title: Constitutional MLH1 methylation presenting with colonic polyposis syndrome and not Lynch syndrome.
abstract: 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.
authors.affiliation: Division of Gastroenterology, University of California, San Francisco, San Francisco, CA, USA.
authors.forename: Trilokesh D
authors.initials: TD
authors.lastname: Kidambi
authors.affiliation: Hereditary GI Cancer Prevention Program, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.
authors.forename: Amie
authors.initials: A
authors.lastname: Blanco
authors.affiliation: Department of Pathology, University of California, San Francisco, San Francisco, CA, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Van Ziffle
authors.affiliation: Division of Gastroenterology, University of California, San Francisco, San Francisco, CA, USA. Jonathan.Terdiman@ucsf.edu.|Hereditary GI Cancer Prevention Program, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA. Jonathan.Terdiman@ucsf.edu.|Clinical Medicine and Surgery, University of California, San Francisco, 1701 Divisadero, San Francisco, CA, 94115, USA. Jonathan.Terdiman@ucsf.edu.
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Terdiman
mesh_terms: D000230:Adenocarcinoma / Q000209:etiology / Q000235:genetics; D000328:Adult; D003111:Colonic Polyps / Q000150:complications / Q000175:diagnosis / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000209:etiology / Q000235:genetics; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000175:diagnosis* / Q000235:genetics; D019175:DNA Methylation; D005260:Female; D020022:Genetic Predisposition to Disease; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D053842:Microsatellite Instability; D060885:Multiplex Polymerase Chain Reaction; D000070957:MutL Protein Homolog 1 / Q000235:genetics*; D010375:Pedigree; D011401:Promoter Regions, Genetic
chemical_list: C501486:MLH1 protein, human; D000070957:MutL Protein Homolog 1
keywords: Epimutation; Hereditary colon cancer; Lynch syndrome; MLH1; Polyposis; Promoter hypermethylation