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Genome-wide genetic and epigenetic analyses of pancreatic acinar cell carcinomas reveal aberrations in genome stability and cell cycle control

Jäkel, Cornelia

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Abstract

Pancreatic acinar cell carcinomas (ACC) are rare pancreatic cancers, which affect mainly adult patients in their sixth decade of life, however may also affect young children. Due to late arising clinical symptoms, tumors are often already large at the time of diagnosis but ACC-specific therapeutic options are lacking. This results in poor survival rates of ACC patients. Due to the rarity of this tumor, collections of tumor tissues and patient data are generally scarce. Consequently, studies published up to date are often case studies or molecular studies using only few tumor samples and genome-wide data sets are very limited. Most studies focusing on target genes known in the much more common pancreatic ductal adenocarcinomas have not been successful in identifying frequent recurrent aberrations in ACC. To this end, this thesis aims to unravel the genome- and epigenome-wide molecular aberrations in ACC, thereby investigating point mutations, mutational signatures, DNA methylation, and copy number aberrations (CNA). Two independent cohorts with a total of 73 tumors are included, representing one of the largest tissue-based collections for ACC. The analyses reveal that, although ACC show a high mutational load per tumor, the mutated genes are not frequently recurring. Somatic signatures of mutational processes are calculated based on the sequence context of point mutations and regardless of the genes affected and are similar among different tumors. Mainly signatures due to tobacco consumption and, more interestingly, defective DNA repair mechanisms are identified. DNA methylation patterns of ACC are compared to normal pancreatic tissues, including sorted pancreatic cell types, and to other pancreatic cancers. Analyses demonstrate that acinar cells are the likely cell of origin of ACC. Further, ACC display a distinct methylation pattern compared to normal pancreatic tissues, pancreatic ductal adenocarcinoma, and neuroendocrine tumors. Differentially methylated genes are enriched in pathways involved in embryonic development and cell adhesion pathways. As example the protocadherin cluster is depicted with wide-spread hypermethylation which influences RNA expression. Massive CNA are detected in ACC and many CNA identified are shared among the tumors. Furthermore, many cancer-relevant genes map to these regions. Mixed acinar-neuroendocrine carcinomas display a very similar molecular pattern compared to pure ACC, suggesting these tumor types belong to the same tumor entity. ACC metastases do not display additional molecular events, thus primary tumors already harbor the potential to metastasize. An integrative analysis identifies aberrations in the four tumor suppressor genes ARID1A, APC, CDKN2A, and ID3, which are confirmed by immunohistochemistry. Taken together, this thesis shows that ACC harbor numerous genomic and epigenomic aberrations which mainly concern genome stability and cell cycle control. These can be exploited by targeted therapies in basket trials which are the most promising approach for patients with rare cancers in which traditional clinical trial designs are not feasible.

Item Type: Dissertation
Supervisor: Popanda, PD Dr. Odilia
Date of thesis defense: 8 May 2017
Date Deposited: 12 May 2017 05:10
Date: 2017
Faculties / Institutes: The Faculty of Bio Sciences > Dean's Office of the Faculty of Bio Sciences
Service facilities > German Cancer Research Center (DKFZ)
Subjects: 610 Medical sciences Medicine
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