Streamlining the diagnostic pathway for Lynch syndrome in colorectal cancer patients: A ten-year experience in a single Italian center

Lynch syndrome (LS) is largely underdiagnosed, although universal screening in colorectal cancer (CRC) patients through MisMatch Repair (MMR) testing, followed by genetic counseling and testing, is widely endorsed. The presence of BRAFV600E mutation and/or MLH1 promoter methylation rules out LS in MLH1-deficient (dMLH1) patients. Patients with stage I-IV CRC referred to our center for primary surgery between 2011 and 2021 were selected. Referral to genetic counseling and its yield of Lynch Syndrome diagnoses were compared in two cohorts of patients: cohort A (from 2011 to 2019) when only universal MMR IHC was performed, and cohort B (from 2019 to 2021) when in dMLH1 patients, BRAFV600E mutation and subsequent MLH1 promoter methylation in BRAF WT cases were implemented. Overall, defective MMR (dMMR) was found in 401 of 3263 patients (12.3%), 346 of them due to loss of MLH1 expression (86.3%) and 55 due to loss of MSH2, MSH6 or PMS2 (13.7%). Out of 401, 89 were from February 2019 (cohort B). Among cohort B dMLH1 patients (N=84), BRAFV600E testing reduced the number of genetic counseling sessions by 76.5%. Performing MLH1 promoter hypermethylation testing in the BRAF wild-type patients, reduced the number of genetic counseling sessions by 84%. Overall, 62 BRAFV600E mutated patients and 16 with MLH1 promoter hypermethylation in cohort B did not require genetic counselling for Lynch syndrome, which led to a 93% reduction in the number of pre-test sessions needed (78/84). The diagnostic yield of genetic counseling sessions with patients with MLH1 loss in Cohort B showed a 72% increase compared to Cohort A (1/9 vs 2/69, i.e. 11% vs 3%). Overall, low oncologist adherence to diagnostic guidelines was observed in both cohorts. Combining BRAFV600E and MLH1 promoter methylation testing for dMLH1 CRC patients may lead to substantial reductions in the number of genetic counseling sessions needed, while increasing their diagnostic yield for LS. However, multistep patient selection by oncologists may be impractical in routine clinical practice. Reflex testing, adding a ‘LS suspicion alert’ in pathology reports[LB1], and mainstreaming genetic testing could improve oncologists’ awareness of LS and their adherence to relevant diagnostic guidelines. A diagnostic pathway for LS that includes such strategies is being currently tested in an ongoing Italian multicenter prospective study, ItaLynch.