Colorectal cancer (CRC) is driven in part by dysregulated Wnt, Ras-Raf-MAPK, TGF-β, and PI3K-Akt signaling. The progression of CRC is also promoted by molecular alterations and heterogeneous—yet interconnected—gene mutations, chromosomal instability, transcriptomic subtypes, and immune signatures. Genomic alterations of CRC progression lead to changes in RNA expression, which support CRC metastasis. An RNA-based classification system used for CRC, known as consensus molecular subtyping (CMS), has four classes. CMS1 has the lowest survival after relapse of the four CRC CMS phenotypes. Here, we identify gene signatures and associated coding mRNAs that are co-expressed during CMS1 CRC progression. Using RNA-seq data from CRC primary tumor samples, acquired from The Cancer Genome Atlas (TCGA), we identified co-expression gene networks significantly correlated with CMS1 CRC progression. CXCL13, CXCR5, IL10, PIK3R5, PIK3AP1, CCL19, and other co-expressed genes were identified to be positively correlated with CMS1. The co-expressed eigengene networks for CMS1 were significantly and positively correlated with the TNF, WNT, and ERK1 and ERK2 signaling pathways, which together promote cell proliferation and survival. This network was also aligned with biological characteristics of CMS1 CRC, being positively correlated to right-sided tumors, microsatellite instability, chemokine-mediated signaling pathways, and immune responses. CMS1 also differentially expressed genes involved in PI3K-Akt signaling. Our findings reveal CRC gene networks related to oncogenic signaling cascades, cell activation, and positive regulation of immune responses distinguishing CMS1 from other CRC subtypes.

Prostate cancer (PCa) is the second most common cause of cancer death in American men. Metastatic castration-resistant prostate cancer (mCRPC) is the most lethal form of PCa and preferentially metastasizes to the bones through incompletely understood molecular mechanisms. Herein, we processed RNA sequencing data from patients with mCRPC (n = 60) and identified 14 gene clusters (modules) highly correlated with mCRPC bone metastasis. We used a novel combination of weighted gene co-expression network analysis (WGCNA) and upstream regulator and gene ontology analyses of clinically annotated transcriptomes to identify the genes. The cyan module (M14) had the strongest positive correlation (0.81, p = 4 × 10⁻¹⁵) with mCRPC bone metastasis. It was associated with two significant biological pathways through KEGG enrichment analysis (parathyroid hormone synthesis, secretion, and action and protein digestion and absorption). In particular, we identified 10 hub genes (ALPL, PHEX, RUNX2, ENPP1, PHOSPHO1, PTH1R, COL11A1, COL24A1, COL22A1, and COL13A1) using cytoHubba of Cytoscape. We also found high gene expression for collagen formation, degradation, absorption, cell-signaling peptides, and bone regulation processes through Gene Ontology (GO) enrichment analysis.

Prostate cancer (PCa) is the second most cancer-related cause of death in men. Most PCa are characterized as slow-growing or indolent, though some patients are at a high risk of for recurrent and eventually metastatic disease. The most lethal form of PCa is metastatic castration-resistant prostate cancer (mCRPC) that has progressed to the bone. The molecular mechanism underlying PCa progression to bone has not been fully elucidated. Here, we identify gene networks associated with CRPC bone metastasis and survival risk. Networks were investigated by using a novel weighted gene network co-expression analysis (WGCNA) method and examining overrepresentation of upstream regulators and signaling pathways within co-expressed transcriptome modules across clinically annotated transcriptomes from mCRPC patients (N=60). Functional Enrichment analysis was used, including Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment, and protein-protein interaction analysis, to identify biological functions of related hub genes overrepresented in our module of interest. WGCNA identified that cyan module was significantly associated with castration-resistant prostate cancer (CRPC) bone metastasis. KEGG and GO analysis results revealed genes in blue module were mainly related to collagen formation, cell signaling peptides, and bone regulation processes, including alkaline phosphatase, osteoblast formation, and endochondral ossification. Genes positively correlated with bone metastasis exhibited the following biological pathways: PI3K-Akt signaling, ECM-receptor interaction, and protein digestion and absorption pathways. This study provides novel insights into the biological pathways associated with CPRC metastasis to the bone. The module associated with bone metastasis and overall survival represent both known and novel pathways. Citation Format: Lawrence P. McKinney, Rajesh Singh, I. King Jordan, Sooryanarayana Varambally, Martin G. Sanda, Eric B. Dammer, James W. Lillard. Multivariate transcriptome analysis identifies networks and key drivers of metastatic castration-resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2701.

The collection of family health history (FHH) is integral to the implementation of population screening that could identify those at high cancer risk who could benefit most from life-saving interventions. Although most individuals believe FHH is important to their health, few actually collect or know their FHH. Recent findings have identified a reduced likelihood of FHH collection among minority populations who may already be at an increased risk for familial cancers such as kidney, cervical, prostate, ovarian, and triple-negative breast cancer. The community health worker (CHW) workforce is especially well positioned to address these challenges in FHH collection, as they are trusted members of their community and well recognized for their work in creating community-clinical linkages. Engaging CHWs in promoting FHH collection could help improve cancer risk assessment utilization among minority populations. We conducted 30 semistructured interviews with CHWs in Georgia to understand their current roles and opportunities to expand their roles to include the gathering and sharing FHH information. Interview questions were guided by the Consolidated Framework for Implementation Research and also included current engagement in FHH collection, beliefs and understanding of FHH collection, and perceived training needs to complete an FHH record using an FHH collection tool. All interviews were double coded in MAXQDA using a codebook developed, adapted, and agreed upon by the research team. Findings demonstrate that most CHWs believe that there is value in collecting FHH and that they are well suited to gather basic FHH information, but the majority had no experience collecting FHH, either formally as part of their jobs or from their own family members. Some concerns raised about this role include the potential for community members to be resistant to providing the information, CHWs' lack of medical knowledge required to address questions from clients about genetics, and the potential complexity of information needed to complete FHH tools. CHWs also provided recommendations for reducing the burden of FHH collection such as tutorials about how to gather accurate and complete information. They also suggested providing resources to clients that focus on the importance of knowing FHH and how it can be used to improve health and become knowledgeable about cancer risk-reduction resources and prevention strategies. Understanding opportunities for CHWs to extend their role in this way could help improve health care delivery and access by enhancing patient-provider communication about FHH in order to tailor recommendations, prevention, and treatment of diseases. Results from this study may inform efforts to strengthen the utility of existing FHH collection tools and accompanying materials to promote the uptake of FHH assessment among patients and providers. Citation Format: Caitlin G. Allen, Lawrence McKinney, Brittaney Bethea, Cam Escoffery, Gail McCray, Colleen McBride, Tabia Akintobi. Exploring the roles of CHWs in improving uptake of family health history assessment among patients and providers: Implications for cancer risk reduction and prevention among minority populations [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr B090.