Format

Send to

Choose Destination
J Med Genet. 2018 Apr;55(4):240-248. doi: 10.1136/jmedgenet-2017-104744. Epub 2018 Feb 22.

Comprehensive analysis of the MLH1 promoter region in 480 patients with colorectal cancer and 1150 controls reveals new variants including one with a heritable constitutional MLH1 epimutation.

Author information

1
Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich, Bavaria, Germany.
2
Center of Medical Genetics, Medizinisch Genetisches Zentrum, Munich, Bavaria, Germany.
3
Department of Human Genetics, Ruhr University Bochum, Bochum, North Rhine-Westphalia, Germany.
4
Institute of Pathology, Technical University Munich, Munich, Bavaria, Germany.
5
Praxis für Humangenetik, Praxis für Humangenetik, Hamburg, Hamburg, Germany.

Abstract

BACKGROUND:

Germline defects in MLH1, MSH2, MSH6 and PMS2 predisposing for Lynch syndrome (LS) are mainly based on sequence changes, whereas a constitutional epimutation of MLH1(CEM) is exceptionally rare. This abnormal MLH1 promoter methylation is not hereditary when arising de novo, whereas a stably heritable and variant-induced CEM was described for one single allele. We searched for MLH1 promoter variants causing a germline or somatic methylation induction or transcriptional repression.

METHODS:

We analysed the MLH1 promoter sequence in five different patient groups with colorectal cancer (CRC) (n=480) composed of patients with i) CEM (n=16), ii) unsolved loss of MLH1 expression in CRC (n=37), iii) CpG-island methylator-phenotype CRC (n=102), iv) patients with LS (n=83) and v) MLH1-proficient CRC (n=242) as controls. 1150 patients with non-LS tumours also served as controls to correctly judge the results.

RESULTS:

We detected 10 rare MLH1 promoter variants. One novel, complex MLH1 variant c.-63_-58delins18 is present in a patient with CRC with CEM and his sister, both showing a complete allele-specific promoter methylation and transcriptional silencing. The other nine promoter variants detected in 17 individuals were not associated with methylation. For four of these, a normal, biallelic MLH1 expression was found in the patients' cDNA.

CONCLUSION:

We report the second promoter variant stably inducing a hereditary CEM. Concerning the classification of promoter variants, we discuss contradictory results from the literature for two variants, describe classification discrepancies between existing rules for five variants, suggest the (re-)classification of five promoter variants to (likely) benign and regard four variants as functionally unclear.

KEYWORDS:

cancer: colon; epigenetics; genetic screening/counselling; genetics

PMID:
29472279
DOI:
10.1136/jmedgenet-2017-104744
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center