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

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.

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miRNAs Copy Number Variations repertoire as hallmark indicator of cancer species predisposition

10.1101/2021.09.21.461294 ◽

2021 ◽

Author(s):

Chiara Vischioni ◽

Fabio Bove ◽

Federica Mandreoli ◽

Riccardo Martoglia ◽

Valentino Pisi ◽

...

Keyword(s):

Cancer Progression ◽

Copy Number ◽

Molecular Mechanisms ◽

Gene Families ◽

Copy Number Variations ◽

Gene Copy ◽

Cancer Resistance ◽

Entire Genome ◽

Significant Gene ◽

Living Organisms

Aging is one of the hallmarks of multiple human diseases, including cancer. However, the molecular mechanisms associated with high longevity and low cancer incidence percentages characterizing long-living organisms have not been fully understood yet. In this context, we hypothesized that variations in the number of copies (CNVs) of specific genes may protect some species from cancer onset. Based on the statistical comparison of gene copy numbers within the genomes of cancer -prone and -resistant organisms, we identified novel gene targets linked to the tumor predisposition of a species, such as CD52, SAT1 and SUMO protein family members. Furthermore, for the first time, we were able to discover that, considering the entire genome copy number landscape of a species, microRNAs (miRNAs) are among the most significant gene families enriched for cancer progression and predisposition. However, their roles in ageing and cancer resistance from a comparative perspective remains largely unknown. To this end, we identified through bioinformatics analysis, several alterations in miRNAs copy number patterns, represented by duplication of miR-221, miR-222, miR-21, miR-372, miR-30b, miR-30d and miR-31 among others. Therefore, our analysis provides the first evidence that an altered copy number miRNAs signature is able to statistically discriminate species more susceptible to cancer than those that are tumor resistant, helping researchers to discover new possible therapeutic targets involved in tumor predisposition.

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Circulating Cell-Free DNA-Based Detection of Tumor Suppressor Gene Copy Number Loss and Its Clinical Implication in Metastatic Prostate Cancer

Frontiers in Oncology ◽

10.3389/fonc.2021.720727 ◽

2021 ◽

Vol 11 ◽

Author(s):

Xiaoxi Dong ◽

Tiantian Zheng ◽

Minhua Zhang ◽

Chao Dai ◽

Lili Wang ◽

...

Keyword(s):

Prostate Cancer ◽

Tumor Suppressor ◽

Tumor Suppressor Gene ◽

Cancer Progression ◽

Liquid Biopsy ◽

Copy Number ◽

Metastatic Prostate Cancer ◽

Suppressor Gene ◽

Gene Copy ◽

Copy Number Loss

Current liquid biopsy assays lack sufficient sensitivity to detect copy number loss, which limits the interrogation of critical tumor suppressor gene deletions during cancer progression and treatment. Here we describe a liquid biopsy assay with improved sensitivity for detection of copy number loss in blood samples with low levels of circulating tumor DNA, and demonstrate its utility by profiling PTEN, RB1, and TP53 genetic loss in metastatic prostate cancer patients.

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Assessment of HER-2/neu, с-MYC and CCNE1 gene copy number variations and protein expression in endometrial carcinomas

Experimental Oncology ◽

10.32471/exp-oncology.2312-8852.vol-41-no-2.12973 ◽

2019 ◽

Vol 41 (2) ◽

Author(s):

L.G. Buchynska ◽

◽

O.V. Brieieva* ◽

N.P. Iurchenko ◽

◽

...

Keyword(s):

Protein Expression ◽

Copy Number ◽

Gene Copy Number ◽

Copy Number Variations ◽

Gene Copy ◽

Her 2 ◽

Endometrial Carcinomas

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

The International Journal of Biological Markers ◽

10.1177/1724600818791463 ◽

2018 ◽

Vol 33 (4) ◽

pp. 540-544 ◽

Cited By ~ 3

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.

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

Frontiers in Genetics ◽

10.3389/fgene.2021.608742 ◽

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.

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

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e20548 ◽

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.

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