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Integrated multi-omics approach to distinct molecular characterization and classification of early-onset colorectal cancer.

ABSTRACT: Incidence of early-onset colorectal cancer (EOCRC), defined by a diagnosed age under 50 years, is increasing, but its heterogeneous etiologies that differ from general CRC remain undetermined. We initially characterize the genome, epigenome, transcriptome, and proteome of tumors from 79 patients in a Chinese CRC cohort. Data for an additional 126 EOCRC subjects are obtained from the International Cancer Genome Consortium Chinese cohort and The Cancer Genome Atlas European cohort. We observe that early-onset tumors have a high tumor mutation burden; increased DNA repair features by mutational signature 3 and multi-layer pathway enrichments; strong perturbations at effects of DNA methylation and somatic copy-number alteration on gene expression; and upregulated immune infiltration as hot tumors underlying immunophenotypes. Notably, LMTK3 exhibits ancestral mutation disparity, potentially being a functional modulator and biomarker that drives molecular alterations in EOCRC development and immunotherapies. This integrative omics study provides valuable knowledge for precision oncology of CRC.

SUBMITTER: Du M

PROVIDER: S-EPMC10040411 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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Integrated multi-omics approach to distinct molecular characterization and classification of early-onset colorectal cancer.

Du Mulong M Gu Dongying D Xin Junyi J Peters Ulrike U Song Mingyang M Cai Guoshuai G Li Shuwei S Ben Shuai S Meng Yixuan Y Chu Haiyan H Chen Lianmin L Wang Qianghu Q Zhu Lingjun L Fu Zan Z Zhang Zhengdong Z Wang Meilin M

Cell reports. Medicine 20230314 3

Incidence of early-onset colorectal cancer (EOCRC), defined by a diagnosed age under 50 years, is increasing, but its heterogeneous etiologies that differ from general CRC remain undetermined. We initially characterize the genome, epigenome, transcriptome, and proteome of tumors from 79 patients in a Chinese CRC cohort. Data for an additional 126 EOCRC subjects are obtained from the International Cancer Genome Consortium Chinese cohort and The Cancer Genome Atlas European cohort. We observe that ...[more]

PMID: 36921601

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Project description:ObjectivesCervical Squamous Cell Carcinoma (CESC) is one of the most fatal female malignancies, and the underlying molecular mechanisms governing this disease have not been fully explored. In this research, we planned to conduct the analysis of Gene Expression Omnibus (GEO) cervical squamous cell carcinoma microarray datasets by a detailed in silico approach and to explore some novel biomarkers of CESC.MethodsThe top commonly differentially expressed genes (DEGs) from the GSE138080 and GSE113942 datasets were analyzed by Limma package-based GEO2R tool. The protein-protein interaction (PPI) network of the DEGs was drawn through Search Tool for the Retrieval of Interacting Genes (STRING), and top 6 hub genes were obtained from Cytoscape. Expression analysis and validation of hub genes expression in CESC samples and cell lines were done using UALCAN, OncoDB, GENT2, and HPA. Additionally, cBioPortal, Gene set enrichment analysis (GSEA) tool, Kaplan-Meier (KM) plotter, ShinyGO, and DGIdb databases were also used to check some important values of hub genes in CESC.ResultsOut of 79 DEGs, the minichromosome maintenance complex component 4 (MCM4), nucleolar and spindle-associated protein 1 (NUSAP1), cell division cycle associated 5 (CDCA5), cell division cycle 45 (CDC45), denticleless E3 ubiquitin protein ligase homolog (DTL), and chromatin licensing and DNA replication factor 1 (CDT1) genes were regarded as hub genes in CESC. Further analysis revealed that the expressions of all these hub genes were significantly elevated in CESC cell lines and samples of diverse clinical attributes. In this study, we also documented some important correlations between hub genes and some other diverse measures, including DNA methylation, genetic alterations, and Overall Survival (OS). Last, we also identify hub genes associated ceRNA network and 31 important chemotherapeutic drugs.ConclusionThrough detailed in silico methodology, we identified 6 hub genes, including MCM4, NUSAP1, CDCA5, CDC45, DTL, and CDT1, which are likely to be associated with CESC development and diagnosis.

Project description:BackgroundEstimates suggest that up to 30% of colorectal cancers (CRC) may develop due to an increased genetic risk. The mean age at diagnosis for CRC is about 70 years. Time of disease onset 20 years younger than the mean age is assumed to be indicative of genetic susceptibility. We have compared high resolution tumor genome copy number variation (CNV) (Roche NimbleGen, 385 000 oligo CGH array) in microsatellite stable (MSS) tumors from two age groups, including 23 young at onset patients without known hereditary syndromes and with a median age of 44 years (range: 28-53) and 17 elderly patients with median age 79 years (range: 69-87). Our aim was to identify differences in the tumor genomes between these groups and pinpoint potential susceptibility loci. Integration analysis of CNV and genome wide mRNA expression data, available for the same tumors, was performed to identify a restricted candidate gene list.ResultsThe total fraction of the genome with aberrant copy number, the overall genomic profile and the TP53 mutation spectrum were similar between the two age groups. However, both the number of chromosomal aberrations and the number of breakpoints differed significantly between the groups. Gains of 2q35, 10q21.3-22.1, 10q22.3 and 19q13.2-13.31 and losses from 1p31.3, 1q21.1, 2q21.2, 4p16.1-q28.3, 10p11.1 and 19p12, positions that in total contain more than 500 genes, were found significantly more often in the early onset group as compared to the late onset group. Integration analysis revealed a covariation of DNA copy number at these sites and mRNA expression for 107 of the genes. Seven of these genes, CLC, EIF4E, LTBP4, PLA2G12A, PPAT, RG9MTD2, and ZNF574, had significantly different mRNA expression comparing median expression levels across the transcriptome between the two groups.ConclusionsTen genomic loci, containing more than 500 protein coding genes, are identified as more often altered in tumors from early onset versus late onset CRC. Integration of genome and transcriptome data identifies seven novel candidate genes with the potential to identify an increased risk for CRC.

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Integrated multi-omics approach to distinct molecular characterization and classification of early-onset colorectal cancer.

Publications

Integrated multi-omics approach to distinct molecular characterization and classification of early-onset colorectal cancer.

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