Polymorphisms in the Nonhomologous End-joining DNA Repair Pathway are Associated with HPV Integration in Cervical Dysplasia.

Previous evidence indicates that human papillomavirus (HPV) integration status may be associated with cervical cancer development and progression. However, host genetic variation within genes that may play important roles in the viral integration process is understudied. The aim of this study was to examine the association between HPV16 and HPV18 viral integration status and SNPs in nonhomologous-end-joining (NHEJ) DNA repair pathway genes on cervical dysplasia. Women enrolled in two large trials of optical technologies for cervical cancer detection and positive for HPV16 or HPV18 were selected for HPV integration analysis and genotyping. Associations between SNPs and cytology (normal, low-grade, or high-grade lesions) were evaluated. Among women with cervical dysplasia, polytomous logistic regression models were used to evaluate the effect of each SNP on viral integration status. Of the 710 women evaluated [149 high-grade squamous intraepithelial lesion (HSIL), 251; low-grade squamous intraepithelial lesion (LSIL, 310 normal)], 395 (55.6%) were positive for HPV16 and 192 (27%) were positive for HPV18. Tag-SNPs in 13 DNA repair genes, including RAD50, WRN, and XRCC4, were significantly associated with cervical dysplasia. HPV16 integration status was differential across cervical cytology, but overall, most participants had a mix of both episomal and integrated HPV16. Four tag-SNPs in the XRCC4 gene were found to be significantly associated with HPV16 integration status. Our findings indicate that host genetic variation in NHEJ DNA repair pathway genes, specifically XRCC4, are significantly associated with HPV integration, and that these genes may play an important role in determining cervical cancer development and progression. PREVENTION RELEVANCE: HPV integration in premalignant lesions and is thought to be an important driver of carcinogenesis. However, it is unclear what factors promote integration. The use of targeted genotyping among women presenting with cervical dysplasia has the potential to be an effective tool in assessing the likelihood of progression to cancer.

Evaluation of the Association Between Congenital Cytomegalovirus Infection and Pediatric Acute Lymphoblastic Leukemia.

Importance: Acute lymphoblastic leukemia (ALL) is the most common form of pediatric cancer, and a leading cause of death in children. Understanding the causes of pediatric ALL is necessary to enable early detection and prevention; congenital cytomegalovirus (cCMV) has recently been identified as a potential moderate-to-strong factor associated with risk for ALL. Objective: To compare the prevalence of cCMV infection between ALL cases and matched controls. Design, Setting, and Participants: In this population-based case-control study of ALL cases and matched controls, cases consisted of children aged 0 to 14 years between 1987 and 2014 with an ALL diagnosis identified through the Michigan Cancer Surveillance Program and born in Michigan on or after October 1, 1987. Cancer-free controls were identified by the Michigan BioTrust for Health and matched on age, sex, and mother's race and ethnicity. Data were analyzed from November to May 2022. Exposures: cCMV infection measured by quantitative polymerase chain reaction in newborn dried blood spots. Main Outcomes and Measures: ALL diagnosed in children aged 0 to 14 years. Results: A total of 1189 ALL cases and 4756 matched controls were included in the study. Bloodspots were collected from participants at birth, and 3425 (57.6%) participants were male. cCMV was detected in 6 ALL cases (0.5%) and 21 controls (0.4%). There was no difference in the odds of cCMV infection comparing ALL cases with controls (odds ratio, 1.30; 95% CI, 0.52-3.24). Immunophenotype was available for 536 cases (45.1%) and cytogenetic data for 127 (27%). When stratified by subtype characteristics, hyperdiploid ALL (74 cases) was associated with 6.26 times greater odds of cCMV infection compared with unmatched controls (95% CI, 1.44-27.19). Conclusions and Relevance: In this case-control study of cCMV and pediatric ALL, cCMV was associated with increased risk of hyperdiploid ALL. These findings encourage continued research.

Cancer risk associated with cytomegalovirus infection among solid organ transplant recipients in the United States.

