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Study Objectives: Sex differences are related to both biological factors and the gendered environment. We constructed measures to model sex-related differences beyond binary sex., Methods: Data came from the baseline visit of the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). We applied the least absolute shrinkage and selection operator penalized logistic regression of male versus female sex over sociodemographic, acculturation, and psychological factors jointly. Two "gendered indices," the gendered index of sociodemographic environment (GISE) and gendered index of psychological and sociodemographic environment, summarizing the sociodemographic environment (GISE) and psychosocial and sociodemographic environment (GIPSE) associated with sex, were calculated by summing these variables, weighted by their regression coefficients. We examined the association of these indices with insomnia, a phenotype with strong sex differences, in sex-adjusted and sex-stratified analyses., Results: The distribution of GISE and GIPSE differed by sex with higher values in male individuals. In an association model with insomnia, male sex was associated with a lower likelihood of insomnia (odds ratio [OR] = 0.60, 95% CI [0.53, 0.67]). Including GISE in the model, the association was slightly weaker (OR = 0.63, 95% CI [0.56, 0.70]), and weaker when including instead GIPSE in the association model (OR = 0.78, 95% CI [0.69, 0.88]). Higher values of GISE and of GIPSE, more common in the male sex, were associated with a lower likelihood of insomnia, in analyses adjusted for sex (per 1 standard deviation of the index, GISE OR = 0.92, 95% CI [0.87, 0.99], GIPSE OR = 0.65, 95% CI [0.61, 0.70])., Conclusions: New measures such as GISE and GIPSE capture sex-related differences beyond binary sex and have the potential to better model and inform research studies of sleep health., (© The Author(s) 2024. Published by Oxford University Press on behalf of Sleep Research Society.)

Background: Medulloblastoma, the most common malignant pediatric brain tumor, displays marked sex differences in prevalence of the four main molecular subgroups: SHH, WNT, Group 3 and Group 4. Males are more frequently diagnosed with SHH, Group 3 and 4 tumors, which have worse prognoses than WNT tumors. Little is known about sex differences in methylation profiles within subgroups., Methods: Using publicly available methylation data (Illumina HumanMethylation450K array), we compared beta values for males versus females. Differentially methylated positions (DMP) by sex within medulloblastoma subgroups were identified on the autosomes. DMPs were mapped to genes and Reactome pathway analysis was run by subgroup. Kaplan-Meier survival curves (Log-Rank p-values) were assessed for each sex within subgroup. MethylCIBERSORT was used to investigate the tumor microenvironment using deconvolution to estimate the abundances of immune cell types using DNA methylation data., Results: There were statistically significant differences in sex by medulloblastoma subgroups (chi-squared p-value=0.00004): Group 3 (n=144; 65% male), Group 4 (n=326; 67% male), SHH (n=223; 57% male) and WNT (n=70; 41% male). Females had worse survival than males for SHH (p-value=0.02). DMPs by sex were identified within subgroups: SHH (n=131), Group 4 (n=29), Group 3 (n=19), and WNT (n=16) and validated in an independent dataset. Unsupervised hierarchical clustering showed that sex-DMPs in SHH did not correlate with other tumor attributes. Ten genes with sex DMPs ( RFTN1 , C1orf103 , FKBP1B , COL25A1 , NPDC1 , B3GNT1 , FOXN3 , RNASEH2C , TLE1 , and PHF17) were shared across subgroups. Significant pathways (p<0.05) associated with DMPs were identified for SHH (n=22) and Group 4 (n=4) and included signaling pathways for RET proto-oncogene, advanced glycosylation end product receptor, regulation of KIT, neurotrophic receptors, NOTCH, and TGF-β. In SHH, we identified DMPs in four genes ( CDK6 , COL25A1 , MMP16 , PRIM2) that encode proteins which are the target of therapies in clinical trials for other cancers. There were few sex differences in immune cell composition within tumor subgroups., Conclusion: There are sexually dimorphic methylation profiles for SHH medulloblastoma where survival differences were observed. Sex-specific therapies in medulloblastoma may impact outcomes., Competing Interests: DAL is a co-founder and co-owner of NeoClone Biotechnologies, Inc., Discovery Genomics, Inc. recently acquired by Immunsoft, Inc., B-MoGen Biotechnologies, Inc. recently acquired by Bio-Techne corporation, and Luminary Therapeutics, Inc. DAL holds equity in, is a Board of Directors member, and serves as a senior scientific advisor of Recombinetics, a genome-editing company. DAL holds equity in and consults for Styx Biotechnologies Inc. as a member of their scientific advisory board. DAL consults for Genentech, Inc., which is funding some of his research. The business of all these companies is unrelated to the contents of this manuscript. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor SR declared a shared affiliation with the author TH at the time of review., (Copyright © 2023 Moss, Sorajja, Mills, Moertel, Hoang, Spector, Largaespada and Williams.)

