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Reply to: “Development of an MSI-positive colon tumor with aberrant DNA methylation in a PPAP patient”

Journal of Human Genetics volume 65, pages 513–514 (2020)Cite this article

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Yamaguchi et al. [1] identified a germline frameshift variant in the POLE gene, c.4191_4192delCT (p.Tyr1398*), located outside the exonuclease domain, in a case with multiple adenomatous polyps and three synchronous colon tumours, directly assigning the truncating variant a causal role in polymerase proofreading-associated polyposis (PPAP) [1].

As its name indicates, PPAP is a polyposis and cancer predisposing syndrome caused by aberrant polymerase proofreading activity, leading, in the associated tumours, to the accumulation of mutations (frequently >100 mutations/Mb), characterized by an overrepresentation of C:G → A:T transversions [2]. To date, the only functionally relevant variants unequivocally linked to PPAP have been missense variants located in the sequence coding for the exonuclease domains of POLE and POLD1. Loss-of function (LoF) variants and/or genetic changes in these genes outside the exonuclease domain have not been shown to be causal for PPAP [3]. Here, we present evidence showing that LoF POLE and POLD1 variants do not cause PPAP or colorectal cancer predisposition, and in particular, that the tumours from the POLE c.4191_4192delCT (p.Tyr1398*) carrier analysed by Yamaguchi et al. do not show the molecular characteristics of cancers driven by pathogenic POLE mutations.

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References

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Acknowledgements

Spanish Ministry of Science, Innovation and Universities, co-funded by FEDER funds—a way to build Europe—[SAF2016-80888-R], Instituto de Salud Carlos III [CIBERONC CB16/12/00234, Sara Borrell postdoctoral contract], Fundación Olga Torres, Bowel Cancer UK 18PG0010, and the EU COST Action CA17118.

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Authors and Affiliations

  1. Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL, Hospitalet de Llobregat, Barcelona, Spain

    Pilar Mur & Laura Valle

  2. Program in Molecular Mechanisms and Experimental Therapy in Oncology (Oncobell), IDIBELL, Hospitalet de Llobregat, Barcelona, Spain

    Pilar Mur & Laura Valle

  3. Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain

    Pilar Mur & Laura Valle

  4. Gastrointestinal Cancer Genetics Laboratory, Institute of Cancer and Genomic Sciences, University of Birmingham, Edgbaston, Birmingham, UK

    Claire Palles

  5. Edinburgh Cancer Research Centre, IGMM, University of Edinburgh, Edinburgh, UK

    Ian Tomlinson

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  1. Pilar Mur
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Correspondence to Laura Valle.

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Mur, P., Palles, C., Tomlinson, I. et al. Reply to: “Development of an MSI-positive colon tumor with aberrant DNA methylation in a PPAP patient”. J Hum Genet 65, 513–514 (2020). https://doi.org/10.1038/s10038-019-0701-6

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