BACKGROUND: Cytomegalovirus (CMV) is among the most common viral infections after solid organ transplantation (SOT). Associations of CMV with cancer risk among SOT recipients have been incompletely evaluated. METHODS: The authors used linked data from the US SOT registry and 32 cancer registries. Poisson regression was used to compare cancer incidence across CMV risk groups based on donor (D) and recipient (R) immunoglobulin G (IgG) serostatus: high risk (R-negative/D-positive), moderate risk (R-positive), and low risk (R-negative/D-negative). RESULTS: In total, 247,318 SOT recipients were evaluated during 2000-2017 (R-negative/D-positive, 20.3%; R-positive, 62.9%; R-negative/D-negative, 16.8%). CMV-seropositive recipients were older, more racially/ethnically diverse, and had lower socioeconomic status than CMV-seronegative recipients. Compared with R-negative/D-negative recipients, recipients in the R-negative/D-positive and R-positive groups had a lower incidence of diffuse large B-cell lymphoma (DLBCL; R-negative/D-positive: adjusted incidence rate ratio [aIRR], 0.74; 95% confidence interval [CI], 0.59-0.91; R-positive: aIRR, 0.83; 95% CI, 0.69-1.00). CMV serostatus modified the association between Epstein-Barr virus (EBV) status and DLBCL (p = .0006): DLBCL incidence was increased for EBV R-negative/D-positive recipients (aIRR, 3.46; 95% CI, 1.50-7.95) among CMV R-negative/D-negative recipients but not among the other CMV risk groups. Compared with recipients who were CMV R-negative/D-negative, those who were R-negative/D-positive had a lower incidence of small intestine cancer (aIRR, 0.23; 95% CI, 0.09-0.63), and R-positive recipients had a higher incidence of lung cancer (aIRR, 1.24; 95% CI, 1.05-1.46). CMV status was not associated with risk for other cancers. CONCLUSIONS: CMV status was not associated with risk for most cancers among SOT recipients. The inverse association with DLBCL may reflect the protective effects of CMV prophylaxis or treatment with off-target efficacy against EBV infection (the major cause of lymphoma in SOT recipients).

Declining Epstein-Barr Virus Antibody Prevalence in College Freshmen Strengthens the Rationale for a Prophylactic EBV Vaccine.

BACKGROUND: To better understand the epidemiology of primary Epstein-Barr virus (EBV) infection and to identify EBV-naïve candidates eligible to receive a prophylactic EBV vaccine, we screened freshmen from the University of Minnesota Class of 2025 for circulating EBV antibody, which is indicative of previous infection. This permitted us to compare their EBV antibody prevalence with that of 4 other freshman classes (Classes of 2010, 2011, 2016, 2021) that have been previously published. METHODS: Freshman students were recruited during screening sessions in the residence halls. Venous blood was collected and the serum fraction tested for IgG antibody against EBV viral capsid antigen (VCA IgG) using commercial enzyme immunoassays. RESULTS: All classes combined, 1196 participants were tested (female, 677; male, 513; did not identify gender, 6) who were 18-23 years old (median, 18; mean, 18.37). The EBV VCA IgG antibody prevalence was 58% (689/1196) and was higher in women than men. The EBV antibody prevalence of 64% (170/267) in the 2010 freshman class versus 52% (78/150) in the Class of 2025 was statistically significantly different (p = 0.0223, Fisher exact test)." CONCLUSIONS: Sufficient participants are available for a prophylactic vaccine trial. Antibody prevalence decreased over 15 years from 64% to 52%. If this trend continues, the number of EBV-naïve adolescents and young adults who are in the age group most susceptible to infectious mononucleosis will increase, strengthening the rationale to develop an effective prophylactic EBV vaccine.

Rapid antibody responses to Epstein-Barr virus correlate with reduced severity of primary infection.

BACKGROUND: We investigated Epstein-Barr virus (EBV) antibody kinetics in university freshmen who developed laboratory-documented primary EBV infection during prospective studies and correlated these kinetics with disease severity. METHODS: EBV-naïve participants had blood collected periodically and sera tested for EBV-specific antibodies with line blot and enzyme immunoassays. The line blot assay contained EBNA-1, p18, p23, BZLF-1, p138, and p54 antigens; the enzyme immunoassay contained viral capsid antigen and EBNA-1. Severity of illness (SOI) was graded 0 (asymptomatic) to 6 (bedridden). Participants with maximum SOI scores 0-2 were compared with those whose maximum SOI scores were 3-6. Time to first antibody response was analyzed using the semi-parametric COX model. RESULTS: A total of 201 sera from 38 college students collected before, during, and after primary EBV infection were tested. Earlier antibody responses correlated with milder symptoms. This was most pronounced for late-developing antibodies. The median time to development of p18 IgG was significantly earlier among low-SOI participants (64 days) than high-SOI patients (119 days; P = 0.0003).). Participants with mild disease developed EBNA-1 antibodies sooner than participants with more severe disease (125 days versus >270 days; P = 0.017). Participants with mild disease also showed more rapid loss of antibodies against IgG EA p138 and p54 ≥12 weeks post-infection (P = 0.012 and P = 0.026, respectively). CONCLUSIONS: These data suggest that rapid antibody responses to EBV correlate with reduced severity of primary EBV infection.

High prevalence of asymptomatic CMV shedding in healthy children attending the minnesota state fair.

