Impact of Different Selection Approaches for Identifying Lynch Syndrome-Related Colorectal Cancer Patients: Unity Is Strength

Abstract

Lynch syndrome (LS) is an inherited genetic condition associated with increased predisposition to colorectal cancer (CRC) and other tumors and is caused by germline mutations in Mismatch Repair (MMR) or EPCAM genes. The identification of LS carriers is currently based on germline testing of subjects with MMR-deficient (dMMR) tumors or fulfilling clinical criteria, but the most efficient strategies to select patients who should be offered genetic testing are yet not well defined. In order to assess the most suitable selection mode to identify LS-related CRC patients, we retrospectively collected and analyzed all clinical and molecular information of 854 CRC patients, recruited from 2013 to 2021 at the University Hospital Policlinico “P. Giaccone” of Palermo (Italy), 100 of which were selected based on revised Bethesda guidelines, Amsterdam criteria II, or tissue MMR deficiency, and genetically tested for germline variants in LS-susceptibility genes. Our study showed that 32 out of 100 CRC patients harbored germline likely pathogenic/pathogenic variants in MMR genes. The analysis of tissue microsatellite instability (MSI) status according to the revised Bethesda guidelines has been to be the best selection approach. However, using different selection approaches as complementary strategies is useful to identify LS carriers, reducing underdiagnosis of this syndrome.

A novel mutation of MET in hereditary non-polyposis colorectal cancer identified by whole exome sequencing: report of a family

“…Because the clinical criteria are not sensitive enough to include all CRC cases with genetic risk, the idea of universal screening has been proposed by various institutions (15)(16)(17). With universal genome testing, various studies have reported detecting pathogenic variants in MMR in 0.2-2.2% of CRC cases, although 2.6-5.0% ful lled the Amsterdam II criteria (9,10,18). Beginning from CRC who ful lled Amsterdam criteria, 71% of the cases had micro-satellite instability, and 44% had pathogenic variants in MMR (19).…”

“…Apart from CRC, patients with Lynch syndrome have a higher risk of developing extracolonic cancers including endometrial cancer and ovarian cancer (1). Apart from Lynch syndrome, more than 50% of patients who meet the criteria of HNPCC but no detectable MMR mutations (9,10). Mutations in POLD1, POLE, which function in DNA proof reading, have been identi ed in a number of cases with this condition (11).…”

Genetic analysis of Japanese patients with small bowel adenocarcinoma using next-generation sequencing

“…However, there is a lack of consensus regarding individual gene mutation rates among studies. The relationship between individual gene mutations and mismatch repair (MMR) status and patients’ prognosis also remains controversial [ 11 , 13 , 14 ]. Moreover, there is a lack of comprehensive data on SBA genomic alterations reported from Asia, apart from one study on the genomic profile of Chinese SBA cohorts [ 15 ].…”