Inherited lung cancer risk, particularly in nonsmokers, is poorly understood. Genomic and ancestry analysis of 1,153 lung cancers from Latin America revealed striking associations between Native American ancestry and their somatic landscape, including tumor mutational burden, and specific driver mutations in EGFR, KRAS, and STK11. A local Native American ancestry risk score was more strongly correlated with EGFR mutation frequency compared with global ancestry correlation, suggesting that germline genetics (rather than environmental exposure) underlie these disparities. Significance: The frequency of somatic EGFR and KRAS mutations in lung cancer varies by ethnicity, but we do not understand why. Our study suggests that the variation in EGFR and KRAS mutation frequency is associated with genetic ancestry and suggests further studies to identify germline alleles that underpin this association. See related commentary by Gomez et al., p. 534. This article is highlighted in the In This Issue feature, p. 521

Triple-negative breast cancer (TNBC) is one of the most aggressive tumors, with poor prognosis and high metastatic capacity. The aggressive behavior may involve inflammatory processes characterized by deregulation of molecules related to the immunological responses in which interleukin-1β(IL-1β) and tumor necrosis factor-α(TNF-α) are involved. It is known that calcitriol, the active vitamin D metabolite, modulates the synthesis of immunological mediators; however, its role in the regulation of IL-1βand TNF-αin TNBC has been scarcely studied. In the present study, we showed that TNBC cell lines SUM-229PE and HCC1806 expressed vitamin D, IL-1β, and TNF-αreceptors. Moreover, calcitriol, its analogue EB1089, IL-1β, and TNF-αinhibited cell proliferation. In addition, we showed that synthesis of both IL-1βand TNF-αwas stimulated by calcitriol and its analogue. Interestingly, the antiproliferative activity of calcitriol was significantly abrogated when the cells were treated with anti-IL-1βreceptor 1 (IL-1R1) and anti-TNF-αreceptor type 1 (TNFR1) antibodies. Furthermore, the combination of calcitriol with TNF-αresulted in a greater antiproliferative effect than either agent alone, in the two TNBC cell lines and an estrogen receptor-positive cell line. In summary, this study demonstrated that calcitriol exerted its antiproliferative effects in part by inducing the synthesis of IL-1βand TNF-αthrough IL-1R1 and TNFR1, respectively, in TNBC cells, highlighting immunomodulatory and antiproliferative functions of calcitriol in TNBC tumors.

Lung cancer (LC) is the first cause of cancer-related deaths worldwide. Elucidating the pathogenesis of LC will give information on key elements of tumor initiation and development while helping to design novel targeted therapies. LC is an heterogeneous disease that has the second highest mutation rate surpassed only by melanoma, since 90% of LC occurs in tobacco smokers. However, only a small percent of smokers develops LC, indicating an inherent genomic instability. Additionally, LC in never smokers suggests other molecular mechanisms not causally linked to tobacco carcinogens. This review presents a current outlook of the connection between LC and genomic instability at the molecular and clinical level summarizing its implications for diagnosis, therapy, and prognosis. The genomic landscape of LC shows widespread alterations such as DNA methylation, point mutations, copy number variation, chromosomal translocations, and aneuploidy. Genome maintenance mechanisms including cell cycle control, DNA repair, and mitotic checkpoints open a window to translational research for finding novel diagnostic biomarkers and targeted therapies in LC.

Introduction. Epilepsy affects millions of people and its geographical patterns are usually linked to etiological aspects. Our objective was to describe main etiologies of epilepsy in Mexico. Patients and methods. We selected patients from the Multicenter Epilepsy Registry carried out from 2021 to 2022 in 89 Mexican hospitals in 31 states, a sample predominantly of pediatric age. Only patients with electroencephalography and neuroimaging studies were included. Results. We analyzed 6,653 patients with documented etiologies. Etiology frequency with confidence interval (95% CI) was: structural 46.1% (44.9-47.3), genetic 12.9% (12.1-13.7), infectious 2.9%. (2.5-3.3), metabolic 1.4% (1.1-1.7), immune 0.9% (0.8-1.3) and unknown 40.9% (39.8-42.2). The two main structural etiologies were malformations of cortical development and hypoxic-ischemic encephalopathy. Neurocysticercosis represented a minority with only 1%. Structural and genetic etiologies were associated with focal and generalized onset seizures respectively. Status epilepticus was identified, mostly with motor component, associated with immune and infectious etiologies. Comorbidities were found in 61.6%, mainly neurological development disorders. Drug-resistant epilepsy was more common in patients with immune, infectious and structural etiologies. Conclusions. The main etiology of epilepsy was structural. The frequency of genetic etiology was relatively lower than in other series, possibly due to the limited availability of genetic tests. Despite technological advances, a large fraction of epilepsies still has unknown origin.

Breast cancer (BC) is the most common cancer in women, with incidence rates increasing globally in recent years. Therefore, it is important to find new molecules with prognostic and therapeutic value to improve therapeutic response and quality of life. The polyunsaturated fatty acids (PUFAs) metabolic pathway participates in various physiological processes, as well as in the development of malignancies. Although aberrancies in the PUFAs metabolic pathway have been implicated in carcinogenesis, the functional and clinical relevance of this pathway has not been well explored in BC. To evaluate the clinical significance of soluble epoxide hydrolase (EPHX2) expression in Mexican patients with BC using tissue microarrays (TMAs) and digital pathology (DP). Immunohistochemical analyses were performed on 11 TMAs with 267 BC samples to quantify this enzyme. Using DP, EPHX2 protein expression was evaluated solely in tumor areas. The association of EPHX2 with overall survival (OS) was detected through bioinformatic analysis in public databases and confirmed in our cohort via Cox regression analysis. Clear nuclear expression of EPHX2 was identified. Receiver operating characteristics (ROC) curves revealed the optimal cutoff point at 2.847062 × 10⁻³ pixels, with sensitivity of 69.2% and specificity of 67%. Stratification based on this cutoff value showed elevated EPHX2 expression in multiple clinicopathological features, including older age and nuclear grade, human epidermal growth factor receptor 2 (HER2) and triple negative breast cancer (TNBC) subtypes, and recurrence. Kaplan–Meier curves demonstrated how higher nuclear expression of EPHX2 predicts shorter OS. Consistently, multivariate analysis confirmed EPHX2 as an independent predictor of OS, with a hazard ratio (HR) of 3.483 and a 95% confidence interval of 1.804–6.724 (p < 0.001). Our study demonstrates for the first time that nuclear overexpression of EPHX2 is a predictor of poor prognosis in BC patients. The DP approach was instrumental in identifying this significant association. Our study provides valuable insights into the potential clinical utility of EPHX2 as a prognostic biomarker and therapeutic target in BC.