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Molecular profiling and identification of prognostic factors in Chinese patients with small bowel adenocarcinoma.

ABSTRACT: Small bowel adenocarcinoma (SBA) is a rare malignancy with a poor prognosis and limited treatment options. Despite prior studies, molecular characterization of this disease is not well defined, and little is known regarding Chinese SBA patients. In this study, we conducted multigene next-generation sequencing and 16S ribosomal RNA gene sequencing on samples from 76 Chinese patients with surgically resected primary SBA. Compared with colorectal cancer and Western SBA cohorts, a distinctive genomic profile was revealed in Chinese SBA cohorts. According to the levels of clinical actionability to targetable alterations stratified by OncoKB system, 75% of patients harbored targetable alterations, of which ERBB2, BRCA1/2, and C-KIT mutations were the most common targets of highest-level actionable alterations. In DNA mismatch repair-proficient (pMMR) patients, significant associations between high tumor mutational burden and specific genetic alterations were identified. Moreover, KRAS mutations/TP53 wild-type/nondisruptive mutations (KRAS^mut /TP53^wt/non-dis ) were independently associated with an inferior recurrence-free survival (hazard ratio [HR] = 4.21, 95% confidence interval [CI] = 1.94-9.14, P < .001). The bacterial profile revealed Proteobacteia, Actinobacteria, Firmicutes, Bacteroidetes, Fusobacteria, and Cyanobacteria were the most common phyla in SBA. Furthermore, patients were clustered into three subgroups based on the relative abundance of bacterial phyla, and the distributions of the subgroups were significantly associated with the risk of recurrence stratified by TP53 and KRAS mutations. In conclusion, these findings provided a comprehensive molecular basis for understanding SBA, which will be of great significance in improving the treatment strategies and clinical management of this population.

SUBMITTER: Pan H

PROVIDER: S-EPMC8586671 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ImportanceSmall-bowel adenocarcinomas (SBAs) are rare cancers with a significantly lower incidence, later stage at diagnosis, and worse overall survival than other intestinal-derived cancers. To date, comprehensive genomic analysis of SBA is lacking.ObjectiveTo perform in-depth genomic characterization of a large series of SBAs and other gastrointestinal tumors to draw comparisons and identify potentially clinically actionable alterations.Design, setting, and participantsProspective analysis was performed of clinical samples from patients with SBA (n?=?317), colorectal cancer (n?=?6353), and gastric carcinoma (n?=?889) collected between August 24, 2012, and February 3, 2016, using hybrid-capture-based genomic profiling, at the request of the individual treating physicians in the course of clinical care for the purpose of making therapy decisions.ResultsOf the 7559 patients included in analysis, 4138 (54.7%) were male; the median age was 56 (range, 12-101) years. The frequency of genomic alterations seen in SBA demonstrated distinct differences in comparison with either colorectal cancer (APC: 26.8% [85 of 317] vs 75.9% [4823 of 6353], P?<?.001; and CDKN2A: 14.5% [46 of 317] vs 2.6% [165 of 6353], P?<?.001) or gastric carcinoma (KRAS: 53.6% [170 of 317] vs 14.2% [126 of 889], P?<?.001; APC: 26.8% [85 of 317] vs 7.8% [69 of 889], P?<?.001; and SMAD4: 17.4% [55 of 317] vs 5.2% [46 of 889], P?<?.001). BRAF was mutated in 7.6% (484 of 6353) of colorectal cancer and 9.1% (29 of 317) of SBA samples, but V600E mutations were much less common in SBA, representing only 10.3% (3 of 29) of BRAF-mutated cases. The ERBB2/HER2 point mutations (8.2% [26 of 317]), microsatellite instability (7.6% [13 of 170]), and high tumor mutational burden (9.5% [30 of 317]) were all enriched in SBA. Significant differences were noted in the molecular profile of unspecified SBA compared with duodenal adenocarcinoma, as well as in inflammatory bowel disease-associated SBAs. Targetable alterations in several additional genes, including PIK3CA and MEK1, and receptor tyrosine kinase fusions, were also identified in all 3 series.Conclusions and relevanceThis study presents to our knowledge the first large-scale genomic comparison of SBA with colorectal cancer and gastric carcinoma. The distinct genomic differences establish SBA as a molecularly unique intestinal cancer. In addition, genomic profiling can identify potentially targetable genomic alterations in the majority of SBA cases (91%), and the higher incidence of microsatellite instability and tumor mutational burden in SBA suggests a potential role for immunotherapy.

Project description:PurposeEsophageal adenocarcinoma (EAC) is the most common type of esophageal cancer in Western countries. It is usually detected at an advanced stage and has a poor prognosis. The aim of this study was to identify key genes and miRNAs in EAC.MethodsThe mRNA microarray data sets GSE1420, GSE26886, and GSE92396 and miRNA data set GSE16456 were downloaded from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) and differentially expressed miRNAs (DEMs) were obtained using R software. Functional enrichment analysis was performed using the DAVID database. A protein-protein interaction (PPI) network and functional modules were established using the STRING database and visualized by Cytoscape. The targets of the DEMs were predicted using the miRecords database, and overlapping genes between DEGs and targets were identified. The prognosis-related overlapping genes were identified using Kaplan-Meier analysis and Cox proportional hazard analysis based on The Cancer Genome Atlas (TCGA) database. The differential expression of these prognosis-related genes was validated using the expression matrix in the TCGA database.ResultsSeven hundred and fifteen DEGs were obtained, consisting of 313 upregulated and 402 downregulated genes. The PPI network consisted of 281 nodes; 683 edges were constructed and 3 functional modules were established. Forty-four overlapping genes and 56 miRNA- mRNA pairs were identified. Five genes, FAM46A, RAB15, SLC20A1, IL1A, and ACSL1, were associated with overall survival or relapse-free survival. FAM46A and IL1A were found to be independent prognostic indicators for overall survival, and FAM46A, RAB15, and SLC20A1 were considered independent prognostic indicators for relapse-free survival. Among them, the overexpression of RAB15 and SLC20A1 and lower expression of ACSL1 were also identified in EAC tissues based on the expression matrix in the TCGA database.ConclusionThese prognosis-related genes and differentially expressed miRNA have provided potential biomarkers for EAC diagnosis and treatment.

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Molecular profiling and identification of prognostic factors in Chinese patients with small bowel adenocarcinoma.

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