Low-level APC mutational mosaicism is the underlying cause in a substantial fraction of unexplained colorectal adenomatous polyposis cases

Familial Adenomatous Polyposis (FAP), caused by germline mutations in the tumor suppressor gene APC, is one of the most common types of hereditary colorectal cancer. However, in a considerable fraction of families the disease remains unexplained.

This is the first study which comprehensively explored the impact of low-level APC mutational mosaicism. Multiple colorectal polyps in addition to leukocyte DNA were systematically analysed in a sufficient number (n=20) of patients with unexplained sporadic polyposis using high-throughput sequencing techniques. In 25% of patients, the same pathogenic APC mutation was identified in ≥ two polyps, strongly suggesting APC mosaicism as underlying cause of the disease. In 60% of these cases, the mosaic level in leukocyte DNA was clearly below the sensitivity threshold of routine diagnostics.

Our multiple polyp approach demonstrates that low-level APC mosaic mutations contribute significantly to the etiology of adenomatous polyposis. This has important implications for both routine work-up and strategies to identify new causative genes in patient with unexplained polyposis. (By Dr. med. Isabel Spier, http://jmg.bmj.com/content/early/2015/11/26/jmedgenet-2015-103468 )


Drs. Stefan Aretz and Isabel Spier

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