABSTRACT FROM AUTHOR]

Background: Breast cancer sentinel lymph nodes (SLNs) with metastases (mets) are often palpably enlarged. We hypothesized that the volume of the SLN and the size of mets are directly related. SLNs harboring mets are often firm, with increased intra-nodal pressure (INP), and we hypothesized that SLN volume, as well as INP, would correlate directly with SLN metastasis size. Methods: The SLN volume, INP and met size were measured in 296 SLNs and compared using linear regression analysis. The SLNs were subsequently grouped based upon pN stage. SLN INP and volume were compared between these resultant groups. Results: Increased SLN volume significantly predicted increased SLN met size on univariate and multivariate analysis (p = 0.001 and p = 0.011, respectively). SLN met size predicted increased SLN INP on both univariate and multivariate analysis (both p = 0.001). SLN volume only significantly correlated with increased SLN INP on univariate analysis (p = 0.001). On subgroup analysis of nodal disease, pNl/2/3 nodes (SLN met sizes >2 mm) were significantly larger (p = 0.039 and p = 0.003, respectively) than pNO and pNl(mi) nodes, and had significantly increased INP (all p = 0.001) as compared to pNO, pNO(i+), and pNl(mi) nodes. Conclusions: SLN volume and INP increased with increasing SLN met size. The threshold met size for this increase was >2 mm (pNl disease). [ABSTRACT FROM AUTHOR]

Background: Breast cancer sentinel lymph nodes (SLNs) with metastases (mets) are often palpably enlarged. We hypothesized that the volume of the SLN and the size of mets are directly related. SLNs harboring mets are often firm, with increased intra-nodal pressure (INP), and we hypothesized that SLN volume, as well as INP, would correlate directly with SLN metastasis size. Methods: The SLN volume, INP and met size were measured in 296 SLNs and compared using linear regression analysis. The SLNs were subsequently grouped based upon pN stage. SLN INP and volume were compared between these resultant groups. Results: Increased SLN volume significantly predicted increased SLN met size on univariate and multivariate analysis (p =0.001 and p =0.011, respectively). SLN met size predicted increased SLN INP on both univariate and multivariate analysis (both p =0.001). SLN volume only significantly correlated with increased SLN INP on univariate analysis (p =0.001). On subgroup analysis of nodal disease, pN1/2/3 nodes (SLN met sizes >2 mm) were significantly larger (p =0.039 and p =0.003, respectively) than pN0 and pN1(mi) nodes, and had significantly increased INP (all p =0.001) as compared to pN0, pN0(i+), and pN1(mi) nodes. Conclusions: SLN volume and INP increased with increasing SLN met size. The threshold met size for this increase was >2 mm (pN1 disease). [ABSTRACT FROM AUTHOR]

The biological significance of DNA methylation in the regulation of gene expression and its role in cancer is increasingly recognized. The underlying hypothesis of this study is that strategic global approaches will identify aberrantly methylated genes that underlie the pathogenesis of ER-negative (ER-) breast cancer (BC). We used the Infinium HumanMethylation450 BeadChip to profile the methylome of ER- breast cancers. The 450K array includes 485,577 cytosine positions of the human genome. From these cytosine sites, 99.3% are CpG dinucleotides. Whole genomic DNA from 20 primary ER- and 8 normal breast tissue samples were assayed for genome-wide methylation using the Illumina 450K array. We had 8634 hypermethylated CpGs or 1.8% of the 485,577 sites on the 450K array. The proportion with hypermethylation was higher for promoter regions (2.1% vs 1.5%), and highest for the "FirstExon" promoter subregion. Of the 8634 CpGs, 2980 (adjusted p = 0.05) were differentially methylated between tumor and normal samples. This resulted in 206 genes with significant hypermethylation (all mean breast cancer betas >= -0.2, and ratio of tumor to normal mean beta >= 2.0). Estrogen receptor-negative BC is a more aggressive form than ER positive BC with approximately double the incidence in African Americans than in Caucasian Americans. The emerging differential methylation pattern within hormone receptor negative breast cancers would further help stratify them into distinct subgroups. Promotor methylation being potentially reversible, methylated genes may serve as future molecular targets for demethylating therapies. [ABSTRACT FROM AUTHOR]