Ulrika A. Hänninen 1 , 2 , Riku Katainen 1 , 2 , Tomas Tanskanen 1 , 2 , Roosa-Maria Plaketti 1 , 2 , Riku Laine 1 , 2 , Jiri Hamberg 1 , 2 , Ari Ristimäki 1 , 3 , Eero Pukkala 4 , 5 , Minna Taipale 6 , Jukka-Pekka Mecklin 7 , 8 , Linda M. Forsström 1 , 2 , Esa Pitkänen 1 , 2 , Kimmo Palin 1 , 2 , Niko Välimäki 1 , 2 , Netta Mäkinen 1 , 2 , Lauri A. Aaltonen 1 , 2 , *
9 March 2018
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 is a rare but aggressive disease with limited treatment options. Of gastrointestinal tumors, small bowel tumors account for 3%, of which around one third are adenocarcinomas. Due to the scarcity of evidence-based treatment recommendations there is a dire need for knowledge on the biology of these tumors. Here, we performed the first large exome sequencing effort of 106 small bowel adenocarcinomas from a Finnish population-based cohort to comprehensively characterize the genetic background of this tumor type. The set included tumors from all three small bowel segments allowing us to also compare the genetic differences between these subsets. We defined significantly mutated genes and frequently affected pathways, providing potential therapeutic targets, such as BRAF, ERBB2, ERBB3, ERBB4, PIK3CA, KRAS, ATM, ACVR2A, ACVR1B, BRCA2, and SMARCA4, for this disease.