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

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• 作者：Trilokesh D. Kidambi ; Amie Blanco ; Jessica Van Ziffle…
• 关键词：Lynch syndrome ; Hereditary colon cancer ; Polyposis ; MLH1 ; Epimutation ; Promoter hypermethylation
• 刊名：Familial Cancer
• 出版年：2016
• 出版时间：April 2016
• 年：2016
• 卷：15
• 期：2
• 页码：275-280
• 全文大小：674 KB
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• 作者单位：Trilokesh D. Kidambi (1)
  Amie Blanco (2)
  Jessica Van Ziffle (3)
  Jonathan P. Terdiman (1) (2) (4)
  
  1. Division of Gastroenterology, University of California, San Francisco, San Francisco, CA, USA
  2. Hereditary GI Cancer Prevention Program, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA
  3. Department of Pathology, University of California, San Francisco, San Francisco, CA, USA
  4. Clinical Medicine and Surgery, University of California, San Francisco, 1701 Divisadero, San Francisco, CA, 94115, USA
  
• 刊物类别：Medicine
• 刊物主题：Medicine & Public Health
  Oncology
  Human Genetics
  Epidemiology
  
• 出版者：Springer Netherlands
• ISSN：1573-7292

文摘

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.