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CTNNB1-mutant colorectal carcinomas with immediate invasive growth: a model of interval cancers in Lynch syndrome

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Abstract

The implementation of regular colonoscopy programs has significantly decreased the mortality associated with colorectal cancer (CRC) in Lynch syndrome patients. However, interval CRCs in Lynch syndrome that remain undetected by colonoscopy still represent a substantial problem in the management of the syndrome. One possible reason of interval cancers could be a non-polypous pathway of cancer development. To examine the possibility of a non-polypous pathway of CRC development in Lynch syndrome, we analyzed the histological appearance of 46 Lynch syndrome-associated CRCs and compared them to 34 sporadic microsatellite unstable cancers. We observed that 25 (62.5 %) out of 40 assessable Lynch syndrome-associated carcinomas lacked evidence of polypous growth, compared to 17 (50 %) out of 34 sporadic MSI-H cancers. We detected CTNNB1 mutations in 8 (17.4 %) out of 46 Lynch syndrome-associated cancers compared to 0 out of 34 sporadic MSI-H cancers (p = 0.01). The majority of CTNNB1-mutant cancers presented with a histological appearance suggesting immediate invasive growth. Our results suggest that a distinct subgroup of CRCs in Lynch syndrome may in fact emerge from a non-polypous precursor, thus potentially explaining the phenomenon of interval cancers. Such a non-polypous precursor may be the recently described mismatch repair-deficient crypt focus, which remains invisible for the examiner during colonoscopy. This calls for considering the implementation of active, primary preventive measures in the management of Lynch syndrome. Future studies on pathogenic pathways and precursor lesions in Lynch syndrome are strongly encouraged, and the clinical efficacy of new prevention approaches should be evaluated in prospective clinical trials.

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Acknowledgments

This study was partially funded by the German Research Foundation (DFG, Klinische Forschergruppe KFO 227). The excellent technical assistance of Beate Kuchenbuch, Petra Höfler and Nina Nelius is gratefully acknowledged.

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    Authors and Affiliations

    1. Department of Applied Tumor Biology, Institute of Pathology, University Hospital Heidelberg, Im Neuenheimer Feld 224, 69120, Heidelberg, Germany

      Aysel Ahadova, Magnus von Knebel Doeberitz & Matthias Kloor

    2. Clinical Cooperation Unit Applied Tumor Biology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany

      Aysel Ahadova, Magnus von Knebel Doeberitz & Matthias Kloor

    3. Molecular Medicine Partnership Unit (MMPU), University Hospital Heidelberg, Heidelberg, Germany

      Aysel Ahadova, Magnus von Knebel Doeberitz & Matthias Kloor

    4. European Molecular Biology Laboratory (EMBL), Meyerhofstraße 1, 69117, Heidelberg, Germany

      Aysel Ahadova, Magnus von Knebel Doeberitz & Matthias Kloor

    5. Department of General Pathology, University Hospital Charité, Charitéplatz 1, 10117, Berlin, Germany

      Hendrik Bläker

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    1. Aysel Ahadova
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    Correspondence to Matthias Kloor.

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    All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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    Hendrik Bläker and Matthias Kloor have contributed equally to the manuscript.

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    Ahadova, A., von Knebel Doeberitz, M., Bläker, H. et al. CTNNB1-mutant colorectal carcinomas with immediate invasive growth: a model of interval cancers in Lynch syndrome. Familial Cancer 15, 579–586 (2016). https://doi.org/10.1007/s10689-016-9899-z

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