Validation of the NCCN/Yale criteria for the identification of pathogenic variant carriers.

Background: Diffuse gastric and lobular breast cancer (LBC) syndrome is an autosomal-dominant syndrome characterised by early-onset diffuse gastric cancer and LBC most often caused by germline pathogenic variants (PVs) in . We previously showed the International Gastric Cancer Linkage Consortium (IGCLC) criteria for genetic testing to have poor sensitivity for PV and proposed our own simpler and more sensitive Yale criteria. The European Reference Network on Genetic Tumour Risk Syndromes subsequently proposed expanding the IGCLC criteria and showed its LBC-expanded criteria to be more sensitive than the IGCLC criteria in a European cohort of PV carriers.

Molecular and Sociodemographic Colorectal Cancer Disparities in Latinos Living in Puerto Rico.

Background: The incidence of sporadic colorectal cancer (CRC) among individuals <50 years (early-onset CRC) has been increasing in the United States (U.S.) and Puerto Rico.

Systems approach to enhance Lynch syndrome diagnosis through tumour testing.

Background: Guidelines recommend universal mismatch repair (MMR) tumour testing of colorectal adenocarcinomas (CRCs) to screen for Lynch syndrome (LS). However, its implementation remains disjointed and referral for genetic testing dismal, particularly among minorities. We aimed to increase referral, cancer genetic testing and eventually LS diagnosis by developing the CLEAR LS (Closed Loop Enhanced Assessment and Referral for Lynch Syndrome) intervention, a systems approach which in the second phase was automated.

Mutational signature profiling classifies subtypes of clinically different mismatch-repair-deficient tumours with a differential immunogenic response potential.

Background: Mismatch repair (MMR) deficiency is the hallmark of tumours from Lynch syndrome (LS), sporadic MLH1 hypermethylated and Lynch-like syndrome (LLS), but there is a lack of understanding of the variability in their mutational profiles based on clinical phenotypes. The aim of this study was to perform a molecular characterisation to identify novel features that can impact tumour behaviour and clinical management.

Methods: We tested 105 MMR-deficient colorectal cancer tumours (25 LS, 35 LLS and 45 sporadic) for global exome microsatellite instability, cancer mutational signatures, mutational spectrum and neoepitope load.

Simplified and more sensitive criteria for identifying individuals with pathogenic variants.

Background: Hereditary diffuse gastric cancer (HDGC) is an autosomal-dominant syndrome most often caused by pathogenic variants in . The International Gastric Cancer Linkage Consortium (IGCLC) recently updated its criteria for genetic testing. The purpose of this study was to estimate the sensitivity of IGCLC's 2020 criteria for identifying carriers of pathogenic variants and to formulate a new set of criteria that is simpler and more sensitive.