Familial Cancer

, Volume 15, Issue 2, pp 275–280 | Cite as

Constitutional MLH1 methylation presenting with colonic polyposis syndrome and not Lynch syndrome

  • Trilokesh D. Kidambi
  • Amie Blanco
  • Jessica Van Ziffle
  • Jonathan P. Terdiman
Short Communication


At least one-third of patients meeting clinical criteria for Lynch syndrome will have no germline mutation and constitutional epimutations leading to promoter methylation of MLH1 have been identified in a subset of these patients. We report the first case of constitutional MLH1 promoter methylation associated with a colonic polyposis syndrome in a 39 year-old man with a family history of colorectal cancer (CRC) and a personal history of 21 polyps identified over 8 years as well as the development of two synchronous CRCs over 16 months who was evaluated for a hereditary cancer syndrome. Immunohistochemistry (IHC) of multiple tumors showed absent MLH1 and PMS2 expression, though germline testing with Sanger sequencing and multiplex ligation-dependent probe amplification of these mismatch repair genes (MMR) genes was negative. A next generation sequencing panel of 29 genes also failed to identify a pathogenic mutation. Hypermethylation was identified in MLH1 intron 1 in tumor specimens along with buccal cells and peripheral white blood cells, confirming the diagnosis of constitutional MLH1 promoter methylation. This case highlights that constitutional MLH1 methylation should be considered in the differential diagnosis for a polyposis syndrome if IHC staining shows absent MMR gene expression.


Lynch syndrome Hereditary colon cancer Polyposis MLH1 Epimutation Promoter hypermethylation 


Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Informed consent

Informed consent was obtained from the patient described in this study.


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Copyright information

© Springer Science+Business Media Dordrecht 2016

Authors and Affiliations

  • Trilokesh D. Kidambi
    • 1
  • Amie Blanco
    • 2
  • Jessica Van Ziffle
    • 3
  • Jonathan P. Terdiman
    • 1
    • 2
    • 4
  1. 1.Division of GastroenterologyUniversity of California, San FranciscoSan FranciscoUSA
  2. 2.Hereditary GI Cancer Prevention Program, Helen Diller Family Comprehensive Cancer CenterUniversity of California, San FranciscoSan FranciscoUSA
  3. 3.Department of PathologyUniversity of California, San FranciscoSan FranciscoUSA
  4. 4.Clinical Medicine and SurgeryUniversity of California, San FranciscoSan FranciscoUSA

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