Browsing by Author "Wei, Peng"

Now showing 1 - 4 of 4
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    Association Studies in Human Cancers: Metabolic Expression Subtypes and Somatic Mutations/Germline Variations
    (2019-07-29) Chen, Zhongyuan; Scott, David W; Liang, Han; Wei, Peng
    Cancer is a highly complex genetic disease caused by certain gene mutations. This thesis focuses on two critical categories of association studies for human cancers: associations between tumor metabolic subtypes and various other cancer aspects, and associations between somatic mutations and germline variations. In the first category, we classify metabolic expression subtypes in multiple TCGA (the Cancer Genome Atlas) cancer types, identify consistent prognostic patterns, and analyze master regulators of metabolic subtypes. We apply various statistical methods to study the associations between the metabolic expression subtypes and patients' survival, somatic mutations, copy number variations, and hallmark pathways. The results show that the metabolic expression subtypes are extensively correlated with patients' survival. The work gives a systematic view of metabolic heterogeneity and indicates the values of metabolic expression subtypes as predictive, prognostic, and therapeutic markers. In the second category, we design data-adaptive and pathway-based large-sample score test methods for association studies between somatic mutations and germline variations. A combination of multiple statistical techniques is used. Extensive information aggregation at both SNP and gene levels is involved. p-values from different parameters are combined to yield data-adaptive tests for somatic mutations and germline variations. To avoid using too many parameters so as to reduce costs, a randomized low-rank parameter preselection strategy is proposed to predict parameters that are likely more effective. In comparison with some commonly used methods, our data-adaptive somatic mutations/germline variations test methods are much more flexible, can apply to multiple germline SNPs/genes/pathways, and generally have much higher statistical powers. The test models are applied to both simulations and real-world ICGC (International Cancer Genome Consortium) datasets. For the ICGC data, a sequence of filtering, screening, and processing techniques is applied, followed by extensive association studies with our models. Our studies systematically identify the associations between various germline variations and somatic mutations across different cancer types. Our research provides valuable statistical tools for cancer risk prediction. The work leads to deeper understanding of molecular mechanisms of specific cancer genes and brings new insights into the development of novel cancer therapy.
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    Loss of LPAR6 and CAB39L dysregulates the basal-to-luminal urothelial differentiation program, contributing to bladder carcinogenesis
    (Elsevier, 2024) Lee, Sangkyou; Bondaruk, Jolanta; Wang, Yishan; Chen, Huiqin; Lee, June Goo; Majewski, Tadeusz; Mullen, Rachel D.; Cogdell, David; Chen, Jiansong; Wang, Ziqiao; Yao, Hui; Kus, Pawel; Jeong, Joon; Lee, Ilkyun; Choi, Woonyoung; Navai, Neema; Guo, Charles; Dinney, Colin; Baggerly, Keith; Mendelsohn, Cathy; McConkey, David; Behringer, Richard R.; Kimmel, Marek; Wei, Peng; Czerniak, Bogdan
    We describe a strategy that combines histologic and molecular mapping that permits interrogation of the chronology of changes associated with cancer development on a whole-organ scale. Using this approach, we present the sequence of alterations around RB1 in the development of bladder cancer. We show that RB1 is not involved in initial expansion of the preneoplastic clone. Instead, we found a set of contiguous genes that we term “forerunner” genes whose silencing is associated with the development of plaque-like field effects initiating carcinogenesis. Specifically, we identified five candidate forerunner genes (ITM2B, LPAR6, MLNR, CAB39L, and ARL11) mapping near RB1. Two of these genes, LPAR6 and CAB39L, are preferentially downregulated in the luminal and basal subtypes of bladder cancer, respectively. Their loss of function dysregulates urothelial differentiation, sensitizing the urothelium to N-butyl-N-(4-hydroxybutyl)nitrosamine-induced cancers, which recapitulate the luminal and basal subtypes of human bladder cancer.
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    The origin of bladder cancer from mucosal field effects
    (Cell Press, 2022) Bondaruk, Jolanta; Jaksik, Roman; Wang, Ziqiao; Cogdell, David; Lee, Sangkyou; Chen, Yujie; Dinh, Khanh Ngoc; Majewski, Tadeusz; Zhang, Li; Cao, Shaolong; Tian, Feng; Yao, Hui; Kuś, Paweł; Chen, Huiqin; Weinstein, John N.; Navai, Neema; Dinney, Colin; Gao, Jianjun; Theodorescu, Dan; Logothetis, Christopher; Guo, Charles C.; Wang, Wenyi; McConkey, David; Wei, Peng; Kimmel, Marek; Czerniak, Bogdan
    Whole-organ mapping was used to study molecular changes in the evolution of bladder cancer from field effects. We identified more than 100 dysregulated pathways, involving immunity, differentiation, and transformation, as initiators of carcinogenesis. Dysregulation of interleukins signified the involvement of inflammation in the incipient phases of the process. An aberrant methylation/expression of multiple HOX genes signified dysregulation of the differentiation program. We identified three types of mutations based on their geographic distribution. The most common were mutations restricted to individual mucosal samples that targeted uroprogenitor cells. Two types of mutations were associated with clonal expansion and involved large areas of mucosa. The α mutations occurred at low frequencies while the β mutations increased in frequency with disease progression. Modeling revealed that bladder carcinogenesis spans 10–15 years and can be divided into dormant and progressive phases. The progressive phase lasted 1-2 years and was driven by β mutations.
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    Urothelial-to-Neural Plasticity Drives Progression to Small Cell Bladder Cancer
    (Cell Press, 2020) Yang, Guoliang; Bondaruk, Jolanta; Cogdell, David; Wang, Ziqiao; Lee, Sangkyou; Lee, June Goo; Zhang, Shizhen; Choi, Woonyoung; Wang, Yan; Liang, Yu; Wang, Gang; Wang, Ying; Yao, Hui; Dadhania, Vipulkumar; Gao, Jianjun; Logothetis, Christopher; Siefker-Radtke, Arlene; Kamat, Ashish; Dinney, Colin; Theodorescu, Dan; Kimmel, Marek; Wei, Peng; Guo, Charles C.; Weinstein, John N.; McConkey, David J.; Czerniak, Bogdan
    We report a comprehensive molecular analysis of 34 cases of small cell carcinoma (SCC) and 84 cases of conventional urothelial carcinoma (UC), with The Cancer Genome Atlas cohort of 408 conventional UC bladder cancers used as the reference. SCCs showed mutational landscapes characterized by nearly uniform inactivation of TP53 and were dominated by Sanger mutation signature 3 associated with loss of BRCA1/2 function. SCCs were characterized by downregulation of luminal and basal markers and were referred to as double-negative. Transcriptome analyses indicated that SCCs displayed lineage plasticity driven by a urothelial-to-neural phenotypic switch with a dysregulated epithelial-to-mesenchymal transition network. SCCs were depleted of immune cells, and expressed high levels of the immune checkpoint receptor, adenosine receptor A2A (ADORA2A), which is a potent inhibitor of immune infiltration. Our observations have important implications for the prognostication and development of more effective therapies for this lethal bladder cancer variant.