Evaluation of the genetic basis of familial-associated early-onset hematologic cancers in an ancestral/ethnically diverse population.

Genetic predisposition to hematologic malignancies has historically been addressed utilizing patients recruited from clinical trials and pedigrees constructed at major treatment centers. Such efforts leave unexplored the genetic basis of variations in risk by race/ethnic group shown in population-based surveillance data where cancer registration, compulsory by law, delivers universal enrollment. To address this, we performed exome sequencing on DNA isolated from newborn bloodspots derived from sibling pairs with early-onset cancers across California in which at least one of the siblings developed a hematologic cancer, using unbiased recruitment from the full state population. We identified pathogenic/likely pathogenic (P/ LP) variants among 1,172 selected cancer genes that were private or present at low allele frequencies in reference populations. Within 64 subjects from 32 families, we found 9 LP variants shared between siblings, and an additional 7 such variants in singleton children (not shared with their sibling). In 8 of the shared cases, the ancestral origin of the local haplotype that carries P/LP variants matched the dominant global ancestry of study participant families. This was the case for Latino sibling pairs on FLG and CBLB, non-Latino White sibling pairs in TP53 and NOD2, and a shared GATA2 variant for a non-Latino Black sibling pair. A new inherited mutation in HABP2 was identified in a sibling pair, one with diffuse large B-cell lymphoma and the other with neuroblastoma. Overall, the profile of P/LP germline variants across ancestral/ethnic groups suggests that rare alleles contributing to hematologic diseases originate within their race/ethnic origin parental populations, demonstrating the value of this discovery process in diverse, population-based registries.

RNF167-mediated ubiquitination of Tollip inhibits TNF-α-triggered NF-κB and MAPK activation.

Toll-interacting protein (Tollip) is a multifunctional regulator in cellular activities. However, whether its functions are subjected to post-translational modifications remains elusive. Here, we identified ubiquitination as a post-translational modification on Tollip. We found that Tollip interacted with ring finger protein 167 (RNF167) through its C-terminal coupling of ubiquitin to ER degradation (CUE) domain, and RNF167 functioned as the potential E3 ligase to attach K33-linked poly-ubiquitin chains to the Lys235 (K235) site of Tollip. Furthermore, we discovered Tollip could inhibit TNF-α-induced nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) activation, and substitution of Lys235 on Tollip to arginine failed to suppress TNF-α-NF-κB/MAPK (JNK) cascades, revealing the role of Tollip and its ubiquitination in NF-κB/MAPK pathways. Thus, our study reveals the novel biological function of Tollip and RNF167-dependent ubiquitination of Tollip in TNF-α signaling.

Birth characteristics and risk of Ewing sarcoma.

PURPOSE: The incidence of Ewing sarcoma varies according to race and ethnicity, and genetic susceptibility is known to affect disease risk. Apart from these factors, the etiology of Ewing sarcoma is largely unknown. METHODS: We compared the birth characteristics of a population-based series of 556 Ewing sarcoma cases born in California in 1978-2015 and diagnosed in 1988-2015 with those of 27,800 controls selected from statewide birth records and frequency-matched to cases on the year of birth, using multivariable logistic regression models. We also assessed whether Ewing sarcoma clustered within families. RESULTS: Compared to non-Hispanic White subjects, Black (odds ratio [OR] = 0.07, 95% confidence interval [CI] 0.03-0.18), Asian (OR = 0.57, 95% CI 0.41-0.80), and Hispanic (OR = 0.73, 95% CI 0.62-0.88) individuals had a significantly lower risk of Ewing sarcoma. Race and ethnicity differences were more profound for metastatic Ewing sarcoma. Birthweight was also identified as a significant risk factor (OR = 1.09, 95% CI 1.00-1.18 for each 500 g increase in birthweight). A separate family-based cancer clustering analysis did not suggest any strong role for familial predisposition alleles. CONCLUSIONS: This population-based study with minimal selection bias provides support for a role of accelerated fetal growth in the etiology of Ewing sarcoma in addition to more precise estimates of racial and ethnic variations in disease risk. This comparatively large analysis of birth characteristics and Ewing sarcoma in a multiethnic population should stimulate further investigations into genetic and environmental causes.

Trends in Acute Lymphoblastic Leukemia Incidence in the United States by Race/Ethnicity From 2000 to 2016.

