Identification of constitutional MLH1 epimutations and promoter variants in colorectal cancer patients from the colon cancer family registry

Robyn L. Ward, Timothy Dobbins, Noralane Morey Lindor, Robert W. Rapkins, Megan P. Hitchins

Research output: Contribution to journalArticle

45 Citations (Scopus)

Abstract

Purpose:Constitutional MLH1 epimutations manifest as promoter methylation and silencing of the affected allele in normal tissues, predisposing to Lynch syndrome-Associated cancers. This study investigated their frequency and inheritance.Methods:A total of 416 individuals with a colorectal cancer showing loss of MLH1 expression and without deleterious germline mutations in MLH1 were ascertained from the Colon Cancer Family Registry (C-CFR). Constitutive DNA samples were screened for MLH1 methylation in all 416 subjects and for promoter sequence changes in 357 individuals.Results:Constitutional MLH1 epimutations were identified in 16 subjects. Of these, seven (1.7%) had mono-or hemi-Allelic methylation and eight had low-level methylation (2%). In one subject the epimutation was linked to the c.-27C>A promoter variant. Testing of 37 relatives from nine probands revealed paternal transmission of low-level methylation segregating with a c.+27G>A variant in one case. Five additional probands had a promoter variant without an MLH1 epimutation, with three showing diminished promoter activity in functional assays.Conclusion:Although rare, sequence changes in the regulatory region of MLH1 and aberrant methylation may alone or together predispose to the development of cancer. Screening for these changes is warranted in individuals who have a negative germline sequence screen of MLH1 and loss of MLH1 expression in their tumor.Genet Med 2013:15(1):25-35.

Original languageEnglish (US)
Pages (from-to)25-35
Number of pages11
JournalGenetics in Medicine
Volume15
Issue number1
DOIs
StatePublished - Jan 2013

Fingerprint

Colonic Neoplasms
Methylation
Registries
Colorectal Neoplasms
Viverridae
Hereditary Nonpolyposis Colorectal Neoplasms
Neoplasms
Germ-Line Mutation
Nucleic Acid Regulatory Sequences
Alleles
DNA

Keywords

  • colorectal cancer
  • epimutation
  • Lynch
  • methylation
  • MLH1

ASJC Scopus subject areas

  • Genetics(clinical)

Cite this

Identification of constitutional MLH1 epimutations and promoter variants in colorectal cancer patients from the colon cancer family registry. / Ward, Robyn L.; Dobbins, Timothy; Lindor, Noralane Morey; Rapkins, Robert W.; Hitchins, Megan P.

In: Genetics in Medicine, Vol. 15, No. 1, 01.2013, p. 25-35.

Research output: Contribution to journalArticle

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N2 - Purpose:Constitutional MLH1 epimutations manifest as promoter methylation and silencing of the affected allele in normal tissues, predisposing to Lynch syndrome-Associated cancers. This study investigated their frequency and inheritance.Methods:A total of 416 individuals with a colorectal cancer showing loss of MLH1 expression and without deleterious germline mutations in MLH1 were ascertained from the Colon Cancer Family Registry (C-CFR). Constitutive DNA samples were screened for MLH1 methylation in all 416 subjects and for promoter sequence changes in 357 individuals.Results:Constitutional MLH1 epimutations were identified in 16 subjects. Of these, seven (1.7%) had mono-or hemi-Allelic methylation and eight had low-level methylation (2%). In one subject the epimutation was linked to the c.-27C>A promoter variant. Testing of 37 relatives from nine probands revealed paternal transmission of low-level methylation segregating with a c.+27G>A variant in one case. Five additional probands had a promoter variant without an MLH1 epimutation, with three showing diminished promoter activity in functional assays.Conclusion:Although rare, sequence changes in the regulatory region of MLH1 and aberrant methylation may alone or together predispose to the development of cancer. Screening for these changes is warranted in individuals who have a negative germline sequence screen of MLH1 and loss of MLH1 expression in their tumor.Genet Med 2013:15(1):25-35.

AB - Purpose:Constitutional MLH1 epimutations manifest as promoter methylation and silencing of the affected allele in normal tissues, predisposing to Lynch syndrome-Associated cancers. This study investigated their frequency and inheritance.Methods:A total of 416 individuals with a colorectal cancer showing loss of MLH1 expression and without deleterious germline mutations in MLH1 were ascertained from the Colon Cancer Family Registry (C-CFR). Constitutive DNA samples were screened for MLH1 methylation in all 416 subjects and for promoter sequence changes in 357 individuals.Results:Constitutional MLH1 epimutations were identified in 16 subjects. Of these, seven (1.7%) had mono-or hemi-Allelic methylation and eight had low-level methylation (2%). In one subject the epimutation was linked to the c.-27C>A promoter variant. Testing of 37 relatives from nine probands revealed paternal transmission of low-level methylation segregating with a c.+27G>A variant in one case. Five additional probands had a promoter variant without an MLH1 epimutation, with three showing diminished promoter activity in functional assays.Conclusion:Although rare, sequence changes in the regulatory region of MLH1 and aberrant methylation may alone or together predispose to the development of cancer. Screening for these changes is warranted in individuals who have a negative germline sequence screen of MLH1 and loss of MLH1 expression in their tumor.Genet Med 2013:15(1):25-35.

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