RESUMO
A genetic diagnosis facilitates personalized cancer treatment and clinical care of relatives at risk, however, although 25% of colorectal cancer cases are familial, around 95% of the families are genetically unresolved. In this study, we performed gene panel analysis on germline DNA of 32 established or candidate colorectal cancer predisposing genes in 149 individuals from either families with an accumulation of colorectal cancers or families with only one sporadic case of very early onset colorectal cancer (≤40 years at diagnosis). We identified pathogenic or likely pathogenic genetic variants in 10.1% of the participants in genes such as APC, POLE, MSH2 or PMS2. The MSH2 variant, c.2168C>T, p.(Ser723Phe) was previously described as a variant of unknown significance, but we have now reclassified it to be likely pathogenic. The POLE variant, c.1089C>A, p.(Asn363Lys) was identified in a patient with three metachronous colorectal cancers from age 28 and turned out to be de novo. One pathogenic PMS2 variant was novel. We also identified a number of highly interesting variants of unknown significance in APC, BUB1, TP53 and RPS20. The RPS20 variant is novel and was found in a large Amsterdam I positive family with a multi tumor phenotype including 12 cases of CRC from as early as age 24. This variant was found to segregate with cancer in the family and multiple in silico tools predict it to be pathogenic. Our data further support the shift from phenotypic-based cancer panels to large panels including all established genes involved in hereditary cancer syndromes or (targeted) whole genome sequencing. Additionally, identification of a likely disease-predisposing variant in RPS20 expands the phenotypic spectrum of RPS20-related cancers and emphasize that this gene is relevant to include in colorectal cancer gene panels.
RESUMO
OBJECTIVE: Most angiotensin-converting enzyme inhibitors (ACEIs) are prodrugs activated by carboxylesterase 1 (CES1). We investigated the prognostic importance of CES1 gene (CES1) copy number variation and the rs3815583 single-nucleotide polymorphism in CES1 among ACEI-treated patients with congestive heart failure (CHF). METHODS: Danish patients with chronic CHF enrolled in the previously reported Echocardiography and Heart Outcome Study were categorized according to their CES1 variants and followed up for up to 10 years. Risk for cardiovascular death and all-cause death was modeled by Cox proportional hazard analyses. RESULTS: A total of 491 ACEI-treated patients were included in the analyses. After a mean follow-up of 5.5 years, we found no difference in the risk for cardiovascular death and all-cause death between patients having three [hazard ratios (HRs) 1.06 (95% confidence interval (CI) 0.77-1.45) and 1.16 (95% CI 0.88-1.52)] or four [HRs 0.88 (95% CI 0.39-2.01) and 1.37 (95% CI 0.74-2.54)] CES1 copies and those with two copies, respectively. Similarly, no difference in the risk for cardiovascular and all-cause death was found for patients heterozygous [HRs 0.91 (95% CI 0.70-1.19) and 0.88 (95% CI 0.69-1.12)] or homozygous [HRs 0.58 (95% CI 0.30-1.15) and 0.82 (95% CI 0.48-1.39)] for the rs3815583 minor allele versus patients homozygous for the major allele. The active promoter of CES1A2 and the rs71647871 single-nucleotide polymorphism minor allele were detected at very low frequencies. CONCLUSION: This study did not support the use of CES1 copy number variation or rs3815583 as a predictor of fatal outcomes in ACEI-treated patients with CHF.