Unraveling the complexities of early-onset colorectal cancer: a perspective on dietary and microbial influences.

While advances in screening have resulted in declining rates of colorectal cancer (CRC) among adults ≥50 years of age since the mid-2000s, the incidence of early-onset CRC (EOCRC) has steadily increased over the last decade. This increase is not fully accounted for by hereditary factors, and the hypothesis that a sedentary lifestyle and obesity are the primary culprits is not fully supported by recent reports indicating that many affected individuals lead active lifestyles, maintain normal weight, and are otherwise healthy. Attention has shifted toward dietary patterns, notably the consumption of processed and ultra-processed foods found in Western diets, which are suspected of disrupting the gut microbiome balance that potentially leads to EOCRC. The impact of antibiotic use on the gut microbiome is also posited as a contributing factor, given its rising prevalence in medical and agricultural practices. We propose that a paradigm shift is necessary for EOCRC research, moving beyond metabolic factors to a broader exploration of dietary and microbial influences. Future research must prioritize understanding the relationship between dietary habits, particularly processed food intake, antibiotic exposure, and gut microbiome dynamics, to unravel the complex etiology of EOCRC. This will be crucial in developing comprehensive preventive strategies to address the increasing incidence of this malignancy in younger populations.

Using genome and transcriptome data from African-ancestry female participants to identify putative breast cancer susceptibility genes.

African-ancestry (AA) participants are underrepresented in genetics research. Here, we conducted a transcriptome-wide association study (TWAS) in AA female participants to identify putative breast cancer susceptibility genes. We built genetic models to predict levels of gene expression, exon junction, and 3' UTR alternative polyadenylation using genomic and transcriptomic data generated in normal breast tissues from 150 AA participants and then used these models to perform association analyses using genomic data from 18,034 cases and 22,104 controls. At Bonferroni-corrected P < 0.05, we identified six genes associated with breast cancer risk, including four genes not previously reported (CTD-3080P12.3, EN1, LINC01956 and NUP210L). Most of these genes showed a stronger association with risk of estrogen-receptor (ER) negative or triple-negative than ER-positive breast cancer. We also replicated the associations with 29 genes reported in previous TWAS at P < 0.05 (one-sided), providing further support for an association of these genes with breast cancer risk. Our study sheds new light on the genetic basis of breast cancer and highlights the value of conducting research in AA populations.

Case-Case Genome-Wide Analyses Identify Subtype-Informative Variants That Confer Risk for Breast Cancer.

Breast cancer includes several subtypes with distinct characteristic biological, pathologic, and clinical features. Elucidating subtype-specific genetic etiology could provide insights into the heterogeneity of breast cancer to facilitate the development of improved prevention and treatment approaches. In this study, we conducted pairwise case-case comparisons among five breast cancer subtypes by applying a case-case genome-wide association study (CC-GWAS) approach to summary statistics data of the Breast Cancer Association Consortium. The approach identified 13 statistically significant loci and eight suggestive loci, the majority of which were identified from comparisons between triple-negative breast cancer (TNBC) and luminal A breast cancer. Associations of lead variants in 12 loci remained statistically significant after accounting for previously reported breast cancer susceptibility variants, among which, two were genome-wide significant. Fine mapping implicated putative functional/causal variants and risk genes at several loci, e.g., 3q26.31/TNFSF10, 8q22.3/NACAP1/GRHL2, and 8q23.3/LINC00536/TRPS1, for TNBC as compared with luminal cancer. Functional investigation further identified rs16867605 at 8q22.3 as a SNP that modulates the enhancer activity of GRHL2. Subtype-informative polygenic risk scores (PRS) were derived, and patients with a high subtype-informative PRS had an up to two-fold increased risk of being diagnosed with TNBC instead of luminal cancers. The CC-GWAS PRS remained statistically significant after adjusting for TNBC PRS derived from traditional case-control GWAS in The Cancer Genome Atlas and the African Ancestry Breast Cancer Genetic Consortium. The CC-GWAS PRS was also associated with overall survival and disease-specific survival among patients with breast cancer. Overall, these findings have advanced our understanding of the genetic etiology of breast cancer subtypes, particularly for TNBC. Significance: The discovery of subtype-informative genetic risk variants for breast cancer advances our understanding of the etiologic heterogeneity of breast cancer, which could accelerate the identification of targets and personalized strategies for prevention and treatment.

Genome-wide association analyses of breast cancer in women of African ancestry identify new susceptibility loci and improve risk prediction.

