Stains & molecular markers

Topic Completed: 1 January 2014

Minor changes: 7 April 2021

Copyright: 2002-2021,, Inc.

PubMed Search: MLH1 [title]

Maryam Abdelghani, M.D.
Brian Quigley, M.D.
Page views in 2020: 5,617
Page views in 2021 to date: 1,731
Cite this page: Abdelghani M. MLH1. website. Accessed April 19th, 2021.
Definition / general
  • Mismatch repair gene
  • Mutations associated with Lynch syndrome (hereditary non-polyposis colon cancer) and some cases of sporadic colon cancer
  • Also called MutL homolog 1 colon cancer nonpolyposis type 2 (NCBI-Gene), hMLH1
  • 90% of cases of Lynch syndrome (hereditary non-polyposis colon cancer) are due to autosomal dominant inheritance of a mutation in MLH1 (50%) or MSH2 (40%)
  • Mutations may also occur in MSH6, PMS2 and PMS1 (10% combined) (Sao Paulo Med J 2009;127:46)
  • MLH1 inactivation causes high levels of microsatellite instability (MSI), which alters the cell’s ability to repair errors normally produced during DNA replication, which is associated with carcinogenesis
  • Nongenetic (acquired) inactivation of MLH1 or other mismatch repair genes is associated with 15% of sporadic colorectal carcinomas
  • Acquired promoter hypermethylation often occurs with global hypermethylation of gene promoters known as CpG island methylator phenotype
  • When CpG sites in promoter regions of both copies of MLH1 are hypermethylated, MLH1 expression is lost and genomic instability occurs (Arch Pathol Lab Med 2011;135:1269)
  • MLH1 expression may determine patterns of Kras mutation in colon carcinoma (Hum Mol Genet 2004;13:2303)
  • Loss of MLH1 expression commonly associated with serrated intestinal polyps (Am J Surg Pathol 2003;27:65, Am J Surg Pathol 2007;31:1742), colonic medullary carcinoma (Hum Pathol 2009;40:398)
  • Loss of MLH1 expression also present in ampullary carcinoma and precursor lesions (occasinally, Am J Surg Pathol 2009;33:691), breast cancer (44%, Hum Pathol 2008;39:672), endometrial and ovarian carcinoma with undifferentiated components (Mod Pathol 2010;23:781), uterine carcinosarcoma (33%, Mod Pathol 2011;24:1368)
Diagrams / tables

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Colorectal carcinoma: MMR status

  • Any nuclear staining is considered retained (normal); loss of nuclear staining (with positive directly adjacent internal control) indicates an abnormal result, with caveats:
    • When MLH1 is lost by IHC, PMS2 should also be lost
    • Many colon carcinoma cases with loss of MLH1 expression show a few tiny scattered brown dots in tumor cell nuclei on IHC (still considered lost; correlate with PMS2 staining)
    • If a colon carcinoma has two distinct morphologies (e.g. gland-forming and mucinous) and MLH1 is lost by IHC in one component while retained in the other, this could still represent true loss and Lynch syndrome is a possibility (correlate with PMS2)
    • If there is no nuclear staining whatsoever in tumor or background cells, this is uninterpretable and may represent either a failed stain or (rarely) germline homozygous MLH1 mutation (correlate with control slides and PMS2)
  • Recommended to restrict test to experienced pathologists (Am J Surg Pathol 2008;32:1246), or to have quality assessment programs and classification guidelines (Hum Pathol 2010;41:1387)
  • Use molecular testing to follow up indefinite or aberrant staining results
Uses by pathologists
Microscopic (histologic) images

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Colorectal, gastric tumors

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Medullary carcinoma, MLH1-

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