Colorectal cancer, intestinal carcinoma, colon cancer, bowel neoplasia, 3D illustration
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Research led by scientists at Cedars-Sinai Medical Center has uncovered that under current screening guidelines for Lynch syndrome—one of the most common hereditary cancer conditions, a significant number of younger patients go undiagnosed.

As many as one in every 300 people may be carriers of a mutation associated with Lynch syndrome—a hereditary condition that increases the predisposition to develop endometrial or colorectal cancer under the age of 50. Most commonly, the disease is linked to a mutation in a DNA repair gene causing mismatch repair deficiency, meaning that the tumors form due to mistakes during DNA replication in cell division.

However, mismatch repair deficiency can also be caused by a mutation in the MLH1 gene, responsible for a process known as DNA methylation. Reporting in the Journal of the National Comprehensive Cancer Network, scientists are now suggesting a reconsideration of current Lynch syndrome screening guidelines to include DNA methylation in the blood as a cause of the disease.

“When patients with Lynch syndrome—whose first cancers generally appear at an early age—aren’t diagnosed promptly, they don’t get appropriate follow-up or surveillance. They can go on to have multiple different cancers before they are finally diagnosed. If we could identify them when they have their first cancer, we could prevent additional cancers—or at least detect them earlier,” said Megan Hitchins, PhD, director of Translational Genomics in the Department of Biomedical Sciences at Cedars-Sinai and lead author of the study.

According to the researchers, MLH1 methylation exists in nearly 75% of tumors with mismatch repair deficiency. This methylation is usually present on the tumor directly, rendering the cancer non-hereditary and therefore not connected to Lynch syndrome. However, Hitchins and her team discovered that in a small fraction of patients with the disease, the methylation isn’t confined to the tumor and present in the blood, predisposing the cells to cancer development and leading to undiagnosed cases of the condition.

For their study, the researchers reviewed data from two large retrospective population-based studies and analyzed the blood DNA from mismatch repair deficient colorectal cancer patients who participated. According to the scientists, among patients age 55 and younger who had methylation in their tumors, 25–75% also had methylation in their blood, meaning they had Lynch syndrome but had not been diagnosed.

Following the study results, lead author Hitchins suggests that colorectal cancer patients under the age of 56 and endometrial cancer patients under the age of 50, ask their healthcare provider about additional screening for themselves and their families.

“We’ve been finding young patients with endometrial or colorectal cancer who are told they don’t have Lynch syndrome, then go on to develop a colon or other cancer that might have been prevented, or at least detected earlier. Those patients are walking around oblivious to their risk, and should be made aware of that fact and given the option of having a test,” Hitchins concluded in a press statement.

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