Development, technical validation, and clinical application of a multigene panel for hereditary gastrointestinal cancer and polyposis

Abstract

Introduction: Recent advances in technology and research are rapidly changing the diagnostic approach to hereditary gastrointestinal cancer (HGIC) syndromes. Although the practice of clinical genetics is currently transitioning from targeted criteria-based testing to multigene panels, important challenges remain to be addressed. The aim of this study was to develop and technically validate the performance of a multigene panel for HGIC. Methods: CGT-colon-G14 is an amplicon-based panel designed to detect single nucleotide variants and small insertions/deletions in 14 well-established or presumed high-penetrance genes involved in HGIC. The assay parameters tested were sensitivity, specificity, accuracy, and inter-run and intra-run reproducibility. Performance and clinical impact were determined using 48 samples of patients with suspected HGIC/polyposis previously tested with the targeted approach. Results: The CGT-colon-G14 panel showed 99.99% accuracy and 100% inter- and intra-run reproducibility. Moreover, panel testing detected 1 actionable pathogenic variant and 16 variants with uncertain clinical impact that were missed by the conventional approach because they were located in genes not previously analyzed. Conclusion: Introduction of the CGT-colon-G14 panel into the clinic could provide a higher diagnostic yield than a step-wise approach; however, results may not always be straightforward without the implementation of new genetic counseling models.

Targeted next-generation sequencing as a diagnostic tool in gastrointestinal system cancer/polyposis patients

“…The genes with pathogenic variations were MUTYH (*604933), PALB2 (*610355), ATM (*607585), MLH1 (*120436), MSH2 (*609309), BRCA1 (*113705), APC (*611731), NBN (*602667), CHEK2 (+604373), RECQL3 (*604610), and FLCN (*607273); the genes with VUS were PMS2 (*600259), TSC2 (*191092), EP300 (*602700), GATA3 (*131320), NBN (*602667), EXT2 (*608210), AXIN2 (*604025), CHEK2 (+604373), MUTYH (*604933), ERBB2 (*164870), and BRCA2 (*600185). In a similar study including 48 cases of CRC/polyposis syndrome, Ricci et al 28 reported 23 pathogenic/likely pathogenic variations and 22 VUS in 14 different genes. The genetic heterogeneity of CRC syndromes indicates that multigene analyzing systems are cost- and time-effective for diagnosis.…”

“…Ricci et al 28 studied 14 genes in 48 hereditary gastrointestinal cancer and polyposis cases and 23 pathogenic/likely pathogenic variations and 22 VUS were detected. In our study, 30 (37.5%) pathogenic/likely pathogenic variations, 19 (23.75%) VUS, and 4 (5%) deletions were detected with MLPA; the mostly pathogenic/likely pathogenic variations were on the MSH2 gene with the diagnosis of colon cancer/colon cancer family history or Lynch syndrome.…”

“…In our study, 30 (37.5%) pathogenic/likely pathogenic variations, 19 (23.75%) VUS, and 4 (5%) deletions were detected with MLPA; the mostly pathogenic/likely pathogenic variations were on the MSH2 gene with the diagnosis of colon cancer/colon cancer family history or Lynch syndrome. Ricci et al 28 detected pathogenic/likely pathogenic variations mostly on the MUTYH gene. The difference may be due to different patient ethnicities or case numbers in the studies.…”

Hereditary colorectal cancer syndromes and the COVID-19 pandemic: results from a survey conducted in patients enrolled in a dedicated registry

“…All participants were selected from the TEAD registry. The inclusion criteria for patients were (1) having an identified pathogenic variant in a gene responsible for gastrointestinal cancer predisposition syndromes such as APC, MUTYH, POLE, SMAD4, MLH1, MSH2, MSH6, PMS2 , or CDH1 [ 14 ]; (2) providing written consent for research purposes; (3) being under active follow-up; (4) being ≥ 18 years of age.…”

Molecular profiling of pediatric and young adult colorectal cancer reveals a distinct genomic landscapes and potential therapeutic avenues

“…For all patients, a colorectal polyposis was endoscopically excluded and a negative family history for CRC/polyps was assessed. Additionally, in order to further exclude gastrointestinal cancer predispositions, we performed genetic testing with a multigene panel in all available PED patients (five out of eight) that resulted not-informative in all of them 32 .…”