OR05: Non-polypous colorectal cancer – a distinct tumour type in Lynch syndrome?

Aysel Ahadova1, Magnus von Knebel Doeberitz1, Hendrik Bläker2, Matthias Kloor1.

1 – Department of Applied Tumor Biology, Institute of Pathology, University Hospital Heidelberg, Im Neuenheimer Feld 224, 69120, Heidelberg, Germany. 2 – University Hospital Charité, Department of General Pathology, Charitéplatz 1, 10117, Berlin, Germany


Regular colonoscopy is recommended for colorectal cancer (CRC) prevention in Lynch syndrome. However, a significant part of interval cancers develop in mutation carriers under surveillance. These cancers could be derived from endoscopically invisible non-polypous precursors such as the recently described mismatch repair-deficient crypt foci. We here aimed to analyze the frequency and mutation pattern of CRCs derived from non-polypous precursors in Lynch syndrome.


We analyzed the histological appearance of 46 Lynch syndrome-associated CRCs and profiled them for mutations by fragment length analysis and Sanger sequencing.


Among 40 analyzable cancers, 25 (62.5%) lacked evidence of polypous growth. CTNNB1 mutations, which were strongly associated with lack of polypous growth, were detected in 8/46 (17.4%) of Lynch syndrome-associated cancers. CTNNB1 mutations were not found in sporadic MSI-H colorectal cancers (n=34).


A significant proportion of Lynch syndrome-associated CRCs, characterized by a distinct mutation profile, appear to develop as immediate invasive cancers from non-polypous precursors. This is of high clinical significance, because it may explain interval cancer formation in Lynch syndrome. In addition, colonoscopy efficacy data in the general population cannot be directly extrapolated to Lynch syndrome. Active, primary preventive measures should be considered in Lynch syndrome mutation carriers to tackle non-polypous precursors.