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 Integrated Multiomics Analyses Revealing Different Molecular Profiles Between Early- and Late-Stage Lung Adenocarcinoma

2021 ◽  
Vol 11 ◽  
Author(s):  
Dongsheng Yue ◽  
Weiran Liu ◽  
Liuwei Gao ◽  
Lianmin Zhang ◽  
Tao Wang ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Cancer Progression ◽  
Late Stage ◽  
Copy Number ◽  
Copy Number Variations ◽  
Regulatory Mechanisms ◽  
Gene Copy ◽  
Molecular Characteristics ◽  
Open Chromatin ◽  
Copy Number Loss

The molecular differences in genetic and epigenetic profiling between early-stage (ES) and late-stage (LS) lung adenocarcinoma (LUAD), which might help to understand cancer progression and biomarker guided precision treatment, need further be investigated. In this study, we performed comprehensive analysis using multi-omics next-generation sequencing (NGS) on tissue samples from 7 ES (stage I) and 10 LS (stage III/IV) LUAD patients to study molecular characteristics between the two groups. Characterization of the genomic and transcriptomic profiles showed stage-specific somatic mutations, copy number variations (CNVs) and differentially expressed genes (DEGs). LS samples tend to have more TP53, ERBB2 and CHD4 mutations. Gene copy number loss occurs in immune-related gene pathways in the late stage of LUAD. ATAC-seq analysis showed that LS samples harbored more open chromatin peaks around promoter regions and transcription start sites (TSS) than ES samples. We then identified the known transcription factor (TF) binding motifs for the differentially abundant ATAC-seq peaks between the ES and LS samples and found distinct regulatory mechanisms related to each stage. Furthermore, integrative analysis of ATAC-seq with WGS and RNA-seq data showed that the degree of chromatin accessibility is related to copy number changes, and the open chromatin regions could directly regulate the expression of some DEGs. In conclusion, we performed a comprehensive multi-omics analysis of the early and late stages of LUAD and highlighted some important molecular differences in regulatory mechanisms during cancer progression. Those findings help to further understand mechanism and biomarker related targeted therapy.

The landscape of germline mutations and the relationship with tumor mutation burden in Chinese patients with lung cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 10522-10522
Author(s):  
Jian Shi ◽  
Rongfeng Liu ◽  
Guanglei Huang ◽  
Lixing Wang ◽  
Baoen Shan ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Germline Mutation ◽  
Germline Mutations ◽  
Gene Panel ◽  
Chinese Patients ◽  
Literature Report ◽  
Pathogenic Mutations ◽  
Incidence And Mortality ◽  
The Media ◽  
The Relationship

10522 Background: Lung cancer is one of the most common types of cancer, ranking the first in the incidence and mortality of malignant tumors in the world and China. Although studies have been reported that genetic susceptibility to lung cancer is associated with certain germline mutations, the relationship between lung cancer risk and inherited genetic factors remains relatively elusive. However, the effect of germline mutation on TMB in lung cancer has not been explored. Herein, DNA genomic profiling was performed through NGS with a 539-gene panel to explore the germline mutations and the relationship with TMB in Chinese patients with lung cancer. Methods: We retrospectively analyzed the germline mutations through a comprehensive 539-gene profiling of 3541 Chinese patients with lung cancer. 539-gene panel contained germline mutations in 90 hereditary tumor-associated genes. We screened out the pathogenic and likely pathogenic germline mutations according to the standards and guidelines for the interpretation of sequence variants of The American College of Medical Genetics and Genomics (ACMG), and picked out there is no records in Clinvar database and no literature report. TMB of tissue or blood ctDNA in 3541 patients were further analyzed in with pathogenic mutations (P group), with likely pathogenic mutations (LP group), and no germline mutations group (Non-P group). The difference in TMB was analyzed via the Wilcoxon sign test. Results: In 3541 patients with lung cancer, 177 (4.999%) patients were identified harboring pathogenic or likely pathogenic germline mutations, in which 78 P group and 99 LP group, the rest 3364 were Non-P group. The highest prevalence of germline mutation was found in BRCA2 (0.565%), ATM (0.339%), MUTYH (0.282%), and BRCA1 (0.254%). In 177 patients with pathogenic or likely pathogenic germline mutations, 67 mutations were recorded as UNK (unknow) in Clinvar database and no literature report. The media TMB of tissue in P group, LP group and Non-P group were 5.149, 5.535 and 5.547 respectively. The media TMB of blood ctDNA in P group, LP group and Non-P group were 4.257, 3.945 and 4.483 respectively. There was no statistical difference in TMB between P and Non-P groups (tissue p = 0.98; ctDNA p = 0.5). Conclusions: In our study, we firstly identified 67 novel germline mutations and studied on the relationship between germline mutations and TMB in lung cancer, which expanded the understanding of germline mutations.

