Abstract B011: Lower incidence of small intestinal adenocarcinomas may be due to constrained copy number karyotype and increased immune surveillance
Authors: Nowinski Salpie , Balarajah Vickna , Baker Ann-Marie , Katainen Riku , Hughes Christine , Guo Qingli , Zapata Luis , Lakatos Eszter , Kocher Hemant M. , Graham Trevor A. 
Published: February 2024

Aim: To evaluate the genomic profiles of duodenal adenocarcinomas and explore the role of the immune system in the evolution of these cancers. Introduction: Tumours of the small intestine are rare and represent the smallest fraction of all gastrointestinal (GI) cancers despite being the largest organ in the GI tract. As a result, they have not been well characterised at the molecular level, and consequently are often clinically managed similarly to colorectal cancers. Methods: Here we performed shallow whole-genome sequencing (sWGS) on 125 cases of the most common adenocarcinomas in the small intestine, duodenal adenocarcinomas, and compared their somatic copy number aberrations to 880 upper and lower GI primary adenocarcinomas from the TCGA. Furthermore, we reanalysed published whole exome sequencing (WEX) from a further 91 small intestinal carcinomas to assess the immune landscape. Results: In our sWGS cohort, we found that duodenal adenocarcinomas have a significantly lower incidence of genome doubling (20%) than elsewhere in the GI tract (colon=43.6%, stomach=44%, rectum=55%, oesophagus=64.3%). Percentage of genome altered (PGA) is affected by the amount of genome doubling present, by median centering the proportion of the genome altered we could circumvent this. Duodenal cancers also had a significantly lower median centered percentage genome aberrated (mPGA) than colon (p=6.3 × 10-4, es=0.176), rectal (p=3 × 10-5, es=0.279), stomach (p=1.5 × 10-8, es=0.309) and oesophageal (p=1.2 × 10-11, es=0.546) adenocarcinomas. Inter-tumour heterogeneity of copy number alterations was lowest in duodenal cancers compared to other GI cancer types (p&lt;2.22 × 10-16 for all and effect size &gt; 0.7 for all). Within the previously published WEX cohort of small intestinal adenocarcinomas, we observed a higher proportion of clonal mutations that are neoantigens (vs not-neoantigens) in immune escaped tumours than non-escaped tumours (p=0.016) and found that small intestinal tumours are more likely to be immune escaped than colon cancers. Escaped small intestinal tumours were associated with a significantly decreased overall survival compared to non-escaped tumours (HR 2.197 (95% CI, 1.736– 46.63); p=0.009). Further, dNdS analysis indicated strong immune-mediated negative selection on clonal non-synonymous mutations in the immunopeptidome in most tumours. Conclusions: The decreased inter-tumour heterogeneity of karyotypes amongst small intestinal cancers compared to other GI cancers could indicate more restricted routes for karyotype evolution in the small intestine. Our data also suggest a more pertinent role for immune-predation than elsewhere in the GI tract. Together this may explain their lower incidence.

Citation Format: Salpie Nowinski, Vickna Balarajah, Ann-Marie Baker, Riku Katainen, Christine Hughes, Qingli Guo, Luis Zapata, Eszter Lakatos, Hemant M. Kocher, Trevor A. Graham. Lower incidence of small intestinal adenocarcinomas may be due to constrained copy number karyotype and increased immune surveillance [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Cancer Evolution and Data Science: The Next Frontier; 2023 Dec 3-6; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_2):Abstract nr B011.