The National Cancer Institute (NCI) coordinates the United States National Cancer Program and is part of the National Institutes of Health (NIH), which is one of eleven agencies that are part of the U.S. Department of Health and Human Services. The NCI conducts and supports research, training, health information dissemination, and other activities related to the causes, prevention, diagnosis, and treatment of cancer; the supportive care of cancer patients and their families; and cancer survivorship.NCI is the oldest and has the largest budget and research program of the 27 institutes and centers of the NIH ($6.9 billion in 2020). It fulfills the majority of its mission via an extramural program that provides grants for cancer research. Additionally, the National Cancer Institute has intramural research programs in Bethesda, Maryland, and at the Frederick National Laboratory for Cancer Research at Fort Detrick, in Frederick, Maryland. The NCI receives more than US$5 billion in funding each year.The NCI supports a nationwide network of 71 NCI-designated Cancer Centers with a dedicated focus on cancer research and treatment and maintains the National Clinical Trials Network.
Cancers of the lip, oral cavity, and pharynx (LOCP) represent a substantial public health challenge worldwide. Using GLOBOCAN national estimates of incidence, detailed cancer registry data from Cancer Incidence in Five Continents, and population statistics from the United Nations, the authors report the distribution of new cases of LOCP cancers in 185 countries by sex in 2022. Age-standardized incidence rates were calculated. For countries lacking registry data, regional averages from high-quality registries were used to impute subsite-specific estimates. Worldwide, 758,000 people were diagnosed with LOCP cancers in 2022, with oral cavity cancer accounting for approximately 42% of cases, followed by oropharynx (19.3%), nasopharynx (15.9%), hypopharynx (11.4%), salivary gland (7.3%), and lip (4.2%) cancers. Oral cavity cancer was the most frequent LOCP subsite among women in 141 countries and among men in 93 countries, and incidence rates were highest in countries in South-Central Asia. Oropharyngeal cancer was the most frequent LOCP subsite among men in 44 countries and among women in five countries across Europe, Northern America, South America, Australia, and New Zealand. Nasopharyngeal cancer was the most common subsite among men in 39 countries and women in 23 countries, mainly in Northern Africa, Middle Africa, and Eastern and South-Eastern Asia. Rates of hypopharyngeal and salivary gland cancers were low globally, although the incidence burden was greater than that of lip cancer. The authors discuss incidence patterns in relation to disease etiology and the prospects of delivering effective cancer control measures, spanning primary prevention, early detection, cancer treatment, and survivorship.
PRSs predict complex traits by aggregating genetic effects across the genome, yet most models focus on common variants, overlooking rare variants that may contribute to hidden heritability. Here, we develop RICE, a PRS framework integrating both common and rare variants to improve genetic risk prediction across diverse ancestries. RICE constructs separate PRSs: for common variants, it integrates methods using ensemble learning; for rare variants, it uses gene-level testing with functional annotations and penalized regression. We evaluate RICE using simulated datasets and sequencing data from UK Biobank and All of Us, involving up to 740 million genetic variants from 361,939 individuals across diverse ancestries and 11 complex traits. In real data analysis, RICE improves predictive accuracy compared to leading common variant methods for traits with distinct rare variant architectures, particularly lipids and height. For lipid traits, incorporating rare variants increased R2 by up to ~11.2% in Europeans and ~60.7% in African ancestry compared to common variant PRS alone. Notably, for lipid traits, RICE captures substantial predictive signal beyond established high-penetrance genes, validating its ability to leverage the broader polygenic architecture of rare variation.
BACKGROUND:Diffuse gastric cancer (DGC) is the most common manifestation in germline CTNNA1 variant carriers, with one study estimating a 49-57% lifetime risk by age 80. Knowledge on CTNNA1-associated hereditary diffuse gastric cancer (HDGC), loss-of-function mechanisms, variant-type causality, disease spectrum and cancer risks remains scarce. OBJECTIVE:Explore CTNNA1 genotype-phenotype associations to improve genetic testing criteria, surveillance and risk-reduction recommendations for carriers. DESIGN:Using molecular, clinical and population data from 1308 individuals from 351 CTNNA1-variant carrier families and 37 428 non-carriers from European and American ancestries, we analysed genotype-phenotype associations with multivariable logistic regression. With CRISPR/Cas9 CTNNA1-knockout gastric cancer (GC) cells and CTNNA1-humanised Drosophila, we assessed CTNNA1-associated loss-of-function mechanisms. RESULTS:CTNNA1-truncating transcripts are degraded by nonsense-mediated mRNA decay (NMD), and DGCs from germline CTNNA1-truncating carriers lose αE-catenin. These transcripts are non-functional in Drosophila, in contrast to non-truncating transcripts. DGC risk is eightfold higher in truncating, compared with non-truncating carriers. The risk of GC and lobular breast cancer (LBC) development in CTNNA1-truncating variant carriers is fivefold and eightfold lower than in CDH1 pathogenic/likely pathogenic variant carriers, respectively. Compared with wild-type individuals, GC risk is 7-fold higher in CTNNA1-truncating and 38-fold higher in CDH1-truncating variant carriers. LBC is recurrent among CTNNA1-truncating carriers, some lacking HDGC criteria. Simplification of previous criteria for CTNNA1 genetic testing produced the 'Porto' criteria, which increased CTNNA1-carrier families' pick-up rate by 9%, without performance loss compared with the HDGC 2020 clinical guidelines. Macular dystrophy patterned-2 was positively associated with non-truncating variants, specifically in the αE-catenin M-fragment. CONCLUSION:We provide compelling evidence supporting that CTNNA1-truncating variants positively associate with DGC and LBC, and NMD as the pathophysiological mechanism leading to CTNNA1 downregulation. We demonstrate that compared with CDH1, CTNNA1 is a moderate penetrance HDGC gene. This new knowledge is essential to define surveillance and/or prophylactic measures for CTNNA1-carrier individuals and families.
Cancer interception is a preventative approach aiming to reduce cancer incidence by targeting precancers and early-stage cancers. Lynch syndrome (LS) is a prevalent hereditary cancer syndrome affecting 1 in 300 individuals, with an overall lifetime cancer risk as high as 80 NCT05078866 ). In a phase 1b/2 trial, an off-the-shelf vaccine using gorilla adenoviral and modified vaccinia Ankara vectors with over 200 mutated peptides known to be present in persons with mismatch-repair-deficient tumors is safe and elicits neoantigen-specific T cells in individuals with Lynch syndrome.
The concept of cellular neighborhoods, defined as recurring structures within the tissue with characteristic cell compositions and interactions, has transformed our understanding of the complexity and dynamics of tumor ecosystems. Recent advances in spatial omics and computational modeling have enabled high-resolution mapping of these neighborhoods, providing unprecedented insights into their roles in shaping tumor heterogeneity, evolution and therapeutic responses. Despite these advances, a unified framework for interpreting cellular neighborhoods remains lacking. This Perspective synthesizes emerging concepts and insights, focusing on the definition and classification of cellular neighborhoods in cancer, computational methods for identifying and comparing them, and their clinical relevance. Tan and colleagues discuss recent advances in spatial omics and computational models that inform the classification and clinical relevance of cellular neighborhoods in cancer.
