From the Guidelines
MLH1 promoter hypermethylation is a critical molecular alteration that should be tested for in the context of colorectal cancer, particularly when loss of MLH1 protein expression is observed, to distinguish sporadic cases from Lynch syndrome, as recommended by the most recent guidelines 1.
Importance of MLH1 Promoter Hypermethylation
MLH1 promoter hypermethylation is an epigenetic change that silences the MLH1 gene, leading to deficient mismatch repair (dMMR) and microsatellite instability (MSI) in various cancers, particularly colorectal cancer. This alteration is the most common cause of sporadic MSI-high colorectal cancers, accounting for approximately 80% of these cases, and is distinct from germline mutations in MLH1 seen in Lynch syndrome.
Testing for MLH1 Promoter Hypermethylation
Testing for MLH1 promoter hypermethylation is typically done after initial immunohistochemistry shows loss of MLH1 protein expression, as this helps distinguish sporadic cases from Lynch syndrome. The presence of MLH1 promoter hypermethylation often coincides with BRAF V600E mutations in colorectal cancer, which further supports a sporadic rather than hereditary origin. According to recent guidelines, if loss of MLH1 expression is observed, methylation analysis of the MLH1 promoter in the tumor and/or analysis for somatic BRAF V600E mutation should be carried out first 1.
Clinical Implications
Patients with tumors showing MLH1 promoter hypermethylation may respond differently to certain treatments, including potential benefits from immunotherapy due to the high mutational burden associated with dMMR/MSI-high status. The identification of MLH1 promoter hypermethylation has important implications for the management of patients with colorectal cancer, and its testing should be considered in the context of standard patient care, as recommended by recent guidelines 1.
Key Recommendations
- Testing for MLH1 promoter hypermethylation should be performed in the context of colorectal cancer, particularly when loss of MLH1 protein expression is observed 1.
- Methylation analysis of the MLH1 promoter in the tumor and/or analysis for somatic BRAF V600E mutation should be carried out first if loss of MLH1 expression is observed 1.
- Patients with tumors showing MLH1 promoter hypermethylation may benefit from immunotherapy due to the high mutational burden associated with dMMR/MSI-high status.
From the Research
MLH1 Promoter Hypermethylation
- MLH1 promoter hypermethylation is a mechanism that can lead to Lynch syndrome, a genetic condition that predisposes individuals to cancer, particularly colorectal and endometrial cancer 2.
- This epigenetic mechanism can result in the same features as sporadic cancers, making it challenging to discern between the two, including microsatellite instability, deficiency of mismatch repair proteins, and methylation of the MLH1 gene 2.
- A study developed a clinical assay for MLH1 promoter hypermethylation using a high-throughput genome-wide methylation array platform, which achieved clinically robust and reproducible results 3.
Diagnosis and Screening
- Universal tumor screening is performed to identify features suggestive of Lynch syndrome, and criteria have been established to decide when to test patients for constitutional MLH1 methylation, including age and type of cancer 2.
- A germline genetic test could be requested for all colorectal cancer patients aged 55 years or younger and all endometrial cancer patients younger than 50 years old, independently of family history 2.
- Screening for Lynch syndrome mainly involves a combination of traditional clinical criteria and molecular techniques, including MMR-immunohistochemistry, microsatellite instability testing, MLH1 promoter methylation testing, and gene sequencing 4.
Clinical Implications
- The prevalence of germline MLH1 epimutations is not precisely known and may be underestimated, and the associated cancer risk could be similar to that due to a MLH1 sequence variant 2.
- MLH1 epimutations could be secondary to other genetic defects and follow an autosomal dominant inheritance, while primary epimutations are often "de novo" events and do not follow Mendelian rules 2.
- Preventive strategies for endometrial cancer in Lynch syndrome include hysterectomy and bilateral salpingo-oophorectomy, as well as chemoprophylaxis using exogenous progestin or aspirin 4.