Rare Disease Report

Gene Sequencing Connects Lynch Syndrome with Other Cancers

JUNE 06, 2018
Krista Rossi
New research presented at the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, Illinois, suggests a link between Lynch syndrome (LS) and more cancer types than previously thought.

The data was grounded in research performed by investigators at Memorial Sloan Kettering Cancer Center in New York who conducted a genetic analysis of 15,000 tumor samples from 50 different cancer types in the search for glitches known as high microsatellite instability (MSI-H).

"Our findings suggest that all patients with MSI-H tumors should be tested for Lynch syndrome, regardless of cancer type or personal history," commented study author, Dr Zsofia Kinga Stadler in a recent statement.

A large number of DNA abnormalities in a tumor is associated with the genetic marker. However, the characterization of LS across heterogeneous MSI-H/MMR-D tumors is currently unknown.

Methods for the study included the utilization of a targeted NGS panel to determine MSI status via MSIsensor. Respectively, scores of < 3, ≥3 to < 10, or ≥10 designated Microsatellite stable (MSS), MSI-Indeterminate (MSI-I) or MSI-H status, and germline mutations were assessed in MLH1, MSH2, MSH6, PMS2, EPCAM. In addition, tumor signatures in LS patients and immunohistochemical staining (IHC) for MMR-D were assessed. Clinical variables were correlated with MSI and compared via Chi square or T-test.

According to the results, 93.2% of 15,045 tumors spanning more than 50 cancers were MSS, 4.6% were MSI-I, and 2.2% were MSI-H. In the MSS, MSI-I, and MSI-H groups, respectively (p-value < 0.001), germline mutations were identified in 0.3% (37/14,020), 1.9% (13/699), and 16.3% (53/326). Of 1,025 MSI-H/MSI-I tumors, 25% were CRC/EC, but 50% (33/66) of LS patients had MSI-H/MSI-I tumors less commonly or not previously associated with LS (mesothelioma, sarcoma, adrenocortical, melanoma, ovarian germ cell).

In 63.6% of cases, LS patients with MSI-H/MSI-I non-CRC/EC tumors only met testing criteria in addition to having had lower MSIsensor scores and being more likely to be MSI-I (MSI-I: non-CRC/EC, 30.3% (10/33) versus CRC/EC 9.1% (3/33); p-value = 0.03). In 86.4% (57/66) of LS MSI-H/MSI-I tumors, IHC was completed with 98.3% MMR-D-concordance. Seventy-eight percent of LS patients with MSS tumors had MSH6/PMS2 mutations, but 71% of LS patients with MSI-H/MSI-I tumors had MLH1/MSH2/EPCAM mutations (p-value < 0.001). 89% (33/37) of MSS tumors of LS pts had non-MMR-D signatures. 

Based off of the results, researchers concluded that LS across tumor types can be predicated by MSI-H/MMR-D. It was also concluded that the data displayed a more heterogeneous spectrum of LS-associated cancers than previously noted. In addition, nearly 40% of LS patients with MSI-H/MMR-D non-CRC/EC tumors did not meet clinical criteria for genetic testing, which implied that MSI-H/MMR-D tumors, regardless of cancer type or family history, should direct germline testing for the evaluation of LS.

"These are tumor types that we would never have referred for genetic counseling," added Dr Shannon Westin of MD Anderson Cancer Center in Houston. "Data like this is going to encourage (these tests) to become the standard of care," Dr Westin said.
 

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