scholarly journals MP51-12 INACTIVATION OF FOXA1 COOPERATES WITH PTEN COPY NUMBER LOSS IN BLADDER CANCER TO PROMOTE TUMOR HETEROGENEITY

2019 ◽  
Vol 201 (Supplement 4) ◽  
Author(s):  
Lauren Shuman* ◽  
Vasty Osei-Amponsa ◽  
Jenna Buckwalter ◽  
Zongyu Zheng ◽  
Hironobu Yamashita ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Copy Number ◽  
Tumor Heterogeneity ◽  
Copy Number Loss

scholarly journals Patient-Specific Network for Personalized Breast Cancer Therapy with Multi-Omics Data

Entropy ◽  
2021 ◽  
Vol 23 (2) ◽  
pp. 225
Author(s):  
Claudia Cava ◽  
Soudabeh Sabetian ◽  
Isabella Castiglioni
Keyword(s):  
Breast Cancer ◽  
Cancer Therapy ◽  
Protein Interaction Network ◽  
Copy Number ◽  
Tumor Heterogeneity ◽  
Copy Number Alteration ◽  
Interaction Network ◽  
Computational Approach ◽  
Patient Specific ◽  
Basal Breast Cancer

The development of new computational approaches that are able to design the correct personalized drugs is the crucial therapeutic issue in cancer research. However, tumor heterogeneity is the main obstacle to developing patient-specific single drugs or combinations of drugs that already exist in clinics. In this study, we developed a computational approach that integrates copy number alteration, gene expression, and a protein interaction network of 73 basal breast cancer samples. 2509 prognostic genes harboring a copy number alteration were identified using survival analysis, and a protein–protein interaction network considering the direct interactions was created. Each patient was described by a specific combination of seven altered hub proteins that fully characterize the 73 basal breast cancer patients. We suggested the optimal combination therapy for each patient considering drug–protein interactions. Our approach is able to confirm well-known cancer related genes and suggest novel potential drug target genes. In conclusion, we presented a new computational approach in breast cancer to deal with the intra-tumor heterogeneity towards personalized cancer therapy.

scholarly journals Genomic Profiling Reveals the Molecular Landscape of Gastrointestinal Tract Cancers in Chinese Patients

2021 ◽  
Vol 12 ◽  
Author(s):  
Chunrong Zhu ◽  
Liangjun Zhu ◽  
Yanhong Gu ◽  
Ping Liu ◽  
Xiaoling Tong ◽  
...  
Keyword(s):  
Gastrointestinal Tract ◽  
Copy Number ◽  
Chinese Patients ◽  
Biliary Duct ◽  
Molecular Characteristics ◽  
Copy Number Loss ◽  
Targeted Interventions ◽  
Gastric Cancers ◽  
Incidence And Mortality ◽  
Molecular Landscape

Gastrointestinal tract cancers have high incidence and mortality in China, but their molecular characteristics have not been fully investigated. We sequenced 432 tumor samples from the colorectum, stomach, pancreas, gallbladder, and biliary tract to investigate cancer-related mutations and detail the landscape of microsatellite instability (MSI), tumor mutation burden (TMB), and chromosomal instability (CIN). We observed the highest TMB in colorectal and gastric cancers and the lowest TMB in gastrointestinal stromal tumors (GISTs). Twenty-four hyper-mutated tumors were identified only in colorectal and gastric cancers, with a significant enrichment of mutations in the polymerase genes (POLE, POLD1, and POLH) and mismatch repair (MMR) genes. Additionally, CIN preferentially occurred in colorectal and gastric cancers, while pancreatic, gallbladder, and biliary duct cancers had a much lower CIN. High CIN was correlated with a higher prevalence of malfunctions in chromosome segregation and cell cycle genes, including the copy number loss of WRN, NAT1, NF2, and BUB1B, and the copy number gain of MYC, ERBB2, EGFR, and CDK6. In addition, TP53 mutations were more abundant in high-CIN tumors, while PIK3CA mutations were more frequent in low-CIN tumors. In colorectal and gastric cancers, tumors with MSI demonstrated much fewer copy number changes than microsatellite stable (MSS) tumors. In colorectal and gastric cancers, the molecular characteristics of tumors revealed the mutational diversity between the different anatomical origins of tumors. This study provides novel insights into the molecular landscape of Chinese gastrointestinal cancers and the genetic differences between tumor locations, which could be useful for future clinical patient stratification and targeted interventions.

scholarly journals Decomposing the subclonal structure of tumors with two-way mixture models on copy number aberrations

2018 ◽  
Author(s):  
An-Shun Tai ◽  
Chien-Hua Peng ◽  
Shih-Chi Peng ◽  
Wen-Ping Hsieh
Keyword(s):  
Head And Neck Cancer ◽  
Head And Neck ◽  
Neck Cancer ◽  
Copy Number ◽  
Tumor Heterogeneity ◽  
Tumor Evolution ◽  
Depth Information ◽  
Sequencing Data ◽  
Single Nucleotide Variants ◽  
Copy Number Aberrations

