Supplementary Table 1, Figure Legends 1-5 from Integrative Microarray Analysis of Pathways Dysregulated in Metastatic Prostate Cancer

Supplementary Figure Legends 1-2, Methods from SLC45A3-ELK4 Is a Novel and Frequent Erythroblast Transformation–Specific Fusion Transcript in Prostate Cancer

Supplementary Figure 2 from Integrative Microarray Analysis of Pathways Dysregulated in Metastatic Prostate Cancer

Supplementary Figure 2 from TMPRSS2:ERG Fusion-Associated Deletions Provide Insight into the Heterogeneity of Prostate Cancer

Supplementary Figure 1 from SLC45A3-ELK4 Is a Novel and Frequent Erythroblast Transformation–Specific Fusion Transcript in Prostate Cancer

Supplementary Figure 2 from SLC45A3-ELK4 Is a Novel and Frequent Erythroblast Transformation–Specific Fusion Transcript in Prostate Cancer

Supplementary Tables 1-2, Supplementary Figures 1-2 from Genetic Variation of Genes Involved in Dihydrotestosterone Metabolism and the Risk of Prostate Cancer

Table S1. Minimally deleted regions (MDR) of recurrent deletions. Table S2. Clinical features of the patients in this study. Table S3. Overall survival is correlated with total copy number events and somatic mutations. Table S4. Details of the RPS15 mutations in this study. Figure S1. IGV Screen shot showing 17p deletions. Figure S2. Overview of CNAs in the tumor samples of 200 independent CLL patients. Figure S3. CNAs and somatic mutations in the 99 patients with both WES and SNP profiles. Figure S4. Analysis of TP53 and SF3B1 mutations. Figure S5. RPS15 mutations. Figure S6. GISTIC analysis discovered novel recurrent deletions in chromosomes 3p, 4p, 8p and 9p in del(17p) CLL. Figure S7. Associations of del(17p) and chromosomal deletions at 8p, 3p, 4p, and 9p. Figure S8. Overall survival in 17p patients with recurrent deletions. Figure S9. IGV screen shot showing 3p deletions. Figure S10. IGV screen shot showing 4p deletions. Figure S11. IGV screen shot showing 8p deletions. Figure S12. IGV screen shot showing 9p deletions. Figure S13. Association between CNAs and complex karyotype. Figure S14. Chromothripsis in del(17p) CLL samples. Figure S15. Sanger sequencing of TP53 with cnLOH at 17p.

Supplementary Figure 5 from Integrative Microarray Analysis of Pathways Dysregulated in Metastatic Prostate Cancer

Supplementary Figure 4 from Integrative Microarray Analysis of Pathways Dysregulated in Metastatic Prostate Cancer

Supplementary Figure 1 from Detection of Early Prostate Cancer Using a Hepsin-Targeted Imaging Agent

Supplementary Figure 3 from TMPRSS2:ERG Fusion-Associated Deletions Provide Insight into the Heterogeneity of Prostate Cancer

Supplementary Figure 1 from Integrative Microarray Analysis of Pathways Dysregulated in Metastatic Prostate Cancer

Supplementary Figure 1 from TMPRSS2:ERG Fusion-Associated Deletions Provide Insight into the Heterogeneity of Prostate Cancer

Supplementary Figure 3 from Integrative Microarray Analysis of Pathways Dysregulated in Metastatic Prostate Cancer

Germline copy number variants (CNVs) and single-nucleotide polymorphisms (SNPs) form the basis of inter-individual genetic variation. Although the phenotypic effects of SNPs have been extensively investigated, the effects of CNVs is relatively less understood. To better characterize mechanisms by which CNVs affect cellular phenotype, we tested their association with variable CpG methylation in a genome-wide manner. Using paired CNV and methylation data from the 1000 genomes and HapMap projects, we identified genome-wide associations by methylation quantitative trait locus (mQTL) analysis. We found individual CNVs being associated with methylation of multiple CpGs and vice versa. CNV-associated methylation changes were correlated with gene expression. CNV-mQTLs were enriched for regulatory regions, transcription factor-binding sites (TFBSs), and were involved in long-range physical interactions with associated CpGs. Some CNV-mQTLs were associated with methylation of imprinted genes. Several CNV-mQTLs and/or associated genes were among those previously reported by genome-wide association studies (GWASs). We demonstrate that germline CNVs in the genome are associated with CpG methylation. Our findings suggest that structural variation together with methylation may affect cellular phenotype.

Abstract Background MicroRNAs have recently emerged as promising circulating biomarkers in diverse cancer types, including ovarian cancer. We utilized conditional, doxycycline‐induced fallopian tube (FT)‐derived cancer models to identify changes in miRNA expression in tumors and plasma, and further validated the murine findings in high‐grade ovarian cancer patient samples. Methods We analyzed 566 biologically informative miRNAs in doxycycline‐induced FT and metastatic tumors as well as plasma samples derived from murine models bearing inactivation of Brca, Tp53, and Pten genes. We identified miRNAs that showed a consistent pattern of dysregulated expression and validated our results in human patient serum samples. Results We identified six miRNAs that were significantly dysregulated in doxycycline‐induced FTs (P < .05) and 130 miRNAs differentially regulated in metastases compared to normal fallopian tissues (P < .05). Furthermore, we validated miR‐21a‐5p, miR‐146a‐5p, and miR‐126a‐3p as dysregulated in both murine doxycycline‐induced FT and metastatic tumors, as well as in murine plasma and patient serum samples. Conclusions In summary, we identified changes in miRNA expression that potentially accompany tumor development in murine models driven by commonly found genetic alterations in cancer patients. Further studies are required to test both the function of these miRNAs in driving the disease and their utility as potential biomarkers for diagnosis and/or disease progression.

