Exome-wide somatic mutation characterization of small bowel adenocarcinoma

Abstract

Small bowel adenocarcinoma (SBA) is an aggressive disease with limited treatment options. Despite previous studies, its molecular genetic background has remained somewhat elusive. To comprehensively characterize the mutational landscape of this tumor type, and to identify possible targets of treatment, we conducted the first large exome sequencing study on a population-based set of SBA samples from all three small bowel segments. Archival tissue from 106 primary tumors with appropriate clinical information were available for exome sequencing from a patient series consisting of a majority of confirmed SBA cases diagnosed in Finland between the years 2003–2011. Paired-end exome sequencing was performed using Illumina HiSeq 4000, and OncodriveFML was used to identify driver genes from the exome data. We also defined frequently affected cancer signalling pathways and performed the first extensive allelic imbalance (AI) analysis in SBA. Exome data analysis revealed significantly mutated genes previously linked to SBA (TP53, KRAS, APC, SMAD4, and BRAF), recently reported potential driver genes (SOX9, ATM, and ARID2), as well as novel candidate driver genes, such as ACVR2A, ACVR1B, BRCA2, and SMARCA4. We also identified clear mutation hotspot patterns in ERBB2 and BRAF. No BRAF V600E mutations were observed. Additionally, we present a comprehensive mutation signature analysis of SBA, highlighting established signatures 1A, 6, and 17, as well as U2 which is a previously unvalidated signature. Finally, comparison of the three small bowel segments revealed differences in tumor characteristics. This comprehensive work unveils the mutational landscape and most frequently affected genes and pathways in SBA, providing potential therapeutic targets, and novel and more thorough insights into the genetic background of this tumor type.

Small Bowel Adenocarcinoma: Etiology, Presentation, and Molecular Alterations

“…53 A similar finding was found in an analysis of 106 cases in which 11 (10.4%) patients had BRAF mutations but none were BRAF V600E. 61 Distinct differences also exist for ERBB2. Despite a similar rate of ERBB2 alterations between SBA and gastric cancer (9.5% for both), the rate of amplification differs greatly, with only 23% of alterations being amplification in SBA compared with 69% in gastric cancer.…”

“…This finding is similar to 3 other studies, which report 70% to 76% of the ERBB2 genomic alterations were mutations. [60][61][62] Studies have reported high rates of MSI-H or dMMR in SBA, with a rate of 21.6% in an 83-patient series 60 and 14.2% in a 106-patient series. 61 However, these rates are highly influenced by the stage distribution of the population, with higher rates seen in earlier-stage disease.…”

Neuroendocrine Neoplasms of the Small Bowel and Pancreas

“…Comprehensive exome and whole-genome sequencing efforts have identified SBNET as mutationally "quiet" compared to other solid neoplasms with 0.1 variants per 10 6 nucleotides, which are mostly transitions (a point mutation in which a purine is changed to the other purine or a pyrimidine to the another) [43]. For comparison, in SB adenocarcinoma the median mutational burden is approximately 3.96 mutations per 10 6 nucleotides [44], comparable to colorectal and gastric carcinoma [45,46]. Sequencing of tumours from 50 individuals with SBNET identified 1,230 genes with somatic mutations; however, 90% were only present in single individuals.…”

CFIm25-regulated lncRNA acv3UTR promotes gastric tumorigenesis via miR-590-5p/YAP1 axis

“…But there is also research demonstrated that acvr1b suppressed early stages of pancreatic tumorigenesis [28]. In small-bowel adenocarcinoma, exome-wide somatic mutation characterization identified acvr1b and acvr2a as novel candidate driver genes [29]. In prostate cancer cells acvr1b promoted lymph node metastasis [30].…”

“…Loss of function of ACVR1B is a primary cause of autosomal-dominant vascular dysplasia syndrome [25], while increase of ACVR1B induces blood vessel branching [26]. In cancer studies, there are several researches showing different roles of ACVR1B based on different cancer types, such as tumor-suppressor role in pancreatic cancer [27,28], oncogenic roles in small-bowel adenocarcinoma [29], prostate cancer [30], and leukemia [31]. To our knowledge, there is no functional study of ACVR1B in GC.…”