Novel Recurrent Altered Genes in Chinese Patients With Anaplastic Thyroid Cancer

2021 ◽  
Author(s):  
Lingyun Zhang ◽  
Zhixiang Ren ◽  
Zhengzheng Su ◽  
Yang Liu ◽  
Tian Yang ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Copy Number ◽  
Treatment Strategies ◽  
Gene Mutations ◽  
Anaplastic Thyroid Cancer ◽  
Chinese Patients ◽  
Driver Gene ◽  
Phosphatidylinositol 3 Kinase ◽  
Entire Cohort ◽  
Whole Exome

Abstract Background Anaplastic thyroid cancer (ATC) is a rare but lethal malignancy, and few systematic investigations on genomic profiles of ATC have been performed in Chinese patients. Methods Fifty-four ATC patients in West China Hospital between 2010 to 2020 were retrospectively analyzed, while 29 patients with available samples were sequenced by whole-exome sequencing (WES). The associations between genomic alterations and clinical characteristics were statistically evaluated. Results The median overall survival was 3.0 months in the entire cohort, which was impacted by multiple clinical features, including age, tumor size, and different treatment strategies. In the WES cohort, totally 797 nonsilent mutations were detected; the most frequently altered genes were TP53 (48%), BRAF (24%), PIK3CA (24%), and TERT promoter (21%). Although these mutations have been well-reported in previous studies, ethnic specificity was exhibited in terms of mutation frequency. Moreover, several novel significantly mutated genes were identified including RBM15 (17%), NOTCH2NL (14%), CTNNA3 (10%), and KATNAL2 (10%). WES-based copy number alteration analysis also revealed a high frequent gain of NOTCH2NL (41%), which induced its increased expression. Gene mutations and copy number alterations were enriched in phosphatidylinositol 3-kinase/AKT/mechanistic target of rapamycin (mTOR), NOTCH, and WNT pathways. Conclusions This study reveals shared and ethnicity-specific genomic profiles of ATC in Chinese patients and suggests NOTCH2NL may act as a novel candidate driver gene for ATC tumorigenesis.

scholarly journals Carcinosarcoma of the prostate: case report with molecular and histological characterization

2018 ◽  
Vol 33 (4) ◽  
pp. 540-544 ◽  
Author(s):  
Samanta Salvi ◽  
Valentina Casadio ◽  
Filippo Martignano ◽  
Giorgia Gurioli ◽  
Maria Maddalena Tumedei ◽  
...  
Keyword(s):  
Copy Number Variation ◽  
Copy Number ◽  
Copy Number Variations ◽  
Molecular Characteristics ◽  
Glutathione S Transferase ◽  
Molecular Alterations ◽  
Positive Expression ◽  
Molecular Pattern ◽  
Programmed Death ◽  
Number Variation

Background: We report a case of prostatic carcinosarcoma, a rare variant of prostatic cancer, which is composed of a mixture of epithelial and mesenchymal components with a generally poor outcome. Aims and methods: We aim to identify molecular alterations, in particular copy number variations of AR and c -MYC genes, methylation and expression of glutathione S-transferase P1 (GSTP1), programmed death-ligand 1 (PD-L1), AR, and phosphorylated AR expression. Results: We found a distinct molecular pattern between adenocarcinoma and carcinosarcoma, which was characterized by high AR copy number variation gain; positive expression of PD-L1, AR, and phosphorylated AR; low espression of GSTP1 in epithelial component. The sarcomatoid component had a lower gain of the AR gene, and no expression of PD-L1, AR, phosphorylated AR, or GSTP1. Both components had a gain of c-MYC copy number variation. Conclusions: Our findings suggest that carcinosarcoma has specific molecular characteristics that could be indicative for early diagnosis and treatment selection.

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

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.

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