High-risk and silent clonal hematopoietic genotypes in patients with nonhematologic cancer.

ABSTRACT: Clonal hematopoiesis (CH) identified by somatic gene variants with variant allele fraction (VAF) ≥ 2% is associated with an increased risk of hematologic malignancy. However, CH defined by a broader set of genotypes and lower VAFs is ubiquitous in older individuals. To improve our understanding of the relationship between CH genotype and risk of hematologic malignancy, we analyzed data from 42 714 patients who underwent blood sequencing as a normal comparator for nonhematologic tumor testing using a large cancer-related gene panel. We cataloged hematologic malignancies in this cohort using natural language processing and manual curation of medical records. We found that some CH genotypes including JAK2, RUNX1, and XPO1 variants were associated with high hematologic malignancy risk. Chronic disease was predicted better than acute disease suggesting the influence of length bias. To better understand the implications of hematopoietic clonality independent of mutational function, we evaluated a set of silent synonymous and noncoding mutations. We found that silent CH, particularly when multiple variants were present or VAF was high, was associated with increased risk of hematologic malignancy. We tracked expansion of CH mutations in 26 hematologic malignancies sequenced with the same platform. JAK2 and TP53 VAF consistently expanded at disease onset, whereas DNMT3A and silent CH VAFs mostly decreased. These data inform the clinical and biological interpretation of CH in the context of nonhematologic cancer.

Associations Between Cancer Predisposition Mutations and Clonal Hematopoiesis in Patients With Solid Tumors.

PURPOSE: Clonal hematopoiesis (CH), the expansion of clones in the hematopoietic system, has been linked to different internal and external features such as aging, genetic ancestry, smoking, and oncologic treatment. However, the interplay between mutations in known cancer predisposition genes and CH has not been thoroughly examined in patients with solid tumors. METHODS: We used prospective tumor-blood paired sequencing data from 46,906 patients who underwent Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) testing to interrogate the associations between CH and rare pathogenic or likely pathogenic (P/LP) germline variants. RESULTS: We observed an enrichment of CH-positive patients among those carrying P/LP germline mutations and identified a significant association between P/LP germline variants in ATM and CH. Germline and CH comutation patterns in ATM, TP53, and CHEK2 suggested biallelic inactivation as a potential mediator of clonal expansion. Moreover, we observed that CH-PPM1D mutations, similar to somatic tumor-associated PPM1D mutations, were depleted in patients with P/LP germline mutations in the DNA damage response (DDR) genes ATM, CHEK2, and TP53. Patients with solid tumors and harboring P/LP germline mutations, CH mutations, and mosaicism chromosomal alterations might be at an increased risk of developing secondary leukemia while germline variants in TP53 were identified as an independent risk factor (hazard ratio, 36; P < .001) for secondary leukemias. CONCLUSION: Our results suggest a close relationship between inherited variants and CH mutations within the DDR genes in patients with solid tumors. Associations identified in this study might translate into enhanced clinical surveillance for CH and associated comorbidities in patients with cancer harboring these germline mutations.

Effectivity of a Program for the Control and Prevention of COVID-19 Healthcare-Associated Infections in a Spanish Academic Hospital.

BACKGROUND: Although recommendations to prevent COVID-19 healthcare-associated infections (HAIs) have been proposed, data on their effectivity are currently limited. OBJECTIVE: The aim was to evaluate the effectivity of a program of control and prevention of COVID-19 in an academic general hospital in Spain. METHODS: We captured the number of COVID-19 cases and the type of contact that occurred in hospitalized patients and healthcare personnel (HCP). To evaluate the impact of the continuous use of a surgical mask among HCP, the number of patients with COVID-19 HAIs and accumulated incidence of HCP with COVID-19 was compared between the preintervention and intervention periods. RESULTS: Two hundred fifty-two patients with COVID-19 have been admitted to the hospital. Seven of them had an HAI origin (6 in the preintervention period and 1 in the intervention period). One hundred forty-two HCP were infected with SARS-CoV-2. Of them, 22 (15.5%) were attributed to healthcare (2 in the emergency department and none in the critical care departments), and 120 (84.5%) were attributed to social relations in the workplace or during their non-work-related personal interactions. The accumulated incidence during the preintervention period was 22.3 for every 1000 HCP and 8.2 for every 1000 HCP during the intervention period. The relative risk was 0.37 (95% confidence interval, 0.25 to 0.55) and the attributable risk was -0.014 (95% confidence interval, -0.020 to -0.009). CONCLUSIONS: A program of control and prevention of HAIs complemented with the recommendation for the continuous use of a surgical mask in the workplace and social environments of HCP effectively decreased the risk of COVID-19 HAIs in admitted patients and HCP.

Frequency, Associated Risk Factors, and Characteristics of COVID-19 Among Healthcare Personnel in a Spanish Health Department.

INTRODUCTION: This study examines the frequency, associated factors, and characteristics of healthcare personnel coronavirus disease 2019 cases in a healthcare department that comprises a tertiary hospital and its associated 12 primary healthcare centers. METHODS: This study included healthcare personnel that showed symptoms or were in contact with a coronavirus disease 2019 case patient from March 2, 2020 to April 19, 2020. Their evolution and characteristics (age, sex, professional category, type of contact) were recorded. Correlations between the different characteristics and risk of developing coronavirus disease 2019 and severe coronavirus disease 2019 were analyzed using chi-square tests. Their magnitudes were quantified with ORs, AORs, and their 95% CIs using a logistic regression model. RESULTS: Of the 3,900 healthcare professionals in the department, 1,791 (45.9%) showed symptoms or were part of a contact tracing study. The prevalence of those with symptoms was 20.1% (784/3,900; 95% CI=18.8, 21.4), with coronavirus disease 2019 was 4.0% (156/3,900; 95% CI=3.4, 4.6), and with severe coronavirus disease 2019 was 0.5% (18/3,900; 95% CI=0.2, 0.7). The frequency of coronavirus disease 2019 in symptomatic healthcare personnel with a nonprotected exposure was 22.8% (112/491) and 13.7% (40/293) in those with a protected exposure (AOR=2.2, 95% CI=1.2, 3.9). The service in which the healthcare personnel performed their activity was not significantly associated with being diagnosed with coronavirus disease 2019. A total of 26.3% (10/38) of male healthcare personnel with coronavirus disease 2019 required hospitalization, compared with 6.8% (8/118) among female healthcare personnel (OR=4.9, 95% CI=1.8, 13.6). CONCLUSIONS: A surveillance and monitoring program centred on healthcare personnel enables an understanding of the risk factors that lead to coronavirus disease 2019 among this population. This knowledge allows the refinement of the strategies for disease control and prevention in healthcare personnel during the coronavirus disease 2019 pandemic.