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

  • Caroline KientzEmail author
  • Fabienne Prieur
  • Alix Clemenson
  • Marie-Odile Joly
  • Marie-Laure Stachowicz
  • Jessie Auclair
  • Valéry Attignon
  • Renaud Schiappa
  • Qing Wang
Original Article


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.


Lynch syndrome MLH1 promoter hypermethylation MLH1 BRAF MSI 


Compliance with ethical standards

Conflict of interest

The authors have declared no conflict of interest.


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Copyright information

© Springer Nature B.V. 2019

Authors and Affiliations

  • Caroline Kientz
    • 1
    Email author
  • Fabienne Prieur
    • 1
  • Alix Clemenson
    • 2
  • Marie-Odile Joly
    • 3
    • 4
  • Marie-Laure Stachowicz
    • 2
  • Jessie Auclair
    • 5
  • Valéry Attignon
    • 5
  • Renaud Schiappa
    • 6
  • Qing Wang
    • 5
    • 7
  1. 1.Department of Genetics, Hôpital NordCHU Saint EtienneSaint-Etienne Cedex 2France
  2. 2.Department of Pathology, Hôpital NordCHU Saint EtienneSaint-Etienne cedex 2France
  3. 3.Hospices Civils de Lyon, Molecular Biopathology, Centre of PathologyGHE HospitalBronFrance
  4. 4.Claude Bernard University Lyon 1, University of LyonVilleurbanne cedexFrance
  5. 5.Centre Léon Bérard, Cancer Genomics PlatformLyon cedex 08France
  6. 6.Epidemiology and Biostatistics Unit, Centre Antoine LacassagneUniversity of Cote d’AzurNiceFrance
  7. 7.Centre Léon Bérard, Joint laboratory for constitutional genetics HCL-CLBLyon cedex 08France

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