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Comprehensive Paired Tumor/Germline Testing for Lynch Syndrome: Bringing Resolution to the Diagnostic Process

Specialty Areas:
Date: January 24, 2019
Authors:
Beth Souders, Brigette Tippin Davis, Brittany Dougall, Carla Mason, Chia-Ling Gau, PhD, DABMG, Daniel Chen, Elizabeth C. Chao, Holly Laduca, Hsiao-Mei Lu, Jessica Profato, Kelly Fulk, Kory Jasperson, Mary Helen Black, Megan Landsverk, Melissa Pronold, Melissa Truelson, Monalyn Umali Salvador, Negar Ghahramani, Phillip N. Gray, Stephanie Gutierrez, Swati Shah
Journal: Journal of Clinical Oncology
Collaborators:
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ABSTRACT

Purpose

The current diagnostic testing algorithm for Lynch syndrome (LS) is complex and often involves multiple follow-up germline and somatic tests. We aimed to describe the results of paired tumor/germline testing performed on a large cohort of patients with colorectal cancer (CRC) and endometrial cancer (EC) to better determine the utility of this novel testing methodology.

Materials and Methods

We retrospectively reviewed a consecutive series of patients with CRC and EC undergoing paired tumor/germline analysis of the LS genes at a clinical diagnostic laboratory (N = 702). Microsatellite instability, MLH1 promoter hypermethylation, and germline testing of additional genes were performed if ordered. Patients were assigned to one of five groups on the basis of prior tumor screening and germline testing outcomes. Results for each group are described.

Results

Overall results were informative regarding an LS diagnosis for 76.1% and 60.8% of patients with mismatch-repair–deficient (MMRd) CRC and EC without and with prior germline testing, respectively. LS germline mutations were identified in 24.8% of patients in the group without prior germline testing, and interestingly, in 9.5% of patients with previous germline testing; four of these were discordant with prior tumor screening. Upon excluding patients with MLH1 promoter hypermethylation and germline mutations, biallelic somatic inactivation was seen in approximately 50% of patients with MMRd tumors across groups.

Conclusion

Paired testing identified a cause for MMRd tumors in 76% and 61% of patients without and with prior LS germline testing, respectively. Findings support inclusion of tumor sequencing as well as comprehensive LS germline testing in the LS testing algorithm. Paired testing offers a complete, convenient evaluation for LS with high diagnostic resolution.