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PDF file - 107K, Significantly expressed genes in regions that are cytogenetically associated with copy-number aberrations in aberrant versus diploid tumors as based by GSEA and integration of protein data

PDF file - 28K, Broad regions of gains and losses in at least 5% of cases (n=154).

PDF file - 50K, Significantly expressed genes located on the 3p and 5q chromosomal arms among aberrant versus normal kidney and integration of protein and miRNA data in ccRCC

PDF file - 30K, Select genes significantly methylated in tumor versus normal kidney in regions associated with copy-number aberrations

PDF file - 34K, Significantly expressed proteins encoded by genes in regions that are cytogenetically associated with copy-number aberrations in aberrant versus diploid tumors

PDF file - 34K, microRNAs expressed concordantly with copy-number aberrations

PDF file - 74K, Copy-number results in relation to results of previous studies

Supplementary Methods from Multilevel Whole-Genome Analysis Reveals Candidate Biomarkers in Clear Cell Renal Cell Carcinoma

County-based health care financial assistance programs offer improved access to health care for indigent populations by reducing or eliminating costs to receive care. We examined health care financial assistance programs serving the 10 most populous U.S. counties. We found that the percent enrollment in a county's program is strongly correlated with the percent uninsured (r=.86) and the percent undocumented (r=.83), and moderately correlated with the percent indigent (r=.43) in a county, suggesting the importance of health care financial assistance programs for these groups. Furthermore, the typical county-based health care financial assistance program covers the same income range (0-138% federal poverty level) and offers similar benefits (including coverage of emergency care and inpatient care) as Medicaid. Counseling services are frequently available to assist applicants. These characteristics allow them to serve as an alternative source of health care funding to those who are ineligible for Medicaid coverage.

Some small businesses and entrepreneurs find it challenging to interact with the U.S. National Aeronautics and Space Agency (NASA). In 2016, the Small Business Innovation Research and Smal...

Renal cell carcinoma (RCC) is the most common neoplasm of the kidney. We conducted an integrated analysis of copy number, gene expression (mRNA and miRNA), protein expression, and methylation changes in clear cell renal cell carcinoma (ccRCC). We used a stepwise approach to identify the most significant copy number aberrations (CNA) and identified regions of peak and broad copy number gain and loss, including peak gains (3q21, 5q32, 5q34-q35, 7p11, 7q21, 8q24, 11q13, and 12q14) and deletions (1p36, 2q34-q37, 3p25, 4q33-q35, 6q23-q27, and 9p21). These regions harbor novel tumor-related genes and miRNAs not previously reported in renal carcinoma. Integration of genome-wide expression data and gene set enrichment analysis revealed 75 gene sets significantly altered in tumors with CNAs compared with tumors without aberration. We also identified genes located in peak CNAs with concordant methylation changes (hypomethylated in copy number gains such as STC2 and CCND1 and hypermethylated in deletions such as CLCNKB, VHL, and CDKN2A/2B). For other genes, such as CA9, expression represents the net outcome of opposing forces (deletion and hypomethylation) that also significantly influences patient survival. We also validated the prognostic value of miRNA let-7i in RCCs. miR-138, located in chromosome 3p deletion, was also found to have suppressive effects on tumor proliferation and migration abilities. Our findings provide a significant advance in the delineation of the ccRCC genome by better defining the impact of CNAs in conjunction with methylation changes on the expression of cancer-related genes, miRNAs, and proteins and their influence on patient survival. Cancer Res; 72(20); 5273–84. ©2012 AACR.

Kallikrein-related peptidase 5 (KLK5) displays aberrant expression in cancer. Recently, we showed KLK5 reconstitution in breast cancer cell lines suppresses malignancy. Present study aims to investigate the functional KLK5 mediated miRNA network on breast cancer progression, molecular subtype and survival. 28 miRNAs were up-regulated and 62 miRNAs were down-regulated upon KLK5 expression. Extracellular matrix (ECM) molecules and cell-adhesion pathways were the most significant KLK5-induced miRNA-mediated regulatory targets. Validation from The Cancer Genome Atlas (TCGA) database indicated KLK5 was specifically down-regulated in luminal B and basal-like breast cancer subtypes. There was a correlation between KLK5, miRNAs and their downstream ECM gene targets. Long-term patient survival correlated with dysregulation of KLK5 and interacting ECM target genes. It suggests biological differences between breast cancer molecular subtypes, patient survival, and their propensity for invasion and metastasis can be explained in part by altered miRNA networks induced by KLK5 dysregulation. We provide the first evidence that KLK5 can affect miRNA networks, which regulate MMPs and other novel ECM targets and a new compelling hypothesis of interplay between serine proteases and miRNAs. We developed a combined KLK5-(ITGB1+COL12A1) predictive score for recurrence-free survival that could be exploited in clinical applications.

The kallikrein-related peptidases (KLKs) have been implicated in many types of cancer, including prostate and ovarian.We performed a comprehensive in silico study to characterize the KLK locus using transcriptomic (gene expression) and genomic (mutations and DNA copy number) data in prostate cancer (n=194), serous ovarian cancer (n=506), glioblastoma multiforme (n=206), and sarcoma (n=207) from The Cancer Genome Atlas and independent publicly available datasets to assess KLKs as cancer biomarkers.Overall, there was mRNA overexpression in prostate and serous ovarian cancer and decreased expression in glioblastoma multiforme. There was higher frequency of genomic loss in serous ovarian cancer, and rare KLK gene mutations observed in serous ovarian cancer and GBM. Dysregulation of KLKs correlates with survival: for prostate cancer, a combination of dysregulation of KLK1, 5 and 13 was associated with worse disease-free survival.We conclude that specific dysregulation of KLKs at the genetic and transcriptomic levels have useful prognostic value.

Renal cell carcinoma (RCC) accounts for 3% of all adult malignancies and currently no diagnostic marker exists. Kallikrein-related peptidases (KLKs) have been implicated in numerous cancers including ovarian, prostate, and breast carcinoma. KLKs 5, 6, 10, and 11 have decreased expression in RCC when compared to normal kidney tissue. Our bioinformatic analysis indicated that theKLK 1,6, and7genes have decreased expression in RCC. We experimentally verified these results and found that decreased expression ofKLKs 1and3were significantly associated with the clear cell RCC subtype (p