查看更多>>摘要:Background:In 2021,the American College of Medical Genetics and Genomics(ACMG)recommended reporting actionable genotypes in 73 genes associated with diseases for which preventive or therapeutic measures are available.Evaluations of the association of actionable genotypes in these genes with life span are currently lacking.Methods:We assessed the prevalence of coding and splice variants in genes on the ACMG Secondary Findings,version 3.0(ACMG SF v3.0),list in the genomes of 57,933 Icelanders.We assigned pathogenicity to all reviewed variants using reported evidence in the ClinVar database,the frequency of variants,and their associations with disease to create a manually curated set of actionable genotypes(variants).We assessed the relationship between these genotypes and life span and further examined the specific causes of death among carriers.Results:Through manual curation of 4405 sequence variants in the ACMG SF v3.0 genes,we identified 235 actionable genotypes in 53 genes.Of the 57,933 participants,2306(4.0%)carried at least one actionable genotype.We found shorter median survival among persons carrying actionable genotypes than among noncarriers.Specifically,we found that carrying an actionable genotype in a cancer gene was associated with survival that was 3 years shorter than that among noncarriers,with causes of death among carriers attributed primarily to cancer-related conditions.Furthermore,we found evidence of association between carrying an actionable genotype in certain genes in the cardiovascular disease group and a reduced life span.Conclusions:On the basis of the ACMG SF v3.0 guidelines,we found that approximately 1 in 25 Icelanders carried an actionable genotype and that carrying such a genotype was associated with a reduced life span.
查看更多>>摘要:Background:Adjuvant pembrolizumab therapy after surgery for renal-cell carcinoma was approved on the basis of a significant improvement in disease-free survival in the KEYNOTE-564 trial.Whether the results regarding overall survival from the third prespecified interim analysis of the trial would also favor pembrolizumab was uncertain.Methods:In this phase 3,double-blind,placebo-controlled trial,we randomly assigned(in a 1:1 ratio)participants with clear-cell renal-cell carcinoma who had an increased risk of recurrence after surgery to receive pembrolizumab(at a dose of 200 mg)or placebo every 3 weeks for up to 17 cycles(approximately 1 year)or until recurrence,the occurrence of unacceptable toxic effects,or withdrawal of consent.A significant improvement in disease-free survival according to investigator assessment(the primary end point)was shown previously.Overall survival was the key secondary end point.Safety was a secondary end point.Results:A total of 496 participants were assigned to receive pembrolizumab and 498 to receive placebo.As of September 15,2023,the median follow-up was 57.2 months.The disease-free survival benefit was consistent with that in previous analyses(hazard ratio for recurrence or death,0.72;95%confidence interval[CI],0.59 to 0.87).A significant improvement in overall survival was observed with pembrolizumab as compared with placebo(hazard ratio for death,0.62;95%CI,0.44 to 0.87;P = 0.005).The estimated overall survival at 48 months was 91.2%in the pembrolizumab group,as compared with 86.0%in the placebo group;the benefit was consistent across key subgroups.Pembrolizumab was associated with a higher incidence of serious adverse events of any cause(20.7%,vs.11.5%with placebo)and of grade 3 or 4 adverse events related to pembrolizumab or placebo(18.6%vs.1.2%).No deaths were attributed to pembrolizumab therapy.Conclusions:Adjuvant pembrolizumab was associated with a significant and clinically meaningful improvement in overall survival,as compared with placebo,among participants with clear-cell renal-cell carcinoma at increased risk for recurrence after surgery.