Incidence trends in acute lymphoblastic leukemia (ALL) demonstrate disparities by race and ethnicity. We used data from the Surveillance, Epidemiology, and End Results Registry to evaluate patterns in ALL incidence from 2000 to 2016, including the association between percentage of people born in a foreign country at the county level and ALL incidence. Among 23,829 persons of all ages diagnosed with ALL, 8,297 (34.8%) were Latinos, 11,714 (49.2%) were non-Latino (NL) Whites, and 1,639 (6.9%) were NL Blacks. Latinos had the largest increase in the age-adjusted incidence rate (AAIR) of ALL during this period compared with other races/ethnicities for both children and adults: The AAIR was 1.6 times higher for Latinos (AAIR = 2.43, 95% confidence interval (CI): 2.37, 2.49) than for NL Whites (AAIR = 1.56, 95% CI: 1.53, 1.59) (P < 0.01). The AAIR for all subjects increased approximately 1% per year from 2000 to 2016 (annual percent change = 0.97, 95% CI: 0.67, 1.27), with the highest increase being observed in Latinos (annual percent change = 1.18, 95% CI: 0.76, 1.60). In multivariable models evaluating the contribution of percentage of county residents who were foreign-born to ALL risk, a positive association was found for percentage foreign-born for NL Whites (P for trend < 0.01) and NL Blacks (P for trend < 0.01), but the reverse was found for Latinos (P for trend < 0.01); this is consistent with tenets of the "Hispanic paradox," in which better health outcomes exist for foreign-born Latinos.

Rural/urban residence and childhood and adolescent cancer survival in the United States.

BACKGROUND: To the authors' knowledge, no previous study has examined the relationship between rural/urban residence and childhood or adolescent cancer survival in the United States. Using the Surveillance, Epidemiology, and End Results 18 registries database, the authors examined childhood and adolescent cancer survival by rural/urban residence as defined by Rural-Urban Continuum Codes (RUCCs). METHODS: The authors obtained data from Surveillance, Epidemiology, and End Results 18 registries for individuals diagnosed at ages birth to 19 years with a first primary malignant cancer from 2000 through 2010. Rural/urban residence at the time of diagnosis was defined using both metropolitan/nonmetropolitan county classifications and individual RUCC categories. Cox proportional hazards regression was used to compute adjusted hazard ratios (HRs) and 95% confidence intervals (95% CIs) for the association between rural/urban residence and cancer survival. The authors also examined effect modification by age group, sex, race/ethnicity, and cancer type. RESULTS: Among 41,879 cancer cases, approximately 54.7% were non-Hispanic white, 54.3% were male, and 90.4% lived in a metropolitan county. Individuals living in nonmetropolitan counties versus metropolitan counties had a similar risk of cancer death (HR,  1.03; 95% CI, 0.94-1.13) as did those living in nonmetropolitan rural counties with <2500 individuals nonadjacent to a metropolitan area versus those living in metropolitan counties of ≥1 million individuals (HR,  0.98; 95% CI, 0.71-1.37). Evidence for effect modification largely was absent. CONCLUSIONS: The results of the current study suggest that childhood and adolescent cancer survival in the United States does not vary by rural/urban residence at the time of diagnosis as defined by RUCCs. The widespread availability of public health insurance for children and adolescents and a nationwide network of pediatric cancer providers may explain this finding.

Characteristics of The Cancer Genome Atlas cases relative to U.S. general population cancer cases.

BACKGROUND: Despite anecdotal reports of differences in clinical and demographic characteristics of The Cancer Genome Atlas (TCGA) relative to general population cancer cases, differences have not been systematically evaluated. METHODS: Data from 11,160 cases with 33 cancer types were ascertained from TCGA data portal. Corresponding data from the Surveillance, Epidemiology, and End Results (SEER) 18 and North American Association of Central Cancer Registries databases were obtained. Differences in characteristics were compared using Student's t, Chi-square, and Fisher's exact tests. Differences in mean survival months were assessed using restricted mean survival time analysis and generalised linear model. RESULTS: TCGA cases were 3.9 years (95% CI 1.7-6.2) younger on average than SEER cases, with a significantly younger mean age for 20/33 cancer types. Although most cancer types had a similar sex distribution, race and stage at diagnosis distributions were disproportional for 13/18 and 25/26 assessed cancer types, respectively. Using 12 months as an end point, the observed mean survival months were longer for 27 of 33 TCGA cancer types. CONCLUSIONS: Differences exist in the characteristics of TCGA vs. general population cancer cases. Our study highlights population subgroups where increased sample collection is warranted to increase the applicability of cancer genomic research results to all individuals.

The impact of epidemic infectious diseases on the relationship between subjective well-being and social class identity in older adults: The mediating role of Self-rated health.

