RESUMEN
Germline pathogenic variants in the DNA mismatch repair (MMR) genes (Lynch syndrome) predispose to colorectal (CRC) and endometrial (EC) cancer. However, mosaic variants in the MMR genes have been rarely described. We identified a likely de novo mosaic MSH6:c.1135_1139del p.Arg379* pathogenic variant in a patient diagnosed with suspected Lynch syndrome/Lynch-like syndrome. The patient developed MSH6-deficient EC and CRC at 54 and 58 years of age, respectively, without a detectable germline MMR pathogenic variant. Multigene panel sequencing of tumor and blood-derived DNA identified an MSH6 somatic mutation (MSH6:c.1135_1139del p.Arg379*) common to both the EC and CRC, raising suspicion of mosaicism. A droplet digital polymerase chain reaction (ddPCR) assay detected the MSH6 variant at 5.34% frequency in normal colonic tissue, 3.49% in saliva and 1.64% in blood DNA, demonstrating the presence of the MSH6 variant in all three germ layers. This study highlights the utility of tumor sequencing to guide sensitive ddPCR testing to detect low-level mosaicism in the MMR genes. Further investigation of the prevalence of MMR mosaicism is needed to inform routine diagnostic approaches and genetic counselling.
Asunto(s)
Neoplasias Colorrectales Hereditarias sin Poliposis , Neoplasias Endometriales , Femenino , Humanos , Neoplasias Colorrectales Hereditarias sin Poliposis/diagnóstico , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Neoplasias Colorrectales Hereditarias sin Poliposis/patología , Mutación de Línea Germinal , Neoplasias Endometriales/genética , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , ADN , Reparación de la Incompatibilidad de ADN , Homólogo 1 de la Proteína MutL/genética , Inestabilidad de MicrosatélitesRESUMEN
AIM: This study investigated temporal trends in the incidence of out-of-hospital cardiac arrests (OHCA) in metropolitan Perth (Western Australia) between 1997 and 2010. METHODS: We calculated crude and age-and-sex-standardised incidence rates (ASIRs) using the 2011 Australian population as the standard population. Incidence rates are reported per 100,000 population, and for eight age categories (0-14, 15-34, 35-64, 65-69, 70-74, 75-79, 80-84, ≥85). Temporal trends were analysed with linear regression. RESULTS: Over the 14-years, 12,421 OHCAs of presumed cardiac aetiology were attended by St John Ambulance Western Australia paramedics. The overall ASIR per 100,000 population decreased significantly over this time (75.7-70.6, p<0.001), but predominantly between 1997 and 2002 (75.7-65.9) and in those aged ≥65 years (410.2-336.7, p<0.001). This trend was observed for both males and females and across all five-year age-groups between 65 and 84 years, but not in those ≥85 years--whom by 2010 represented 30% of the older adult (65+ years) OHCAs attended, up from 16% in 1997 (p<0.001). CONCLUSIONS: Over the study period, a decline in the ASIR for OHCAs of presumed cardiac aetiology in Perth was observed. This is largely attributed to a decreasing incidence in the population aged 65-84 years between 1997 and 2002, and is likely the result of improvements in cardiovascular risk profiles that have previously been reported among Western Australian adults. Future studies of the impact of the ageing population are required.