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Candidate susceptibility variants in angioimmunoblastic T-cell lymphoma

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Abstract

Angioimmunoblastic T-cell lymphoma (AITL) is a subtype of peripheral T-cell lymphoma with a poor prognosis: the 5-year survival rate is approximately 30%. Somatic driver mutations have been found in TET2, IDH2, DNMT3A, RHOA, FYN, PLCG1, and CD28, whereas germline susceptibility to AITL has to our knowledge not been studied. The homogenous Finnish population is well suited for studies on genetic predisposition. Here, we performed an exome-wide rare variant analysis in 23 AITL patients. No germline mutations were found in the driver genes, implying that they are not frequently involved in genetic AITL predisposition. Potentially pathogenic variants present in at least two patients and showing significant (p < 0.01) enrichment in our sample set were found in ten genes: POLK, PRKCB, ZNF676, PRRC2B, PCDHGB6, GNL3L, TTC36, OTOG, OSGEPL1, and RASSF9. The most significantly enriched variants, causing p.Lys469Ter in a splice variant of POLK and p.Pro588His in PRKCB, are intriguing candidates as Polk deficient mice display a spontaneous mutator phenotype, whereas PRKCB was recently shown to be somatically mutated in 33% of another peripheral T-cell lymphoma, adult T-cell lymphoma. If validated, our findings would provide new insight into the pathogenesis of AITL, as well as tools for early detection in susceptible individuals.

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Acknowledgements

This work was supported by the Academy of Finland, Finnish Center of Excellence Program 2012–2017 [Grant Number 250345]. We wish to thank Heikki Metsola, Sini Nieminen, Alison Ollikainen, Marjo Rajalaakso, Sirpa Soisalo, Inga-Lill Svedberg, and Iina Vuoristo for their indispensable assistance.

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Authors and Affiliations

  1. Department of Medical and Clinical Genetics, Medicum, Faculty of Medicine, University of Helsinki, Helsinki, Finland

    Iikki Donner, Riku Katainen, Eevi Kaasinen, Mervi Aavikko, Lauri J. Sipilä & Lauri A. Aaltonen

  2. Genome-Scale Biology Research Program, Research Programs Unit, Faculty of Medicine, University of Helsinki, Helsinki, Finland

    Iikki Donner, Riku Katainen, Eevi Kaasinen, Mervi Aavikko, Lauri J. Sipilä & Lauri A. Aaltonen

  3. Division of Functional Genomics and Systems Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden

    Eevi Kaasinen

  4. Finnish Cancer Registry, Institute for Statistical and Epidemiological Cancer Research, Helsinki, Finland

    Eero Pukkala

  5. Faculty of Social Sciences, University of Tampere, Tampere, Finland

    Eero Pukkala

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  1. Iikki Donner
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  2. Riku Katainen
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  5. Lauri J. Sipilä
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Correspondence to Lauri A. Aaltonen.

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Donner, I., Katainen, R., Kaasinen, E. et al. Candidate susceptibility variants in angioimmunoblastic T-cell lymphoma. Familial Cancer 18, 113–119 (2019). https://doi.org/10.1007/s10689-018-0099-x

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