We performed genome-wide association studies of breast cancer including 18,034 cases and 22,104 controls of African ancestry. Genetic variants at 12 loci were associated with breast cancer risk (P < 5 × 10-8), including associations of a low-frequency missense variant rs61751053 in ARHGEF38 with overall breast cancer (odds ratio (OR) = 1.48) and a common variant rs76664032 at chromosome 2q14.2 with triple-negative breast cancer (TNBC) (OR = 1.30). Approximately 15.4% of cases with TNBC carried six risk alleles in three genome-wide association study-identified TNBC risk variants, with an OR of 4.21 (95% confidence interval = 2.66-7.03) compared with those carrying fewer than two risk alleles. A polygenic risk score (PRS) showed an area under the receiver operating characteristic curve of 0.60 for the prediction of breast cancer risk, which outperformed PRS derived using data from females of European ancestry. Our study markedly increases the population diversity in genetic studies for breast cancer and demonstrates the utility of PRS for risk prediction in females of African ancestry.

Causes of visual loss and their risk factors: an incidence summary from the Barbados Eye Studies / Causas de la pérdida visual y sus factores de riesgo: resumen de la incidencia a partir de los Estudios de Oftalmología de Barbados

Objectives: To summarize incidence and risk factors for each main cause of visual loss in an African-Caribbean population and discuss the implications of these data from a public health perspective. Methods: A nationally representative cohort (n = 4 709; ages 40-84 years at baseline) had ophthalmic and other examinations over 9 years. Incidence rates were estimated by the product-limit approach. Risk factors were evaluated from Cox regression models. Results: Average incidence was ~ 0.1 percent per year for blindness (< 6/120) and 0.7 percent per year for low vision (< 6/18 to 6/120), increasing steeply with age (P < 0.05) and affecting related quality of life (P < 0.05). Age-related cataract and open-angle glaucoma (OAG) accounted for 73.2 percent of blindness and diabetic retinopathy (DR) for 8.9 percent; cataract caused two-thirds of low vision. Average incidence was 5.1 percent per year for all lens changes (gradable/ungradable opacities or aphakia) and 0.4 percent per year for cataract surgery. Incidence of definite OAG was 0.5 percent per year (0.9 percent for suspect or probable); 53 percent of the affected were unaware. Persons with diabetes mellitus (DM) had a DR incidence of 4.4 percent per year. Age-related macular degeneration was rare (0.08 percent per year). Main cataract risk factors were age and DM. OAG incidence increased with age, intraocular pressure, family history, low ocular perfusion pressures, and thinner corneas. DR risk increased with early DM onset, DM duration, oral/insulin treatment, increased systolic and diastolic blood pressures, and hyperglycemia. Antihypertensive treatment halved DR risk. Conclusions: Incidence of visual impairment was high and significantly affected quality of life. Age-related cataract and OAG caused ~ 75 percent of blindness, indicating the need for public health action to increase appropriate cataract surgery and early OAG detection and treatment. Controlling DM and hypertension would help prevent...

Objetivo: Presentar un resumen de la incidencia y los factores de riesgo de cada causa principal de pérdida de la visión en una población afrocaribeña y examinar las implicaciones de estos datos desde una perspectiva de salud pública. Métodos: En una cohorte representativa al nivel nacional (n = 4 709; edades de 40 a 84 años al inicio) se hicieron exploraciones oftálmicas y de otros tipos durante nueve años. Se calcularon las tasas de incidencia mediante el método del producto-límite. Los factores de riesgo se evaluaron mediante modelos de regresión de Cox. Resultados: La incidencia promedio fue ~ 0,1 por ciento al año para la ceguera (< 6/120) y de 0,7 por ciento al año para la visión deficiente (< 6/18 a 6/120), que aumentó de manera pronunciada con la edad (P < 0,05) y afectó a la calidad de vida relacionada (P < 0,05). Las cataratas y el glaucoma de ángulo abierto relacionados con la edad representaron 73,2 por ciento de los casos de ceguera, y 8,9 por ciento de los casos de retinopatía diabética; las cataratas causaron dos tercios de los casos de visión deficiente. La incidencia media fue de 5,1 por ciento al año en todos los cambios del cristalino (opacidades graduables o no graduables o afaquia), y de 0,4 por ciento al año en la cirugía de cataratas. La incidencia del glaucoma de ángulo abierto definitivo fue de 0,5 por ciento al año (0,9 por ciento en el caso de la sospecha o la probabilidad); 53 por ciento de los pacientes afectados no era conciente. Las personas que padecían diabetes tenían una incidencia de retinopatía diabética de 4,4 por ciento al año. La degeneración macular relacionada con la edad fue muy infrecuente (0,08 por ciento al año). Los principales factores de riesgo de las cataratas fueron la edad y la diabetes. La incidencia de glaucoma de ángulo abierto aumentó con la edad, la presión intraocular, los antecedentes familiares, las presiones bajas de perfusión ocular y el grosor más fino de la córnea. El riesgo de retinopatía...