N03: Prevalence, Phenotype And Clinical Consequences Of Mosaicism In APC And Other Colorectal Cancer And Polyposis Associated Genes

M. Suerink1, S. Aretz2,3, A. Wagner4, M. Nielsen1, T. van Wezel5, H. Morreau5

1 – Department of clinical genetics, LUMC, Leiden, The Netherlands. 2 – Institute of Human Genetics, University of Bonn, 53127 Bonn, Germany. 3 – Center for Hereditary Tumor Syndromes, University of Bonn, 53127 Bonn, Germany. 4 – Department of clinical genetics, Erasmuc Medical Centre, Rotterdam, The Netherlands. 5 – Department of pathology, LUMC, Leiden, The Netherlands

Aim: APC mosaicism is identified in ~25% of previously unexplained polyposis patients with >20 adenomas. Prevalence of APC mosaicism in more mildly affected polyposis patients is currently unknown. Furthermore, surveillance advice is now the same for germline and mosaic APC patients, while a milder phenotype in the latter is expected. In the LUMC in Leiden, The Netherlands, a new study will start this year examining the prevalence of APC mosaic mutations in mildly affected polyposis patients as defined below. All mosaic patients will be recorded meticulously to determine phenotype.

Method: FFPE material of colorectal neoplasms (adenomas and/or colorectal cancers) of patients meeting the following criteria will be collected:

–               >5 adenomas and aged <50

–               >10 adenomas and aged <70y

–               >20 adenomas and aged >70y

–               meta- or synchronous CRC <70y

–               10-20 adenomas, between ages 55-75y, identified by population-based screening

We expect inclusion to start in the second half of 2018. DNA will be isolated from the neoplasms (n≥2) and a gene panel (including the following genes: APC, POLE/D1, MUTYH, NTHL1, MSH3, MLH1, MSH2, MSH6, PMS2, SMAD4, BMPR1A, ENG, RNF43, STK11, TP53, BRCA1, BRCA2, PALB2 and PTEN) will be run to identify APC mosaic cases as well as other (mosaic) causes of polyposis/colorectal cancer. Identification of the same mutation in multiple samples of the same patient will be considered to be indicative of mosaicism. Whenever possible, DNA isolated from leucocytes, buccal mucosa and urine will then be analyzed to see whether the variant can be identified in these tissues as well. Eligible patients will need to provide written consent before they are included.

Results: The main outcome will be prevalence of mosaic mutations in the above mentioned patient groups. Furthermore, mutation patterns and clinical phenotype will be recorded to study the mechanisms behind mosaicism and provide data to adapt surveillance guidelines.

Conclusion: A new study is starting this year at the LUMC in Leiden with the aim of further clarifying the prevalence, phenotype and clinical consequences of APC mosaicism. We invite attendees of the EHTG who have several cases that meet the selection criteria to contact us to discuss participation. We require tissue from multiple tumors from well described cases and can accommodate the NGS gene panel.