The role of microsatellite instability as a marker for Lynch syndrome

Tumors with high microsatellite instability (MSI) are often associated with Lynch syndrome. Tumor patients with high MSI, and mutations in DNA mismatch repair genes should be checked for the syndrome.

Lynch syndrome may be the cause of more tumors than previously thought

Tumors with high microsatellite instability (MSI) are often associated with Lynch syndrome. Lynch syndrome is also involved in a much broader spectrum of tumors than previously thought. Therefore, patients with tumors with high MSI, and mutations in the DNA mismatch repair genes should be examined for Lynch syndrome.

The latest finding on the role of Microsatellite Instability (MSI) in relation to Lynch syndrome was provided by Alicia Latham Schwark, Memorial Sloan Kettering Cancer Center, New York, who drew from the results of a large gene analysis presented at the 2018 ASCO Annual Meeting in Chicago on June 4, 2018.

Lynch syndrome (hereditary non-polyposis colorectal cancer or HNPCC) is an autosomal dominant hereditary disease that is associated with a significantly increased risk of cancer - approximately 3% of all colorectal and endometrial cancers are due to Lynch syndrome. It occurs with a frequency of about 0.3 % in the population. Lynch syndrome is caused by mutations in the DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6, PMS2, and EPCAM. Due to the autosomal dominant inheritance, first-degree relatives of an HNPCC asset carrier are at 50% risk of also being asset carriers. Tumors associated with Lynch syndrome are characterized by high microsatellite instability (MSI-H).

MSI in a broad tumor spectrum

MSI is a marker for defective DNA repair mechanisms. This is the occurrence of new alleles within short repetitive DNA sequences (microsatellites). As a result of the defective DNA repair mechanisms, more and more mutations accumulate.

MSI has been tested for colorectal and endometrial cancer to find out whether patients also suffer from Lynch syndrome. However, since the approval of the PD1 inhibitor pembrolizumab for the treatment of all tumors with MSI-H, MSI testing has become much more widely used to identify patients who could benefit from pembrolizumab treatment.

Lynch syndrome not only causes colorectal tumors

The aim of the analysis was to determine the prevalence of germ-line mutations in the MMR genes in MSI-H tumors. The working group prospectively analyzed 15,045 samples from over 50 different tumors and classified the results into 3 groups:

In addition, mutations in the MMR genes were searched for in all samples.

MSS made up 93.2% of tumors, MSI-I 4.6% and 2.2% were MSI-H. Mutations in the Lynch syndrome-associated MMR genes were detected in 16.3% (53/326) of individuals with MSI-H tumors, in 1.9% (13/699) with MSI-I and 0.3% (37/14020) with MSS tumors.

As expected, colorectal and endometrial cancer accounted for approximately 25% and 16%, respectively, of the 1,025 MSI-H and MSI-I tumors. However, 50% (33/66) of patients with MSI-H and MSI-I tumors and Lynch syndrome had other cancers that have not or very rarely been associated with Lynch syndrome. These included, for example, mesothelioma, sarcoma, adenocarcinoma, melanoma, prostate and ovarian carcinoma. Of these, 45% (18/33) did not meet the criteria for Lynch syndrome genetic testing and would not normally have been further investigated for this hereditary disease.

"Our study indicates that the spectrum of cancers associated with Lynch syndrome is much broader than we previously thought," said Zsofia Kinga Stadler, head of the study, at an ASCO press conference. The conclusion was that the results of this analysis show that Lynch syndrome is associated with a wider range of cancers than previously thought and that high MSI and MMR deficiency is predictive of Lynch syndrome, regardless of the type of cancer. "The diagnosis of Lynch syndrome gives us a unique opportunity to help not only our cancer patients but also family members with an increased risk of cancer because it can be reduced through increased monitoring and - in some cases - prophylactic surgery," Stadler explained.

ASCO expert Shannon Westin, from the University of Texas' MD Anderson Cancer Center, Houston, described the study at the ASCO press conference as "absolutely practice-changing". MSI is not only important for the treatment of tumors but also has an effect on cancer prevention. Westin continued: "This is an uncomplicated test strategy that can be implemented immediately and that affects not only patients but also their relatives. That can't be overstated."

Schwark AL et al. Pan-cancer microsatellite instability to predict for the presence of Lynch syndrome.  2018 ASCO Annual Meeting, Chicago, 1. bis 5. Juni  2018, Abstract LBA1509.