Background: Central nervous system (CNS) tumors result in tremendous morbidity and mortality. Incidence of CNS tumors in young adults is less studied. It is unknown how young adult CNS tumor incidence has changed globally in recent decades., Methods: We used Cancer Incidence in Five Continents (CI5) data (1988-2012) to estimate incidence rates (IR), average annual percent change in incidence (AAPC; 95% confidence intervals [95% CI]), and male-to-female incidence rate ratios (IRR; 95% CI) by six histologies and age at diagnosis (20-29years, 30-39years). Tumors were classified as astrocytic, medulloblastoma, ependymal, oligodendroglial, meninges, and other embryonal. Geographic regions were defined using the United Nations Statistics Division geoscheme., Results: There were 78,240 CNS tumor cases included. 20-29-year-old (yo) rates were lower than 30-39 yo in most regions for astrocytic, oligodendroglial and ependymal tumors. Globally, astrocytic tumor incidence decreased (20-29 yo AAPC: - 0.70; 95% CI: - 1.32, - 0.08) while incidence increased for oligodendroglial (20-29 yo AAPC: 3.03; 95% CI: 1.57-4.51; 30-39 yo AAPC: 2.67; 95% CI: 0.79-4.58), ependymal (20-29 yo AAPC: 1.16; 95% CI: 0.31-2.03; 30-39 yo AAPC: 2.29; 95% CI: 1.14-3.46), medulloblastoma (30-39 yo AAPC: 0.6; 95% CI: 0.04-1.24) and tumors of the meninges (20-29 yo AAPC: 1.55; 95% CI: 0.04-3.07). There was a 20-40% male incidence excess in all histologies except for meninge tumors (30-39 yo IRR: 0.71; 95% CI: 0.61, 0.84)., Conclusions: Incidence of oligodendroglial and ependymal tumors increased globally in 20-39 yo suggesting better diagnoses or changes in risk factors. Males had a higher incidence of CNS tumors for most tumors studied and in most regions., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Brain tumors are among the top four cancers in young adults. We assessed important windows of tumor development and examined the interplay of race/ethnicity, age, and sex in young adult brain tumor incidence., Methods: Using SEER 18 data (2000-2017), incidence rates were estimated by Poisson regression in individuals aged 20-39 years at diagnosis. Incidence rate ratios (IRR) and 95% confidence intervals (95% CI) were estimated by race/ethnicity, sex and age for 12 malignant histologies., Results: White incidence for all histologies was higher (White vs. Black IRR: 2.09, 95% CI: 1.94, 2.24; White vs Asian Pacific Islander IRR: 1.88, 95% CI: 1.75, 2.03; White vs Hispanic IRR: 1.70, 95% CI: 1.62, 1.78; White vs American Indian IRR: 1.40, 95% CI: 1.14, 1.73). Minority groups had higher lymphoma incidence (White vs Black IRR: 0.32, 95% CI: 0.25, 0.40, White vs Hispanic HR: 0.55, 95% CI: 0.44, 0.68). Males had higher incidence than females for all histologies (IRR: 1.36, 95% CI: 1.31, 1.41). Male rates were highest for lymphoma (male-to-female [MF] IRR: 2.00, 95% CI: 1.65, 2.42) and glioblastoma (MF IRR: 1.61, 95% CI: 1.48, 1.75). The male excess in incidence was similar by race/ethnicity and increased with age (20-24-year-old IRR: 1.18, 95% CI: 1.07, 1.29; 35-39-year-old IRR: 1.44, 95% CI: 1.35, 1.54)., Conclusions: A White race and male incidence excess was observed among brain tumors., Impact: The male excess was similar by race/ethnicity and increased with age suggesting male sex may be an intrinsic risk factor for brain tumor development., (Copyright © 2021 Elsevier Ltd. All rights reserved.)