Testing Only the 'Tip of the Iceberg' for Common Hereditary Condition in MSI-H Tumors

Lynch syndrome — a hereditary condition that increases a person’s risk for developing several types of cancer – is common among people with microsatellite instability-high (MSI-H) tumors, linking it to several new cancer types, according to large genomic study results presented at the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting.

In turn, this means all patients with MSI-H tumors should also be tested for the hereditary condition.

“Microsatellite instability is a genomic marker in tumors that are characterized by a large number of mutations due to a variant in the length of short DNA sequence repeats … High frequency microsatellite instability, or microsatellite instability-high, is the hallmark of Lynch-associated tumors,” explained senior study author Zsofia Kinga Stadler, M.D., clinic director of the Clinical Genetics Service and medical oncologist at Memorial Sloan Kettering (MSK) Cancer Center.

Traditionally, MSI analysis is done in colorectal and endometrial cancer screening tests for Lynch syndrome, which is one of the most common autosomal dominant cancer predisposition syndromes caused by germline mutations in DNA mismatch repair (MMR) genes, Stadler added.

Since the Food and Drug Administration (FDA) approved Keytruda (pembrolizumab) for the treatment of all MSI-H advanced solid tumors, there has been an increase in MSI testing in metastatic cancer, regardless of type. However, the characterization of Lynch syndrome across various MSI-H and MMR-deficient tumors is unknown.

Therefore, the researchers analyzed 15,045 tumor samples collected from patients with more than 50 different types of advanced cancer using MSI analysis and a comprehensive genomic test called MSK-IMPACT, which designated patients as microsatellite stable (MSS; three or less mutations), MSI-indeterminate (MSI-I; three to 10 mutations), or MSI-H (10 or more mutations).

The majority of tumors were found to be MSS (93.2 percent; 14,020 patients), while 4.6 percent (699 patients) were considered MSI-I, and 2.2 percent (326 patients) had MSI-H tumors. Of these, analyses identified Lynch syndrome in 0.3 percent of MSS patients, 1.9 percent of MSI-I patients and 16.3 percent in the MSI-H group.

MSI-H status was identified in small bowel (25 percent), endometrial (16 percent), colorectal (14 percent), and gastric (6 percent) cancer.

However, nearly 50 percent of patients with MSI-H/MSI-I tumors who were identified as having Lynch syndrome had cancer types not previously, or rarely, linked to the syndrome, including mesothelioma (165 patients), sarcoma (785 patients), adrenocortical cancer (44 patients), melanoma (573 patients), prostate (1,048 patients), and ovarian germ cell cancer (348 patients).

“Our study supports that MSI-high is predictive of Lynch syndrome across tumor type,” Stadler said. “Our study also supports that the spectrum of cancers associated with Lynch syndrome seems to be much broader than previously thought.”

Among the patients with cancers not typically linked to Lynch syndrome, 45 percent did not meet germline genetic testing criteria based on family or personal cancer history. In addition, these patients had lower MSI analysis scores, and their tumors were more likely to test positive for MSI-I status (30.3 percent vs. 9.1 percent).

“Our study suggests that MSI-high signature, regardless of tumor type and irrespective of the family history should prompt germline genetic assessment for the evaluation of Lynch syndrome,” Stadler said. “This will result in an increased ability to recognize lynch syndrome, not only in our cancer patients, but also in at-risk family members who may benefit from genetic testing for Lynch, and subsequent enhanced surveillance and risk reduction measures.”

ASCO Expert Shannon Westin, MD, agreed, saying physicians are only testing “the tip of the iceberg patients that are affected by Lynch syndrome.”

“What we learned is that MSI not only has therapeutic implications, but also has cancer prevention implications,” she added. “And we now know that under the surface there is a larger number of patients with specific cancer types that should be tested for Lynch syndrome.”