BACKGROUND: Young children in the household are a known risk factor for maternal CMV infection and consequently, congenital infection in infants. However, little is known about viral shedding in pre-school aged children. OBJECTIVES: To estimate the prevalence of CMV DNA shedding and CMV antibodies among healthy children and their mothers. STUDY DESIGN: A study of children ages 0 through 5 years was undertaken at the 2019 Minnesota State Fair. Children and their mothers were assessed for CMV shedding by procurement of a saliva swab for CMV PCR testing. An optional finger-stick for capillary blood was used to assess CMV antibodies. RESULTS: A total of 109 children and 85 mothers were enrolled. The prevalence of CMV saliva shedding among children (mean age 3.1 years, SE=0.16) and their mothers was 12/109 (11.0%) and 1/85 (1.2%), respectively. The prevalence of CMV DNA among children peaked at 3 years of age (26%) while the mean viral load was greatest at one year of age (236,693 IU/mL). CMV IgG antibodies among those who agreed to a finger-stick were detected in 16/35 mothers (45.7%) and 0/7 children (0%). Mothers of children aged 5 years or greater had the highest seroprevalence (61.5%). CONCLUSIONS: The prevalence of CMV salivary shedding in this unselected sample of young children was approximately 11.0%. The overall maternal seroprevalence in our sample was <50%, suggesting these women are at risk for acquisition of a primary CMV infection in subsequent pregnancies.

Race, ethnicity, and socioeconomic differences in incidence of pediatric embryonal tumors in the United States.

BACKGROUND: The etiology of childhood cancers and its social patterning remains largely unknown. Accounting for socioeconomic status (SES) when exploring the association between race/ethnicity and cancer incidence is necessary to better understand such etiology. We aimed to investigate differences in the incidence of embryonal tumors (ETs) by SES and race/ethnicity in the United States using population-based registries of the Surveillance, Epidemiology, and End Results (SEER) Program. PROCEDURE: Children with ETs aged 0-19 years diagnosed between 2000 and 2015 were ascertained from the census tract-level SEER database. SES was measured using a tract-level composite index. Incidence rate ratios (IRRs) with 95% confidence intervals (CIs) by SES quintile and race/ethnicity were estimated using multivariable Poisson regression models. RESULTS: The majority of tumors had lower incidence among nonwhite children compared with non-Hispanic (NH) white children, after controlling for SES. NH blacks had a higher incidence of Wilms tumor than NH whites (IRR: 1.26; 95% CI, 1.13-1.39). There was an increasing linear trend (P = 0.0001) across increasing SES quintile for embryonal rhabdomyosarcoma after controlling for race/ethnicity. Effect modification by race/ethnicity of the relationship between SES and tumor incidence was observed for several groups. Hispanics had a significant, linear trend (P = 0.0005) in the incidence of Wilms tumor, while Asian/Pacific Islanders experienced a significant inverse trend (P = 0.0002). CONCLUSIONS: Results from this study suggest differences in the incidence of several ETs by race/ethnicity and that these differences may be modified by SES. Investigation of potential risk factors that are socially patterned is warranted.

The promise of a prophylactic Epstein-Barr virus vaccine.

The worldwide burden of disease due to Epstein-Barr virus (EBV) infection is enormous. Diseases include endemic Burkitt lymphoma, infectious mononucleosis, cancers after transplantation, Hodgkin lymphoma, and nasopharyngeal carcinoma. A prophylactic EBV vaccine has the potential to significantly reduce the incidence and/or the severity of all these diseases. Infectious mononucleosis can be nasty and prolonged with a median duration of 17 days. Patients, especially children, undergoing bone marrow or solid organ transplantation may develop post-transplant lymphoproliferative disorder (PTLD). Preventing or modifying primary EBV infection could reduce the incidence PTLD, and also certain lymphomas and nasopharyngeal carcinoma. EBV is a major environmental risk factor for multiple sclerosis (MS). Contracting EBV is essential to getting MS, and having a childhood case of infectious mononucleosis increases that risk. Vaccinating against EBV could be vaccinating against MS.

Epstein-Barr Virus DNA in Parental Oral Secretions: A Potential Source of Infection for Their Young Children.

Background: A potential source of primary Epstein-Barr virus (EBV) infection for young children is parental oral secretions. If parents who identify with racial/ethnic categories other than white have a higher prevalence of oral EBV DNA, this difference could explain why their children acquire primary EBV infection at an earlier age than white children. Methods: To test this hypothesis, we recruited parents who brought their children <8 years old to routine clinic visits, and tested the parents' oral washes for EBV DNA by real-time polymerase chain reaction. Positive samples were assayed for encapsidated EBV DNA, which is potentially infectious, versus naked EBV DNA, which is not infectious. Results: Overall, 221/800 parents (28%) had EBV DNA in their oral washes. Oral EBV DNA was more prevalent in parents who identified as non-white as compared with white parents (P = .0004), and was more prevalent in male vs female parents (P = .04). The mean quantity of EBV DNA in positive samples was 5000 copies/mL. Encapsidated viral DNA comprised 40.3% of the total EBV DNA found in parental oral secretions. Conclusions: Our data support the hypothesis that parents could be a source of virus for their young children, because 28% of parents had a mean of 5000 EBV copies/mL of oral wash and 40.3% of the EBV DNA was encapsidated. The higher prevalence of EBV DNA in non-white parents could explain why their children acquire EBV at an earlier age than children of white parents.