Overview of Genomics in Small Bowel Adenocarcinoma: A Data Integration Analysis Based on Three Major Databases

Background and Significance of the Study

Small Bowel Adenocarcinoma (SBA) is a rare tumor, but its incidence has increased in recent years, especially in duodenal adenocarcinoma. Approximately 20% of SBA patients have certain susceptibility diseases such as Crohn’s disease and Lynch syndrome. Previous studies have shown that SBA is genomically closer to colorectal adenocarcinoma than gastric adenocarcinoma. However, there is still limited systematic research on the gene profiles of SBA at different stages and their prognostic value.

The authors conducted a large-scale genomic analysis to investigate the distribution of gene mutations in SBA and their relationship with disease prognosis. The content of this research has significant clinical and scientific value.

Study Source and Author Team

This study was jointly completed by multiple top research institutions in France and Italy, with main authors including researchers from Saint Louis Hospital, Sorbonne Université, Georges Pompidou Hospital, etc. The research results were published in the British Journal of Cancer on May 14, 2024.

Methods and Research Process

Data Sources and Study Subjects

This study combined data from three different databases: the AGEO study, the BIONADEGE study, and the Casadei-Gardini study. The study subjects included 188 patients diagnosed with small bowel adenocarcinoma, and detailed genomic analysis was conducted on their tumor samples. The following are the detailed procedures of the study:

1. Pathological Data and Sample Collection: The study subjects included SBA patients at stages I to IV, excluding papillary adenocarcinoma and non-adenocarcinoma tumors. Clinical data collected included demographic characteristics, treatment history, tumor staging, lymph node invasion, and other related data. Tumor samples included biopsy samples or surgically resected samples of primary tumors or metastatic tumors.

2. Immunohistochemical Analysis: For the AGEO and BIONADEGE studies, 0.6mm diameter paraffin-embedded tumor tissues were used to construct tissue microarrays (TMA), and immunohistochemical staining was conducted on DNA mismatch repair (MMR) proteins such as MLH1, MSH2, MSH6, and PMS2 to determine the MSI/dMMR status of the tumors.

3. Gene Sequencing and Mutation Analysis: Next-generation sequencing (NGS) was conducted using Ion Torrent and Foundation CDx technology to analyze 739 hotspot somatic mutations involving 35 cancer-related genes. Data were analyzed using biological software to compare with reference genomes and screen for clinically significant gene mutations.

Data Statistics and Analysis Methods

Data analysis was conducted using SAS 9.3 software. Overall survival (OS) was estimated using the Kaplan-Meier method, and the relationship between different factors and OS was compared using the log-rank test. Hazard ratios (HR) were calculated using the Cox proportional hazards model, including multivariate analysis.

Results

Characteristics of Patients and Tumors

The MSI/dMMR phenotype was detected in 71 patients (29.8%) of the entire cohort, with the primary cancer site being the duodenum (58.5%), and most were localized tumors (80.2%).

Gene Mutation Distribution and Disease Stages

Major gene mutations included: KRAS (42.0%), TP53 (40.4%), APC (19.1%), PIK3CA (18.6%), SMAD4 (12.8%), and ERBB2 (9.6%). The detailed distributions of mutations in different subgroups are as follows:

1. By Tumor Stage: KRAS and SMAD4 mutations were more common in metastatic tumors, while APC mutations were associated with poorer overall survival in localized tumors (P=0.0254). Additionally, ERBB2 mutations were absent in localized tumors.

2. By Susceptibility Diseases and Gene Mutations: Crohn’s disease patients had higher rates of TP53 and IDH1 mutations, whereas APC mutations were more common in patients without specific disease backgrounds (P=0.0088). KRAS and ERBB2 mutations were more prevalent in Lynch syndrome patients.

3. Genotype and Prognosis: Overall survival analysis showed that patients with the MSI/dMMR phenotype had a better prognosis (HR=0.61 [0.39–0.96], P=0.0316). APC mutations were also associated with improved survival in localized tumors, while APC mutations had no significant impact on the prognosis of metastatic tumors.

Conclusion and Significance of the Study

This study is the first to systematically analyze the gene mutation profiles of SBA at different stages and under different susceptibility disease backgrounds, revealing the correlation between the MSI/dMMR phenotype and favorable prognosis. The results provide new biological markers for clinical prediction of SBA prognosis and data support for the development of individualized precision treatment for SBA.

Notably, the prognostic significance of APC mutations in localized tumors and the good prognosis associated with the MSI/dMMR phenotype suggest the need to emphasize the application of genomics in SBA treatment. Additionally, the discovery of the high-frequency KRAS G12C mutation provides a potential target for the development and application of novel specific inhibitors.

Highlighted Points

1. Large-scale Genomic Analysis: By integrating data from three significant research databases and analyzing the gene mutation profiles of 188 SBA patients, the statistical significance and scientific value of the results were enhanced.

2. Correlation between MSI/dMMR and Prognosis: The MSI/dMMR phenotype was identified as a biological marker associated with a good prognosis in small bowel adenocarcinoma, which has important clinical applications.

3. New Findings on APC Mutations: For the first time, APC mutations were shown to be related to a good prognosis in localized small bowel adenocarcinoma, providing new insights for future personalized cancer treatment.

4. Research on Crohn’s Disease and Lynch Syndrome: Systematic evaluation of the gene mutation profiles in patients with Crohn’s disease and Lynch syndrome provided a basis for specific treatment strategies for these susceptible populations.