Abstract Purpose: Chronic lymphocytic leukemia (CLL) with 17p deletion typically progresses quickly and is refractory to most conventional therapies. However, some del(17p) patients do not progress for years, suggesting that del(17p) is not the only driving event in CLL progression. We hypothesize that other concomitant genetic abnormalities underlie the clinical heterogeneity of del(17p) CLL. Experimental Design: We profiled the somatic mutations and copy number alterations (CNA) in a large group of del(17p) CLLs as well as wild-type CLL and analyzed the genetic basis of their clinical heterogeneity. Results: We found that increased somatic mutation number associates with poor overall survival independent of 17p deletion (P = 0.003). TP53 mutation was present in 81% of del(17p) CLL, mostly clonal (82%), and clonal mutations with del(17p) exhibit shorter overall survival than subclonal mutations with del(17p) (P = 0.019). Del(17p) CLL has a unique driver mutation profile, including NOTCH1 (15%), RPS15 (12%), DDX3X (8%), and GPS2 (6%). We found that about half of del(17p) CLL cases have recurrent deletions at 3p, 4p, or 9p and that any of these deletions significantly predicts shorter overall survival. In addition, the number of CNAs, but not somatic mutations, predicts shorter time to treatment among patients untreated at sampling. Indolent del(17p) CLLs were characterized by absent or subclonal TP53 mutation and few CNAs, with no difference in somatic mutation number. Conclusions: We conclude that del(17p) has a unique genomic profile and that clonal TP53 mutations, 3p, 4p, or 9p deletions, and genomic complexity are associated with shorter overall survival. Clin Cancer Res; 23(3); 735–45. ©2016 AACR.

High-grade serous ovarian carcinoma (HGSC) presents significant clinical and therapeutic challenges. Emerging data from The Cancer Genome Atlas (TCGA) have identified a number of new genetic aberrations but their functional significance and the role they play in early tumorigenesis remains to be determined. In addition, identifying the key genetic lesions responsible for tumor initiation and the specific cell of origin is a priority for ovarian cancer research. Although the traditional model of carcinogenesis has focused on the ovary as a tumor initiation site, recent preclinical and clinical studies have suggested that there are additional sites of origin outside the ovary, namely fallopian tubal secretory epithelial cells (FTSECs). This new model of tumorigenesis has further identified novel entities in the fallopian tube epithelium that represent precursors to invasive carcinoma – the TP53 signature and serous tubal intraepithelial carcinoma (STIC). Identifying and characterizing the events leading to the development of TP53 signatures and STICs, the critical steps in their transition to malignancy, and novel methods for detecting this transition prior to cancer development are critical for cancer prevention and development of personalized approaches to therapy. We have successfully developed genetic models of de novo HGSC that originate in FTSECs and mimic the key genetic alterations and precursor lesions characteristic of human invasive ovarian cancer. The murine tumors accurately recapitulate the histologic, immunophenotypic (CK-8, STMN1, PAX2, P53, Ki-67, WT1, and CA-125), and genomic alterations observed in human HGSC, thus providing a compelling argument for serous carcinogenesis originating in the FTSEC. Our models serve as a proof-of-concept that high-grade serous “ovarian” cancer can arise from the FTSEC and progress to metastatic disease via pre-invasive lesions, namely the STICs. We are currently using the Pax8-driven system to interrogate the role of TCGA genes that have been identified as being important for serous tumorigenesis. Successful completion of our studies will demonstrate that the fallopian tubal secretory epithelial cell is indeed a cell-of-origin for ovarian and pelvic serous carcinomas in vivo when using the most common key TCGA-based tumor drivers for BRCA and non-BRCA tumors, respectively. The first goal of our research is be to produce valid models for HGSC tumors. The second is to identify unique characteristics of early serous carcinogenesis in the tube that can be exploited for early detection. The third is to determine the causes of the earliest events preceding malignancy, which will enable more efficient methods of diagnostic imaging and cancer prevention with a focus on the distal fallopian tube. Furthermore, by using a combination of murine model studies and epidemiological data from patients, it will be important to determine if premenopausal women with BRCA mutations can be offered risk-reduction surgery in a multi-step procedure without undergoing surgical menopause and loss of fertility in their younger years. Citation Format: Ruth Perets, Gregory A Wyant, Anders W Ohman, Sunita R Setlur, Christopher P. Crum, Ronny Drapkin, Daniela M. Dinulescu. Novel strategies for targeting high-grade serous ovarian cancer [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-CTRL-1204.