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MLH1 promoter hypermethylation: are you absolutely sure about the absence of MLH1 germline mutation? About a new case

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Abstract

Lynch syndrome accounts for 3–5% of colorectal cancers and is due to a germline mutation in one of the mismatch repair genes MLH1, MSH2, MSH6, and PMS2. Somatic hypermethylation of the MLH1 promoter is commonly associated to sporadic cases. Strategies have been developed to identify patients with Lynch Syndrome based on clinical findings, tumoral phenotype, family history and immunohistochemistry analysis. However, there still are some pitfalls in this strategy, possibly responsible for an underdiagnosis of Lynch syndrome. Here we report the case of a 37 years-old man presenting with two concomitant tumors located in the rectosigmoid and in the ileocecal angle. Both tumors were microsatellites instability-high (MSI-H) and showed a loss of MLH1 and PMS2 protein expression, but only one had MLH1 promoter hypermethylation. Constitutional analysis of mismatch repair genes could not be performed from a blood sample, because of the early death of the patient. However, tumoral tissue analyses revealed in both tumors a pathogenic variant in the MLH1 gene. Further analysis of the surrounding tumor-free tissue also showed the presence of this alteration of the MHL1 gene. Finally, the same pathogenic variant was present constitutionally in one of the siblings of the patient, confirming its hereditary nature. This new case of concomitant presence of MLH1 promoter hypermethylation and MLH1 germline mutation demonstrates that the presence of MLH1 promoter hypermethylation should not rule out the diagnosis of Lynch Syndrome.

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Authors and Affiliations

  1. Department of Genetics, Hôpital Nord, CHU Saint Etienne, 42055, Saint-Etienne Cedex 2, France

    Caroline Kientz & Fabienne Prieur

  2. Department of Pathology, Hôpital Nord, CHU Saint Etienne, 42055, Saint-Etienne cedex 2, France

    Alix Clemenson & Marie-Laure Stachowicz

  3. Hospices Civils de Lyon, Molecular Biopathology, Centre of Pathology, GHE Hospital, Bron, France

    Marie-Odile Joly

  4. Claude Bernard University Lyon 1, University of Lyon, 69622, Villeurbanne cedex, France

    Marie-Odile Joly

  5. Centre Léon Bérard, Cancer Genomics Platform, 69272, Lyon cedex 08, France

    Jessie Auclair, Valéry Attignon & Qing Wang

  6. Epidemiology and Biostatistics Unit, Centre Antoine Lacassagne, University of Cote d’Azur, 33 avenue de valombrose, 06189, Nice, France

    Renaud Schiappa

  7. Centre Léon Bérard, Joint laboratory for constitutional genetics HCL-CLB, 69272, Lyon cedex 08, France

    Qing Wang

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  1. Caroline Kientz
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Correspondence to Caroline Kientz.

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Kientz, C., Prieur, F., Clemenson, A. et al. MLH1 promoter hypermethylation: are you absolutely sure about the absence of MLH1 germline mutation? About a new case. Familial Cancer 19, 11–14 (2020). https://doi.org/10.1007/s10689-019-00151-7

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  • DOI: https://doi.org/10.1007/s10689-019-00151-7

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