Genetic counseling (GC) in the era of next generation sequencing (NGS) to diagnose microsatellite instability (MSI) and deficient mismatch repair (dMMR) expression in colorectal cancer (CRC).

Abstract

e22597 Background: Hereditary Nonpolyposis Colorectal Cancer (HNPCC), known as Lynch syndrome, is inherited in an autosomal dominant manner, characterized by MSI or dMMR genes. Prior to introduction of mandate for dMMR and MSI testing and introduction of NGS, testing for MSI high/MMR deficiency depended on adequate family history used by Revised Bethesda criteria, (RBC). MSI/ dMMR in CRC can result from either germline or sporadic mutations (BRAF mutations or MLH1/PMS2 hypermethylation). Once sporadic causes are ruled out, GC is essential to confirm or exclude HNPCC. The objective of this study was to assess the frequency of referral for GC in MSI-high/dMMR CRC cases after excluding sporadic causes. Methods: Patients diagnosed with CRC were identified from the tumor registry at our institution between January 1st, 2014, and March 2024. Patient charts were reviewed for tumors associated with HNPCC, family history of CRC (FH), MSI status, MMR expression, BRAF mutation, and MLH1/MSH2 hypermethylation status. The percentage of patients with MSI-high status, negative for BRAF mutation and MLH/PMS2 hypermethylation who were referred for GC and percentage of patients who did not have further testing to rule out sporadic causes was calculated. These patients were cross-referenced with the genetic counseling clinic database. Results: 480 charts were reviewed. 60 (12.5%) had documented MSI-high/MMR deficiency status. Twenty patients (4.1%) had BRAF mutations or MLH/PMS2 hypermethylation, excluding HNPCC. Among 40 (66%) subjects qualified for further testing. Three were censored (1 refused further testing,1 switched care, 1 did not due to other reason). Of the remaining 37 subjects, 17 (45%) were referred for GC. Of the 17 referred, 11 (29%) were positive and 6 (16%) were negative for HNPCC. Twenty of the remaining subjects (54%) with MSI-high status did not undergo further testing to rule out sporadic causes and were not referred for GC. Conclusions: Despite the increase in the number of subjects who are tested for MSI/dMMR, a substantial number of patients did not get further testing to rule out sporadic causes and were not referred for necessary germline testing or GC. Category Number (%) Total Patients Tested for MSI/MMR 480 MSI-high/dMMR Subjects 60 (12.5%) BRAF/Hypermethylation + 20 (4.1%) Presumed Germline Subjects requiring further testing 37/60 (61%) 3 censored Germline testing or GC referral 17/37 (45%) Germline Positive 11 (29%) Subjects who did not undergo further testing. 20/37 (54%)