The complexities of analysis for APC mosaicism

Diantha Terlouw1, Manon Suerink1, Carli Tops1, Alexandra Langers1, Frederik Hes2, Sanne ten Broeke3, Leonie Dams1, Tom van Wezel1, Hans Morreau1, Maartje Nielsen1

1Leiden University Medical Center, Leiden, Netherlands. 2University Hospital Brussels, Brussels, Belgium. 3University Medical Center Groningen, Groningen, Netherlands


Objectives Mosaic mutations in the APC gene have been identified as a common cause (25%) for polyposis in patients with >20 adenomas without germline mutation. The frequency remains unknown in patients with milder phenotypes.

Methods The APC gene was sequenced in DNA isolated from 4 adenomas in our cohort (n=132) using Next Generation Sequencing. Patients were considered mosaic if an identical mutation was identified in all lesions. An identical variant in only a subset of the adenomas, was considered a so-called hybrid mosaicism. Detection rates and clinical characteristics were compared between different subgroups.

Results The mosaicism detection rate was 17% in the entire cohort (22/132), 0% in patients with <10 adenomas (0/20), 7% in those with 10-20 adenomas (3/42) and 12% in patients over age 70 (2/17). Interestingly, 26 hybrid cases were identified. The mean age of diagnosis and number of adenomas was comparable in hybrid and non-mosaic cases (both ~61 years and ~23 adenomas) and differed from ‘pure’ mosaic cases (45 years, 54 adenomas). Possible explanations for the occurrence of hybrid cases are; chance, field cancerization, contamination, spread of cells during colonoscopies and partial mosaicism with incidental adenomas. However, no universal explanation could be found.

Conclusions Our results indicate that mosaic APC mutations also play a role in patients with <20 adenomas and/or older age at presentation. No universal explanation is identified to explain the occurrence of hybrid cases. So, case by case evaluation and expansion of the cohort is required.