Universal molecular screening does not effectively detect Lynch syndrome in clinical practice

Abstract

Background:Lynch syndrome (LS) due to an inherited damaging mutation in mismatch repair (MMR) genes comprises 3% of all incident colorectal cancer (CRC). Molecular testing using immunohistochemistry (IHC) for MMR proteins is a recommended screening tool to identify LS in incident CRC. This study assessed outcomes of population-based routine molecular screening for diagnosis of LS in a regional center.Methods:We conducted a prospective, consecutive case series study of universal IHC testing on cases of resected CRC from September 2004–December 2013. Referred cases with abnormal IHC results that attended a familial cancer clinic were assessed according to modified Bethesda criteria (until 2009) or molecular criteria (from 2009).Results:1612 individuals underwent resection for CRC in the study period and had MMR testing by IHC. Of these, 274 cases (16.9%) exhibited loss of expression of MMR genes. The mean age at CRC diagnosis was 68.1 years (± standard deviation 12.7) and the mean age of those with an IHC abnormality was 71.6 (± 11.8). A total of 82 (29.9%) patients with an abnormal result were seen in a subspecialty familial cancer clinic. Patients aged under 50 (p = 0.009) and those with loss of MSH6 staining (p = 0.027) were more likely to be referred and to attend. After germ-line sequencing, 0.6% (10 of 82) were identified as having a clinically significant abnormality. A further eight probands with pathogenic germ-line mutations were identified from other referrals to the service over the same time period.Conclusions:While technically accurate, the yield of ‘universal’ IHC in detecting new Lynch probands is limited by real-world factors that reduce referrals and genetic testing. We propose an alternative approach for universal, incident case detection of Lynch syndrome with ‘one-stop’ MMR testing and sequencing.

Barriers to Lynch Syndrome Testing and Preoperative Result Availability in Earlyonset Colorectal Cancer: A National Physician Survey Study

“…Furthermore, a recent provider study, most of whom were non-gastroenterologists, revealed inconsistent LS identification and ad hoc testing practices with IHC ordered by a variety of providers 25 . Prior research demonstrated that even when institutional universal (all CRC cases) IHC testing was recommended, some might still not undergo testing 26 . Furthermore, if results were abnormal, genetic testing referral was inconsistent.…”

“…Suboptimal availability of genomic resources in these settings is a target for intervention. Decreased access to genetic specialists is a significant barrier to genetic testing and diagnosing LS 26 . Rural location was demonstrated as a barrier to genetics evaluation for hereditary breast cancer for multiple reasons including lack of awareness and distance of services 31 .…”

Recent progress in Lynch syndrome and other familial colorectal cancer syndromes

“…As universal tumor testing has become more widespread in clinical practice, data are now emerging that highlight CA CANCER J CLIN 2018;68:217-231 VOLUME 68 _ NUMBER 3 _ MAY/JUNE 2018 the real-world challenges of capitalizing on its theoretical benefits, particularly with regard to appropriate referral for genetic counseling and testing after abnormal MMR IHC and/or MSI test results. 24,30,74,75 Data also demonstrate that somatic NGS panels have the ability to assess somatic mutational burden as a highly concordant surrogate for MSI/defective MMR (dMMR) status, suggesting that such somatic testing may be able to replace traditional MMR IHC and MSI testing, especially when universally implemented for ascertainment of other clinically relevant somatic mutations (eg, Kirsten rat sarcoma [RAS] proto-oncogene homolog, GTPase [KRAS]; neuroblastoma RAS protooncogene, GTPase [NRAS]; and B-Raf proto-oncogene, serine/threonine kinase [BRAF] mutation status in CRC). 76,77 Another potential pitfall that has emerged as universal MMR IHC/MSI tumor testing has become widespread is the molecular diversity of sporadic forms of MSI/dMMR CRCs and ECs.…”

Next-Generation Service Delivery: A Scoping Review of Patient Outcomes Associated with Alternative Models of Genetic Counseling and Genetic Testing for Hereditary Cancer

“…In tumor-first GC models, genetic screening is first performed on a sample of tumor tissue, often as part of a pathology workflow, with GC offered based on the tumor results. A total of 26 publications from six countries that reviewed patient outcomes of tumor testing were identified ( Table 7 ) [ 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 , 98 , 99 , 100 , 101 , 102 , 103 ]. In total, 23 publications [ 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 , 98 , 99 , 100 ], including four abstracts [ 90 , ...…”