N81: Genomic And Transcriptomic Profiling Of Duodenal Adenomas In Familial Adenomatous (FAP) And MUTYH-Associated Polyposis (MAP)

E. Meuser1, K. Chang2, M. Mort1, J. J. Hurley3, K. Ashelford1, M. Naven1, N. Hawkes3, E. Short1, 4, 5, H. Jundi1, P. Georgiades1, M. W. Taggart6, L. Reyes-Uribe2, P. M. Lynch7, F. Neumann8, S. J. Walton9, 10, S. K. Clark9, 10, J. Sampson1, E. Vilar2, 11, L. E. Thomas1

1 – Division of Cancer and Genetics, School of Medicine, Cardiff University UK. 2 – Department of Clinical Cancer Prevention, UT MD Anderson Cancer Center, Houston USA. 3 – Department of Gastroenterology, Cwm Taf University Health Board, Merthyr Tydfil UK. 4 – Department of Histopathology, Cardiff. 5 – Vale University Health Board, Cardiff UK. 6 – Department of Pathology and Laboratory Medicine, UT MD Anderson Cancer Center, Houston USA. 7 – Department of Gastroenterology, Hepatology and Nutrition, UT MD Anderson Cancer Center, Houston USA. 8 – Science for Life Laboratory, Stockholm University, SE. 9 – The Polyposis Registry, St Marks Hospital, London UK. 10 – Department of Surgery and Cancer, Faculty of Medicine, Imperial College, London UK. 11 – Clinical Cancer Genetics Program, UT MD Anderson Cancer Center, Houston USA.

 

Aim: Duodenal polyposis and cancer are important yet poorly understood causes of morbidity and mortality in FAP and MAP patients. We aimed to characterise the genomic and transcriptomic signatures associated with duodenal adenomas from patients with FAP and MAP, to better understand duodenal tumourigenesis in these hereditary disorders.

Method: A series of 67 samples from patients with a genetically confirmed diagnosis of FAP or MAP were subjected to whole transcriptome sequencing, consisting of 44 duodenal adenomas (FAP n=29, MAP n=15) and 23 duodenal normal mucosa (FAP n=15, MAP n=8). Outcomes were compared to exome sequencing data from 50 duodenal adenomas (FAP n=25, MAP n=25).

Results: We found distinct gene expression profiles in FAP and MAP duodenal adenomas which were absent from the respective normal mucosa. MAP adenomas harboured aberrations in RAS signalling and immune system stimulation, whilst evidence for dysregulation of prostanoid synthesis and NOTCH signalling were found in FAP adenomas. Whole exome analysis revealed that MAP duodenal adenomas carried more somatic mutations than FAP (p=0.0226). Recurrently mutated genes in duodenal adenomas included known drivers (APC, KRAS) and additional potential duodenal-specific tumour initiators.

Conclusion: The identification of commonly deregulated pathways contributes to our understanding of duodenal tumourigenesis in the context of FAP and MAP.

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