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MBD4-associated neoplasia syndrome: screening of cases with suggestive phenotypes

European Journal of Human Genetics volume 31, pages 1185–1189 (2023)Cite this article

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Abstract

Germline mutations in MBD4, which, like MUTYH and NTHL1, encodes a glycosylase of the DNA based excision repair system, cause an autosomal recessive syndrome characterised by increased risk of acute myeloid leukaemia, gastrointestinal polyposis, colorectal cancer (CRC) and, to a lesser extent, uveal melanoma and schwannomas. To better define the phenotypic spectrum and tumour molecular features associated with biallelic MBD4-associated cancer predisposition, and study if heterozygous variants are associated with gastrointestinal tumour predisposition, we evaluated germline MBD4 status in 728 patients with CRC, polyposis, and other suggestive phenotypes (TCGA and in-house cohorts). Eight CRC patients carried rare homozygous or heterozygous germline variants in MBD4. The information gathered on mode of inheritance, variant nature, functional effect of the variant, and tumour mutational characteristics suggested that none of the patients included in the study had an MBD4-associated hereditary syndrome and that the heterozygous variants identified were not associated with the disease.

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Fig. 1: Location within the MBD4 protein sequence (PFAM domains) of the pathogenic variants identified to date.

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Data availability

Data supporting the reported results may be found in the article, supplementary material and public repositories (TCGA, gnomAD).

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Acknowledgements

We thank Adriana Costal and Laura Berrocal (Hereditary Cancer Program, Catalan Institute of Oncology) for technical support.

Funding

This research was funded by the Spanish Ministry of Science and Innovation (Agencia Estatal de Investigación), co-funded by FEDER funds a way to build Europe [SAF2016-80888-R (LV), PID2020-112595RB-I00 (LV), PID2019-111254RB-I00 (GC)]; Instituto de Salud Carlos III [CIBERONC CB16/12/00234]; Government of Catalonia [AGAUR 2021SGR01112, CERCA Programme for institutional support]; Scientific Foundation “Asociación Española Contra el Cáncer” [AECC Investigador (MT)]; Marie Skłodowska-Curie Individual Fellowship [Grant agreement No. 897064 (NG-A)].

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Authors and Affiliations

  1. Hereditary Cancer Programme, Catalan Institute of Oncology; Oncobell Programme, IDIBELL, Hospitalet de Llobregat, Barcelona, Spain

    Mariona Terradas, Noemi Gonzalez-Abuin, Julen Viana-Errasti, Gemma Aiza, Joan Brunet, Gabriel Capellá & Laura Valle

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

    Mariona Terradas, Josep M. Piulats, Joan Brunet, Gabriel Capellá & Laura Valle

  3. Cancer Immunotherapy (CIT) Group-iPROCURE, Catalan Institute of Oncology; Oncobell Programme, IDIBELL, Hospitalet de Llobregat, Barcelona, Spain

    Sandra García-Mulero & Josep M. Piulats

  4. Unit of Biomarkers and Susceptibility, Oncology Data Analytics Programme (ODAP), Catalan Institute of Oncology; Oncobell Programme, IDIBELL, Hospitalet de Llobregat, Barcelona, Spain

    Sandra García-Mulero

  5. Medical Oncology Department, Catalan Institute of Oncology, Hospitalet de Llobregat, Barcelona, Spain

    Josep M. Piulats

  6. Catalan Institute of Oncology, IDIBGi, Girona, Spain

    Joan Brunet

Authors
  1. Mariona Terradas
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  2. Noemi Gonzalez-Abuin
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  5. Gemma Aiza
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  7. Joan Brunet
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  8. Gabriel Capellá
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  9. Laura Valle
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Contributions

LV conceived and supervised the project, analysed and interpreted the obtained results, and wrote the manuscript. MT, NG-A and GA conceived and carried out the experiments. MT, NG-A, SG-M, JV-E and JMP obtained and analysed data. JB and GC provided samples, clinical information, and resources. All authors were involved in writing and/or critically reviewing the manuscript and had final approval of the submitted and published versions.

Corresponding author

Correspondence to Laura Valle.

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Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

The study received the approval of the IDIBELL ethics committee (Reference number: PR247/15), and all patients studied signed an informed consent. The study was performed in accordance with the Declaration of Helsinki.

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Terradas, M., Gonzalez-Abuin, N., García-Mulero, S. et al. MBD4-associated neoplasia syndrome: screening of cases with suggestive phenotypes. Eur J Hum Genet 31, 1185–1189 (2023). https://doi.org/10.1038/s41431-023-01418-5

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