News items Specific DNA mutations are common in atypical tumors of patients with Lynch syndrome

12 April 2023

People with Lynch syndrome are at increased risk of developing colorectal and endometrial cancer, but other forms are also more common. A study conducted by Radboud university medical center shows that many of these and other types of tumors contain specific DNA mutations. This makes these tumors susceptible to treatment with immunotherapy. 

Individuals with Lynch syndrome have a genetic predisposition to develop cancer. Colorectal and endometrial cancer are the most common, but several other tumors are also more prevalent in people with this inherited disorder. An estimated forty to fifty thousand Dutch people have Lynch syndrome.

Because of specific mutations in the DNA of colorectal and endometrial tumors in patients with Lynch syndrome, these cancers are very sensitive to immunotherapy. But is this also the case for other forms of cancer? Researchers from the Departments of Human Genetics and Pathology at Radboud university medical center assessed the prevalence of non-colorectal and non-endometrial tumors in people with Lynch syndrome. Furthermore, they investigated whether these atypical tumors also contain the specific DNA mutations.

DNA mutations are common 

The study was conducted in a group of more than 1,700 people with Lynch syndrome. Of these, more than a third developed colorectal or endometrial cancer. About fifteen percent developed other types of tumors. Many of these have previously been associated with Lynch syndrome, such as cancer of the small intestine, stomach and ureter. These are called Lynch-spectrum tumors. This does not apply to a rare form of breast cancer, the medullary type, but the study now shows that these tumors are also more common in people with Lynch syndrome.

The researchers demonstrated presence of the specific DNA mutations in virtually all Lynch-spectrum tumours. Almost forty percent of the tumors outside the Lynch spectrum also had these mutations. For the medullary form of breast cancer, this was as high as 75 percent. ‘That is remarkably often’, says investigator Richarda de Voer. ‘In cancer patients who do not have Lynch syndrome, these abnormalities are found in less than one percent of tumors.’

Immunotherapy effective

What does this mean for patients? Lead investigator Marjolijn Ligtenberg: 'In people with Lynch syndrome who develop cancer outside the colon or uterus, it is desirable to examine the tumor for the presence of these DNA mutations. If they are found, immunotherapy will likely be effective. This type of treatment is available for all advanced cancers with these characteristics, usually after previous treatments have not been successful enough.'

About the publication

This study was published in the Journal of the National Cancer Institute: Microsatellite instability in non-colorectal and non-endometrial malignancies in patients with Lynch syndrome. L. Elze, R.S. van der Post, J.R. Vos, A.R. Mensenkamp, M.S.C. de Hullu. I.D. Nagtegaal, N. Hoogerbrugge, R.M. de Voer, M.J.L. Ligtenberg. DOI: 10.1093/jnci/djad063.

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Matthijs Kox

senior researcher IC

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