Genomic markers can predict lynch syndrome across tumor types

Microsatellite instability (MSI) and DNA mismatch repair (MMR) deficiencies can predict Lynch syndrome (LS) across tumor types, according to researchers from Memorial Sloan Kettering Cancer Center (MSK), who presented this retrospective data analysis in a press conference at the annual meeting of the American Society of Clinical Oncology. This finding suggests that LS is linked to more types of cancer than previously thought, prompting a call for germline testing for LS in all individuals with MSI-high (MSI-H)/mismatch repair deficient (MMR-D) tumors.

"These findings will create valuable opportunities for precision interception and prevention," explained Zsofia Stadler, MD, clinic director of the Clinical Genetics Service and a medical oncologist at MSK. "We have identified that beyond colorectal and endometrial tumors, the presence of MSI-H/MMR-D predicts for the presence of LS irrespective of cancer type or family cancer history. Our data suggest that all individuals with MSI-H tumors should be tested for LS. For someone with a genetic predisposition such as LS, the benefit of early detection extends beyond the individual with cancer, as family members could also ultimately benefit from such strategies as increased surveillance or risk-reducing surgery, with the goal of early detection or even cancer prevention."

What Is Lynch Syndrome?

Lynch syndrome is among the most common hereditary cancer syndromes. Approximately one in 300 individuals may be affected by LS. This genetic cancer predisposition syndrome is characterized by the presence of germline mutations in the DNA of MMR genes. LS leads to an increased risk of cancer, specifically colorectal cancer and endometrial cancer, in addition to a high lifetime risk of a number of other cancers.

MSI and MMR testing have traditionally been performed in people with colorectal or endometrial cancer as an initial screening test for LS. The presence of MSI-H/MMR-D in colorectal or endometrial cancer prompts clinicians to proceed with further germline genetic testing for LS. Following the US Food and Drug Administration's 2017 tissue-site agnostic approval of pembrolizumab (Keytruda®) for MSI-H/MMR-D solid tumors, MSI testing across all advanced solid tumors is now supported. However, the prevalence of LS across MSI-H solid tumors was previously unknown.

Method and Findings

In this study, MSK researchers sought to determine the prevalence of LS across multiple cancer types as a function of tumor MSI status. The team assessed MSI in more than 15,000 patients with more than 50 types of cancer who went through MSK-IMPACT™ sequencing. The patients were separated into three cohorts: MSI high (2.2 percent of individuals), MSI indeterminate (4.6 percent of individuals), and MSI stable (93.2 percent of individuals). Following that, the researchers examined germline DNA to determine which patients had a mutation in the MMR genes, which is diagnostic of LS. Out of the MSI-H group, 16.3 percent had the presence of a germline mutation in the MMR genes, meaning that almost one in five individuals with MSI-H tumors were found to have LS. In the MSI-I group, 1.9 percent had LS, and in the MSI-S group, 0.3 percent. Based on this data, MSK researchers recommend that people with MSI-H or MMR-D tumors undergo germline testing for LS.

The researchers found that among the MSI-H and MSI-I LS cohorts (66 patients in total), only 50 percent had colorectal or endometrial cancer. Although both of those cancers had been previously associated with LS, the spectrum of tumors within LS appears to be much broader. Out of the 66 people, 33 had colorectal or endometrial cancer, meaning that they would have been identified as having LS with current clinical screening guidelines. However, 45 percent of the other 33 individuals did not meet current clinical testing criteria based on personal or family cancer history, suggesting that they would not have been tested for LS. Given the implications for cancer surveillance and prevention measures in affected families, these data support germline genetic assessment for LS in people with an MSI-H/MMR-D tumor, regardless of cancer type or family history.

Traditionally, people with colorectal or endometrial cancer have been screened for MSI-H/MMR-D, the hallmarks of LS-associated tumors. Until recently, testing for MSI-H/MMR-D has been done through a polymerase chain reaction–based microsatellite instability analysis or immunohistochemical analysis for MMR protein expression. Today, people with colorectal or endometrial cancer can undergo next-generation sequencing (NGS) through such platforms as MSK-IMPACT™. MSK-IMPACT, a 468-gene oncopanel intended to detect gene mutations and other critical genetic aberrations, is one of two FDA-authorized NGS platforms that have an MSI algorithm (MSI-NGS).

Precision Interception and Prevention at MSK

"Cancer is more treatable when it's caught early, and tools like MSK-IMPACT help us do just that by enabling us to analyze both tumor acquired and inherited genetic mutations," explained Dr. Stadler. "From now on, we will be recommending germline genetic testing to all of our patients who are found to have an MSI-H tumor on MSK-IMPACT analysis. These findings have greatly broadened our knowledge of LS, and the more insight we have into such cancer predisposition syndromes, the more we can do to intercept or prevent the associated cancers in those we treat and their family members."

MSK recently launched the Precision Interception and Prevention initiative, led by Luis Diaz, MD, Head of MSK's Division of Solid Tumor Oncology, to advance the developments in early detection. Through the use of NGS, liquid biopsies, early detection methods, and increased screening and surveillance of high-risk individuals, such as smokers, this initiative combines high-impact science and clinical medicine. This institution-wide, broad-ranging effort concentrates not only on catching cancer very early but also on preventing it from developing in the first place.

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