AbstractMultistage tumorigenesis is a dynamic process characterized by the accumulation of mutations. Thus, a tumor mass is composed of genetically divergent cell subclones. With the advancement of next-generation sequencing (NGS), mathematical models have been recently developed to decompose tumor subclonal architecture from a collective genome sequencing data. Most of the methods focused on single-nucleotide variants (SNVs). However, somatic copy number aberrations (CNAs) also play critical roles in carcinogenesis. Therefore, further modeling subclonal CNAs composition would hold the promise to improve the analysis of tumor heterogeneity and cancer evolution. To address this issue, we developed a two-way mixture Poisson model, named CloneDeMix for the deconvolution of read-depth information. It can infer the subclonal copy number, mutational cellular prevalence (MCP), subclone composition, and the order in which mutations occurred in the evolutionary hierarchy. The performance of CloneDeMix was systematically assessed in simulations. As a result, the accuracy of CNA inference was nearly 93% and the MCP was also accurately restored. Furthermore, we also demonstrated its applicability using head and neck cancer samples from TCGA. Our results inform about the extent of subclonal CNA diversity, and a group of candidate genes that probably initiate lymph node metastasis during tumor evolution was also discovered. Most importantly, these driver genes are located at 11q13.3 which is highly susceptible to copy number change in head and neck cancer genomes. This study successfully estimates subclonal CNAs and exhibit the evolutionary relationships of mutation events. By doing so, we can track tumor heterogeneity and identify crucial mutations during evolution process. Hence, it facilitates not only understanding the cancer development but finding potential therapeutic targets. Briefly, this framework has implications for improved modeling of tumor evolution and the importance of inclusion of subclonal CNAs.

SMARCA4-mutated lung adenocarcinoma, a distinctive non-small cell lung cancer with worse prognosis.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e20548-e20548
Author(s):  
Longfeng Zhang ◽  
Weijin Xiao ◽  
Fangjun Wu ◽  
Ran Peng ◽  
Jialong Shi ◽  
...  
Keyword(s):  
Protein Expression ◽  
Lung Adenocarcinoma ◽  
Copy Number ◽  
Enrichment Analysis ◽  
Outcome Data ◽  
Copy Number Loss ◽  
Missense Mutations ◽  
Cellular Processes ◽  
Pathological Characteristics ◽  
Worse Prognosis

e20548 Background: SMARCA4 gene is one of the catalytic subunits of the SWI/SNF chromosomal remodeling complex, which can regulate important cellular processes and functions and is closely associated to tumors. The clinical features, therapeutic efficacy, prognosis and pathological features of lung adenocarcinoma with this genetic variation are still unknown and controversial. Methods: The study recruited 274 patients (pts) with lung adenocarcinoma whose samples were sent to perform parallel hybridization-based next-generation sequencing. Two categories of SMARCA4 mutations were divided into Type1 mutations (frameshift mutations, nonsense mutations, splice-3 mutations, copy number amplification) and Type2 mutations (missense mutations and copy number loss) based on whether the mutation may result in defective protein. Furthermore, comparative analysis by using the clinical outcome data, the genomic and pathological characteristics were be performed in SMARCA4 Type 1 alterations corhort and Type 2 alterations corhort. Results: Among 274 pts were recruited, the mutation rate of SMARCA4 gene in lung adenocarcinoma was 9.1%. Furthermore, the presence of SMARCA4 alteration was associated with smoking (P＜0.05). Missense, nonsense, frameshift and splice were the most common types of mutations (92%). The pts with SMARCA4 Type1 alterations which probably lead to defective protein expression, had a worse prognosis compared with pts with SMARCA4 Type1 alterations (The role leading to defective protein expression is uncertain) and SMARCA4 Wild groups (P＜0.05). In addition, EGFR alterations were strongly associated with SMARCA4 Wild corhort compared to SMARCA4 Type1 alterations corhort (67% vs. 31% ), and SMARCA4 Type1 alterations was more associated with the absence of TP53, RB1, and Robo3 alterations. GO enrichment analysis suggested that the differentiated mutated genes between SMARCA4 Type1 alterations corhort and SMARCA4 Wild corhort were mainly enriched in cell cycle regulation. Pathologically, The SMARCA4 Type1 alterations was mostly poorly or moderately differentiated and strongly accompanied by the loss of expression of TTF-1(83.3%) and BRG1(80%) in immunohistochemistry. Conclusions: SMARCA4 Type1 alterations which probably lead to abnormality of protein was associated with poor prognosis and having different the genomic and pathological characteristics.

scholarly journals ZC3H18 specifically binds and activates the BRCA1 promoter to facilitate homologous recombination in ovarian cancer

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Arun Kanakkanthara ◽  
Catherine J. Huntoon ◽  
Xiaonan Hou ◽  
Minzhi Zhang ◽  
Ethan P. Heinzen ◽  
...  
Keyword(s):  
Homologous Recombination ◽  
Copy Number ◽  
Dna Binding Protein ◽  
Copy Number Loss ◽  
Mrna Levels ◽  
High Grade ◽  
Brca1 Expression ◽  
Brca1 Promoter ◽  
Ovarian Cancers ◽  
Polymerase Inhibitors

Abstract Reduced BRCA1 expression causes homologous recombination (HR) repair defects in high-grade serous ovarian cancers (HGSOCs). Here, we demonstrate that BRCA1 is transcriptionally activated by a previously unknown function of ZC3H18. We show that ZC3H18 is a DNA-binding protein that interacts with an E2F site in the BRCA1 promoter where it facilitates recruitment of E2F4 to an adjacent E2F site to promote BRCA1 transcription. Consistent with ZC3H18 role in activating BRCA1 expression, ZC3H18 depletion induces BRCA1 promoter methylation, reduces BRCA1 expression, disrupts HR, and sensitizes cells to DNA crosslinkers and poly(ADP-ribose) polymerase inhibitors. Moreover, in patient-derived xenografts and primary HGSOC tumors, ZC3H18 and E2F4 mRNA levels are positively correlated with BRCA1 mRNA levels, further supporting ZC3H18 role in regulating BRCA1. Given that ZC3H18 lies within 16q24.2, a region with frequent copy number loss in HGSOC, these findings suggest that ZC3H18 copy number losses could contribute to HR defects in HGSOC.

Sign in / Sign up

Export Citation Format

Share Document