BACKGROUND: The purpose of this paper is to explore the relationship between subjective well-being, social class identity, and Self-rated health among older persons,. Focusing on the mediating role of health and the impact of epidemic infectious diseases on these relationships. METHODS: Based on the 2018 and 2021 China General Social Survey (CGSS) databases, the data were screened, and processed. Using Stata17, we employed ordered probit regression to examine the relationships among variables and Bootstrap methods to assess mediation effects, and the CGSS data for 2018 and 2021 were compared and analyzed. RESULTS: Our results revealed that factors such as social class identity, health status, and personal income significantly positively impact older persons' subjective well-being (P<0.01). Notably, there was a partial mediating effect of health status between the subjective well-being of the elderly and social class identity. And findings showed that when older adults were affected by epidemic diseases, their subjective well-being, social class identity, and Self-rated health remained significantly positively correlated. Subjective well-being, social class identity. What is more noteworthy is that when affected by epidemic infectious diseases, older adults' subjective well-being, social class identity, and Self-rated health remained significantly positively correlated. The mediating role of self-rated health in older adults' subjective well-being and social class identity increased from 9.6% to 12.4%. CONCLUSIONS: In the face of epidemic infectious diseases, we need to pay more attention to the Self-rated health of the elderly, and the Chinese government should take effective measures to improve their health level, which will in turn improve the subjective well-being of the elderly and realize the goal of healthy aging.

DNA methylation at birth in monozygotic twins discordant for pediatric acute lymphoblastic leukemia.

Aberrant DNA methylation constitutes a key feature of pediatric acute lymphoblastic leukemia at diagnosis, however its role as a predisposing or early contributor to leukemia development remains unknown. Here, we evaluate DNA methylation at birth in 41 leukemia-discordant monozygotic twin pairs using the Illumina EPIC array on archived neonatal blood spots to identify epigenetic variation associated with development of pediatric acute lymphoblastic leukemia, independent of genetic influence. Through conditional logistic regression we identify 240 significant probes and 10 regions associated with the discordant onset of leukemia. We identify a significant negative coefficient bias, indicating DNA hypomethylation in cases, across the array and enhanced in open sea, shelf/shore, and gene body regions compared to promoter and CpG island regions. Here, we show an association between global DNA hypomethylation and future development of pediatric acute lymphoblastic leukemia across disease-discordant genetically identical twins, implying DNA hypomethylation may contribute more generally to leukemia risk.

Interaction between maternal killer immunoglobulin-like receptors and offspring HLAs and susceptibility of childhood ALL.

Acute lymphoblastic leukemia (ALL) in children is associated with a distinct neonatal cytokine profile. The basis of this neonatal immune phenotype is unknown but potentially related to maternal-fetal immune receptor interactions. We conducted a case-control study of 226 case child-mother pairs and 404 control child-mother pairs to evaluate the role of interaction between HLA genotypes in the offspring and maternal killer immunoglobulin-like receptor (KIR) genotypes in the etiology of childhood ALL, while considering potential mediation by neonatal cytokines and the immune-modulating enzyme arginase-II (ARG-II). We observed different associations between offspring HLA-maternal KIR activating profiles and the risk of ALL in different predicted genetic ancestry groups. For instance, in Latino subjects who experience the highest risk of childhood leukemia, activating profiles were significantly associated with a lower risk of childhood ALL (odds ratio [OR] = 0.59; 95% confidence interval [CI], 0.49-0.71) and a higher level of ARG-II at birth (coefficient = 0.13; 95% CI, 0.04-0.22). HLA-KIR activating profiles were also associated with a lower risk of ALL in non-Latino Asians (OR = 0.63; 95% CI, 0.38-1.01), although they had a lower tumor necrosis factor-α level (coefficient = -0.27; 95% CI, -0.49 to -0.06). Among non-Latino White subjects, no significant association was observed between offspring HLA-maternal KIR interaction and ALL risk or cytokine levels. The current study reports the association between offspring HLA-maternal KIR interaction and the development of childhood ALL with variation by predicted genetic ancestry. We also observed some associations between activating profiles and immune factors related to cytokine control; however, cytokines did not demonstrate causal mediation of the activating profiles on ALL risk.

Applying Four-Step Characteristic Ion Filtering with HPLC-Q-Exactive MS/MS Spectrometer Approach for Rapid Compound Structures Characterization and Major Representative Components Quantification in Modified Tabusen-2 Decoction.

Modified Tabusen-2 decoction (MTBD) is traditional Chinese Mongolia medicine, mainly used to treat osteoporosis. However, the precise material basis of this prescription is not yet fully elucidated. Herein, we establish an HPLC-Q-Exactive MS/MS spectrometer method with four-step characteristic ion filtering (FSCIF) strategy to quickly and effectively identify the structural features of MTBD and determine the representative compounds content. The FSCIF strategy included database establishment, characteristic ions summarization, neutral loss fragments screening, and secondary mass spectrum fragment matching four steps. By using this strategy, a total of 143 compounds were unambiguously or tentatively annotated, including 5 compounds which were first reported in MTBD. Nineteen representative components were simultaneously quantified with the HPLC-Q-Exactive MS/MS spectrometer, and it is suitable for eight batches of MTBD. Methodology analysis showed that the assay method had good repeatability, accuracy, and stability. The method established above was successfully applied to assess the quality of MTBD extracts. Collectively, our findings enhance our molecular understanding of the MTBD formulation and will allow us to control its quality in a better way. At the same time, this study can promote the development and utilization of ethnic medicine.