1. Fuerst, Mark L.

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CHICAGO-Lynch syndrome is linked to more types of cancer than previously thought, according to a genomic study of more than 15,000 tumor samples.

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Patients with tumors that have high microsatellite instability (MSI-H), a genomic marker associated with a large number of genetic mutations in the tumor, are more likely to have Lynch syndrome, a hereditary condition that increases the risk of developing many different types of cancer. The most common cancers associated with Lynch syndrome are colorectal and endometrial, but there is also a higher risk of developing other gastrointestinal, ovarian, brain, and skin cancers.


"Our findings suggest that all patients with MSI-H tumors should be tested for Lynch syndrome, regardless of cancer type or family or personal history of cancer," said senior study author Zsofia Kinga Stadler, MD, Clinic Director of the Clinical Genetics Service and a medical oncologist at Memorial Sloan Kettering Cancer Center in New York. "Diagnosing Lynch syndrome gives us the unique opportunity of helping not only our cancer patients, but also at-risk family members, as their cancer risk can be lowered."


Stadler presented the results of the study at a press briefing at the 2018 ASCO Annual Meeting (Abstract LBA1509).


An estimated 0.3 percent of people in the general population has Lynch syndrome. The hallmark of Lynch syndrome-associated tumors is MSI-H. "Universal tumor screening of all colorectal and endometrial cancers for markers of Lynch syndrome is recommended," said Stadler.


MSI is a genomic marker that indicates a defect in a cell's ability to repair damaged DNA, resulting in the accumulation of mutations, and is the hallmark of Lynch syndrome-associated cancers. Currently, MSI testing is performed on colorectal and endometrial cancers as an initial screening test to identify those patients who may be at risk for Lynch syndrome. The FDA-approval of pembrolizumab in 2017 for use in all MSI-H tumors, regardless of tumor type, led to a "surge of MSI testing outside of Lynch syndrome" of tumors to identify patients who may benefit from this immunotherapy, noted Stadler.


For the study, Memorial Sloan Kettering researchers analyzed 15,045 tumor samples collected from patients with more than 50 different types of advanced cancer using a comprehensive genomic test called MSK-IMPACT. This is a FDA-authorized, next-generation sequencing platform that also incorporates MSI detection using tumor-normal samples, Stadler explained. All study participants were part of a prospective study of MSK-IMPACT and received cancer treatment at the Memorial Sloan Kettering Cancer Center. The test looks for mutations in hundreds of cancer-related genes, as well as other molecular changes, including MSI.


The researchers also conducted a germline analysis on all tumors to identify mutations in mismatch repair deficiency (MMR-D) genes that included MLH1, MSH2, MSH6, PMS2, and EPCAM, and they assessed distribution of germline mutations across tumor types and according to MSI status. Mutations in these genes cause Lynch syndrome. Tumors caused by Lynch syndrome have MMR-D and are MSI-H.


Key Findings

Based on the results of the genomic analysis, the tumor samples were classified into three groups: MSI-stable (MSS, no MSI instability found), MSI-indeterminate (MSI-I, moderate level of MSI), and MSI-H. The vast majority (93.2%) of tumors were found to be MSS; 4.6 percent were MSI-I; and 2.2 percent were MSI-H.


Inherited mutations in Lynch syndrome-associated genes were found in 16 percent of people with MSI-H tumors as compared to 1.9 percent of those with MSI-I tumors and only 0.3 percent of those with MSS tumors, the same percentage as the general population.


As expected, about one-quarter of the 1,025 MSI-H/MSI-I tumors were colorectal or endometrial cancers. These are the most common cancers linked to Lynch syndrome, and MSI testing is routinely performed on these tumors. However, nearly half 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, sarcoma, adrenocortical cancer, melanoma, prostate cancer, and ovarian germ cell cancer.


Of these patients, 45 percent did not meet Lynch syndrome genetic testing criteria based on family or personal cancer history. "These tumors would not have undergone Lynch syndrome testing," said Stadler. This suggests that Lynch syndrome is linked to a broader spectrum of cancers than previously thought and that MSI-H/MMR-D is predictive of Lynch syndrome, regardless of cancer type.


In the final step of the study, 57 MSI-I/MSI-H tumor samples were also tested for abnormal DNA repair proteins, and MMR-D was found in nearly all (98.3%) of those tumors. These findings suggest that if either MSI-H or MMR-D is found in the tumor, hereditary genetic testing for Lynch syndrome should be performed.


The chance of developing certain cancers linked to Lynch syndrome can be lowered through frequent screening, for example, annual colonoscopy and endoscopy for gastrointestinal cancers, and preventive surgery, such as removal of the uterus and ovaries for gynecologic cancers. More research is needed to develop screening and preventive strategies for other cancers linked to Lynch syndrome, according to Stadler.


"Non-colorectal cancer or endometrial cancer Lynch-associated tumors are less likely to meet clinical criteria for genetic risk assessment," he concluded. "An MSI-H tumor signature, regardless of cancer subtype, should prompt germline genetic assessment for the evaluation of Lynch syndrome. This will increase the ability to recognize Lynch syndrome in other family members, too."


Mark L. Fuerst is a contributing writer.