Rare cause of hereditary cancer missed in younger patients

Cedars-Sinai Cancer investigators, US, have conducted new research that could potentially lead to a revision of current screening guidelines for Lynch syndrome, the most common cause of hereditary colorectal and endometrial cancers. The study, published today in the Journal of the National Comprehensive Cancer Network (JNCCN), highlights the significant number of undiagnosed patients due to existing guidelines.

Lynch syndrome is characterised by a predisposition to early-onset colorectal and endometrial cancers. Prompt diagnosis is crucial for patients with this syndrome as it enables appropriate follow-up and surveillance to detect and prevent additional cancers. However, according to the lead author of the study, Dr Megan Hitchins, Director of Translational Genomics in the Department of Biomedical Sciences at Cedars-Sinai, many patients with Lynch syndrome remain undiagnosed, leading to missed opportunities for early intervention.

The researchers focused on a poorly recognised cause of Lynch syndrome: methylation of a gene called MLH1. In most cases, Lynch syndrome is caused by an inherited mutation in a DNA mismatch repair gene. However, mismatch repair deficiency, a hallmark of Lynch syndrome, can also result from methylation of MLH1. This alteration disrupts DNA replication during cell division, leading to the formation of tumours.

Hitchins explains that methylation is different from a genetic mutation. It is an external modification, like debris clogging an engine, which affects the functioning of the gene. The study found that MLH1 methylation was present in as many as 75 percent of tumours with mismatch repair deficiency. Normally, methylation occurs only in the tumour and is not inherited, indicating that the patient does not have Lynch syndrome. However, the study identified a small fraction of patients where methylation was present in normal tissues, predisposing them to cancer development.

To determine the frequency of this occurrence, the investigators reviewed data from two large retrospective population-based studies and tested the blood DNA of colorectal cancer patients with mismatch repair deficiency. They found that among patients under the age of 55 with methylation in their tumours, 25-75 percent also had methylation in their blood, indicating the presence of undiagnosed Lynch syndrome.

In a previous study published in Gynecologic Oncology, Hitchins and her colleagues also tested the blood of patients with endometrial cancer and found that approximately 30 percent of them had methylation in their tumours. Among those under the age of 50, 15-20 percent had methylation in their blood, indicating the likelihood of Lynch syndrome.

The findings from both studies suggest that a change in screening guidelines is warranted for this particular group of patients. Early detection through appropriate screening can enable potentially life-saving surveillance, as well as early detection and treatment of subsequent cancers.

Hitchins recommends that colorectal cancer patients under the age of 56 and endometrial cancer patients under the age of 50 discuss additional screening with their healthcare providers. She also suggests that primary care providers and oncologists reach out to young patients from the past five years whose tumours tested positive for MLH1 methylation.

The study’s implications are significant, as it raises awareness about the importance of accurate diagnosis and comprehensive screening for Lynch syndrome. Many young patients with colorectal or endometrial cancer may not be aware of their increased risk due to undiagnosed Lynch syndrome. By implementing the suggested changes in screening guidelines, healthcare providers can offer patients the opportunity for timely surveillance, early detection, and potentially life-saving interventions.