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Abstract Background Interpreting genetic variants remains a challenge in prostate cancer (PCa). Although many annotation tools are available for prioritizing causal variants, the clinical relevance of these variants is rarely studied. Methods We collected a cohort study that included 274 PCa patients from June 2017 to December 2020 and sequenced 19 DNA damage repair (DDR) genes in these patients and explored the clinical consequence of these different approaches. We also examined all-cause and PCa-specific survival in DDR gene mutation carriers compared to non-carriers after androgen receptor (AR)-directed therapy. Results We identified 13 variants from 19 DDR genes in a total of 14 (5.1%) patients who had at least one presumed pathogenic mutation using different annotation methods. Four variants were annotated as pathogenic, 11 variants were predicted as protein-truncating variants (PTVs), four variants received proxy-deleterious (Combined Annotation-Dependent Depletion scores of > 30), and only one variant was identified as a pathogenic variant or as having a functional effect by all three methods. PCa patients with PTVs were significantly associated with early onset, high cancer stage, and a worse response to AR-directed treatment. However, patients carrying a proxy-deleterious variant were only associated with a higher T (tumor) stage and N (node) stage than those without such a variant, but not associated with other clinical characteristics. In patients treated with AR-directed therapy, patients with a PTV showed an increased risk of all-cause death (adjusted hazard ratio (aHR) = 3.51, 95% confidence interval (CI): 1.06 ~ 11.56) and PCa-specific death (aHR = 4.49, 95% CI: 1.87 ~ 10.77) compared to non-PTV carriers after adjustment. We were unable to examine gene-specific risks due to the small number of patients. Conclusions PTVs may assist in guiding treatment and early screening in PCa, while population-specific data for pathogenic variants are still being amassed.

IntroductionDementia is associated with many comorbidities while being related to Apolipoprotein E (ApoE) polymorphism. However, it is unclear how these clinical illnesses and genetic factors modify the dementia risk.MethodsWe enrolled 600 dementia cases and 6000 matched non-dementia controls, with identified ApoE genotype (ε4/ε4, ε4/ε3, and ε3/ε3). Eight comorbidities were selected by medical records, and counted if occurring within 3 years of enrollment.ResultsThe dementia group had a higher ratio of carrying ε4 allele and prevalence of comorbidities than the non-dementia group. Homozygous ε4 carriers presented the broken line of dementia risk with the peak age at 65–75 years and odds ratio (OR) up to 6.6. The risk only emerged after 65 years of age in ε3/ε4 subjects with OR around 1.6–2.4 when aged > 75 years. Cerebrovascular accident (CVA) is the commonest comorbidity (14.6%). CVA, sleep disorder, and functional gastrointestinal disorders remained as significant risk comorbidities for dementia throughout all age groups (OR = 1.7–5.0). When functional gastrointestinal disorder and ε4 allele both occurred, the dementia risk exceeded the summation of individual risks (OR = 3.7 and 1.9 individually, OR = 6.0 for the combination). Comorbidities could also be predictors of dementia.ConclusionCombining the genetic and clinical information, we detected cognitive decline and optimize interventions early when the patients present a specific illness in a particular age and carry a specific ApoE allele. Of comorbidities, functional gastrointestinal disorder is the strongest predicting factor for dementia in ε4 allele carriers.