Introduction Lynch syndrome (LS) and constitutional mismatch repair deficiency (CMMRD) are hereditary cancer syndromes associated with mismatch repair (MMR) deficiency. Tumours show microsatellite instability (MSI), also reported at low levels in non-neoplastic tissues. Our aim was to evaluate the performance of high-sensitivity MSI (hs-MSI) assessment for the identification of LS and CMMRD in non-neoplastic tissues.
Materials and methods Blood DNA samples from 131 individuals were grouped into three cohorts: baseline (22 controls), training (11 CMMRD, 48 LS and 15 controls) and validation (18 CMMRD and 18 controls). Custom next generation sequencing panel and bioinformatics pipeline were used to detect insertions and deletions in microsatellite markers. An hs-MSI score was calculated representing the percentage of unstable markers.
Results The hs-MSI score was significantly higher in CMMRD blood samples when compared with controls in the training cohort (p<0.001). This finding was confirmed in the validation set, reaching 100% specificity and sensitivity. Higher hs-MSI scores were detected in biallelic MSH2 carriers (n=5) compared with MSH6 carriers (n=15). The hs-MSI analysis did not detect a difference between LS and control blood samples (p=0.564).
Conclusions The hs-MSI approach is a valuable tool for CMMRD diagnosis, especially in suspected patients harbouring MMR variants of unknown significance or non-detected biallelic germline mutations.
- lynch syndrome
- constitutional mismatch repair deficiency
- microsatellite instability
- next generation sequencing
- highly sensitive methodologies
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GC and MP are joint senior authors.
MG-A, FM and BP are joint first authors.
GC and MP contributed equally.
MG-A, FM and BP contributed equally.
Contributors MG-A, FM and BP designed and performed the research, analysed the data and wrote the manuscript. NB assisted in bioinformatics analyses. AF assisted in molecular analyses. MaN, HS, FB, SI, AV, EGG, VM, LIG-G, PG-G, BF, CK, TiR, ThR, DJ-L, AAA, IR, MiN, H-JP, SL, MS, KD, TI, UD and JB provided samples and clinical data. VM also contributed to the statistical analysis. RA assisted in molecular analyses. CL, DR and KW provided samples, supervised the study and wrote the manuscript. MP and GC conceived the project, supervised the study, analysed the data and wrote the manuscript. All authors revised and approved the manuscript. MP and GC shared the last authorship.
Funding This work was funded by the Spanish Ministry of Economy and Competitiveness and cofunded by FEDER funds - a way to build Europe (grant SAF2015-68016-R), CIBERONC and the Government of Catalonia (grants 2017SGR1282 and PERIS SLT002/16/0037), and the AECC fellowship to MG-A. AF was supported by a grant from the Catalonian Health Department (SLT002/16/00409). FM was supported by CIBERONC. We thank the CERCA Programme for institutional support.
Competing interests None declared.
Patient consent for publication Obtained.
Ethics approval The study was approved by the ethics committee of the Bellvitge University Hospital (HUB) (file no PR255/15). Written informed consent was obtained from all individuals.
Provenance and peer review Not commissioned; externally peer reviewed.
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