The presence of high microsatellite instability (MSI-H) was predictive of Lynch syndrome, a hereditary condition associated with increased cancer risk, across a variety of tumor types, a new study has found (abstract LBA1509). Among people with MSI-H tumors, 16% were later found to have Lynch syndrome, a much greater prevalence than seen in the general population.
This suggests that a more heterogeneous spectrum of cancers are associated with Lynch syndrome than previously thought, according to Zsofia Kinga Stadler, MD, clinic director of clinical genetics service and a medical oncologist at Memorial Sloan Kettering Cancer Center in New York, who presented the results at a press conference at the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting, held June 1–5 in Chicago.
“This study suggests that MSI-H tumor signature, regardless of cancer type and irrespective of family cancer history, should prompt germline genetic assessment for the evaluation of Lynch,” Stadler said. “This will result in an increased ability to recognize Lynch syndrome in our cancer patients but also in at-risk family members who may benefit from genetic testing for Lynch and subsequent enhanced cancer surveillance and risk reduction measures.”
MSI is a genomic marker characterized by a very large number of mutations due to a variation in the length of short DNA sequence repeats in tumor compared with normal tissue. It is the hallmark of Lynch-associated tumors.
Traditionally, MSI screening is performed in colorectal and endometrial cancers as a screen for Lynch syndrome. However, since the US Food and Drug Administration (FDA) approved the anti–PD-1 therapy pembrolizumab for use in all MSI-H tumors, regardless of tumor type, there has been a surge in MSI testing in metastatic cancers.
In this study, Stadler and colleagues analyzed 15,045 tumor samples taken from more than 50 different cancer types. Samples underwent testing with MSK-IMPACT, an FDA-approved next-generation sequencing platform that incorporates MSI detection. MSK-IMPACT stratifies tumors as MSI-H, MSI indeterminate (MSI-I), and microsatellite stable (MSS).
As expected, the highest level of MSI-H was found in small bowel tumors (25%), followed by endometrial cancers (16%), colorectal cancers (14%), and gastric cancers (6%). However, MSI-H was also seen in a number of other tumors, such as adrenocortical carcinoma, sarcoma, and bladder, prostate, and esophageal cancers.
Looking at the distribution of germline mismatch repair mutations across MSI status and tumor type, the study showed that 16.3% of samples that were MSI-H harbored Lynch syndrome. This decreased to only 1.9% of samples in tumors that were MSI-I, and was 0.3% in MSS samples, a number equivalent to the prevalence of Lynch syndrome seen in the general population.
One-half of patients with Lynch syndrome with MSI-H or MSI-I tumors had cancers other than colorectal or endometrial cancer. In addition, 45% of patients with Lynch syndrome with MSI-H or MSI-I non–colorectal or endometrial cancers did not meet clinical testing criteria for Lynch syndrome and would not have otherwise undergone Lynch syndrome testing.
Commenting on the results of the study, ASCO Expert Shannon Westin, MD, said that the results are “absolutely practice changing.”
“MSI-H status not only has therapeutic implications but also cancer prevention implication,” she said. “This shows us that we have only been testing the tip of the iceberg of patients affected by Lynch syndrome and under the surface are a large number of patients with specific cancer types that should be tested for Lynch syndrome. This is a straightforward testing strategy that can be immediately implemented.”