Background: The incidence of sporadic colorectal cancer (CRC) among individuals <50 years (early-onset CRC) has been increasing in the United States (U.S.) and Puerto Rico. CRC is currently the leading cause of cancer death among Hispanic men and women living in Puerto Rico (PRH). The objective of this study was to characterize the molecular markers and clinicopathologic features of colorectal tumors from PRH to better understand the molecular pathways leading to CRC in this Hispanic subpopulation. Methods: Microsatellite instability (MSI), CpG island methylator phenotype (CIMP), and KRAS and BRAF mutation status were analyzed. Sociodemographic and clinicopathological characteristics were evaluated using Chi-squared and Fisher’s exact tests. Results: Of the 718 tumors analyzed, 34.2% (n = 245) were early-onset CRC, and 51.7% were males. Among the tumors with molecular data available (n = 192), 3.2% had MSI, 9.7% had BRAF, and 31.9% had KRAS mutations. The most common KRAS mutations observed were G12D (26.6%) and G13D (20.0%); G12C was present in 4.4% of tumors. A higher percentage of Amerindian admixture was significantly associated with early-onset CRC. Conclusions: The differences observed in the prevalence of the molecular markers among PRH tumors compared to other racial/ethnic groups suggest a distinct molecular carcinogenic pathway among Hispanics. Additional studies are warranted.

Background: Colorectal cancer (CRC) is a leading cause of death worldwide. Despite its preventability through screening, compliance still needs to improve due to the invasiveness of current tools. There is a growing demand for validated molecular biomarker panels for minimally invasive blood-based CRC screening. This study assessed the diagnostic accuracy of four promising blood-based CRC biomarkers, individually and in combination. Methods: This case–control study involved plasma samples from 124 CRC cases and 124 age- and sex-matched controls. Biomarkers tested included methylated DNA encoding the Septin-9 gene (mSEPT9) using Epi proColon^® 2.0 CE, insulin-like growth factor binding protein 2 (IGFBP2), dickkopf-3 (DKK3), and pyruvate kinase M2 (PKM2) by ELISA. Diagnostic accuracy was measured using the receiver operating characteristic (ROC), area under the curve (AUC), as well as sensitivity and specificity. Results: Diagnostic accuracy for mSEPT9, IGFBP2, DKK3, and PKM2 was 62.9% (95% CI: 56.8–62.9%), 69.7% (95% CI: 63.1–69.7%), 61.6% (95% CI: 54.6–61.6%), and 50.8% (95% CI: 43.4–50.8%), respectively. The combined biomarkers yielded an AUC of 74.4% (95% CI: 68.1–80.6%), outperforming all biomarkers except IGFBP2. Conclusions: These biomarkers show potential for developing a minimally invasive CRC detection tool as an alternative to existing approaches, potentially increasing adherence, early detection, and survivorship.

Globally, gastric adenocarcinoma is the fourth leading cause of cancer mortality and a major cancer disparity in the United States. Chemoprevention strategies are lacking for high-risk individuals with gastric premalignant conditions (GPMC). Curcumin, the principal curcuminoid in turmeric, exerts immunomodulatory effects in the epithelium and against Helicobacter pylori, and studies suggest chemoprevention potential. We conducted a double-blind, phase IIa randomized controlled trial in high-risk populations in Puerto Rico and Honduras. We investigated the utility of a bioavailable formulation of curcumin (Meriva) among individuals with H. pylori–negative GPMC, specifically, multifocal atrophic gastritis (MAG) or gastric intestinal metaplasia (GIM). Patients were 1:1 randomized to 1,000 mg Meriva daily or placebo for a 6-month intervention with endoscopy at baseline and 6 months. Outcomes included assessment of epithelial cytokine and chemokine levels, histology, and DNA damage as assessed by γ-H2AX phosphorylation IHC. Of the 110 subjects screened, 50 participants were randomized, and 48 completed the trial. A significant reduction in gastric mucosal IL1β levels from baseline in the gastric body, the primary endpoint, was observed in the Meriva group (P = 0.032). Changes in epithelial IL8, TNFα, and inducible protein 10 levels and gastric mucosal histology and DNA damage (secondary endpoints) were similar between arms. Curcumin (Meriva) was safe, well-tolerated, and showed potential as a curcuminoid chemoprevention agent in H. pylori–negative patients with GPMC. A potential reduction in gastric inflammation as measured by gastric mucosal IL1β levels was observed. Further studies are warranted, including studies in H. pylori–positive individuals, based upon the curcuminoid direct effects on H. pylori. Prevention Relevance: Gastric adenocarcinoma is a leading cause of cancer mortality worldwide. Chemoprevention candidates for GPMCs are limited. This randomized phase IIa trial evaluated a bioavailable curcumin formulation in high-risk individuals with MAG and GIM. The results support further study of curcuminoids for gastric cancer risk reduction. See related article by Morgan et al., p. XX . See related article by Park and Moy, p. XX .

Colorectal cancer (CRC) is the leading cause of cancer-related death in Puerto Rico, a U.S. territory with noted disparities in CRC incidence, particularly among those with early-onset disease (EOCRC). Although EOCRC incidence has been consistently increasing in the U.S. mainland, and a disparate burden has been reported among Hispanics, EOCRC mortality and survival are yet to be assessed among Hispanics living in Puerto Rico (PRH). In this study, we analyzed EOCRC mortality and survival trends in PRH and compared these to those of other U.S. populations. Mortality data were obtained from the Puerto Rico Central Cancer Registry and the Surveillance, Epidemiology, and End Results (SEER) program. Descriptive characteristics and temporal trends were derived via SEER*Stat software (version 9.0.42) and Joinpoint regression models, respectively. Relative survival was estimated using the Actuarial method and the Ederer II approach. Overall, CRC mortality trends showed a decline, but an increase in EOCRC mortality among Hispanics. PRH exhibited the lowest 5-year survival in regional cancers (54.10%), with NHB having the lowest survival among younger individuals. This study highlights significant disparities in EOCRC mortality trends and underscores an urgent need for targeted public health strategies and research efforts to address the disproportionate burden of EOCRC among PRH.

Colorectal cancer (CRC) is the third most commonly diagnosed malignancy worldwide, with molecular heterogeneity complicating early detection and treatment stratification. The insulin-like growth factor (IGF) axis interacts bidirectionally with immune regulatory mechanisms in ways that shape tumor phenotype and therapeutic vulnerability. This review synthesizes evidence on how IGF signaling orchestrates immunosuppression through effects on tumor-associated macrophages, regulatory T cells, and myeloid-derived suppressor cells, while inflammatory cytokines reciprocally modulate IGF bioavailability. Three mechanistic principles emerge: IGF binding protein 2 (IGFBP-2) functions as a central coordinator linking growth factor signaling to immune evasion through STAT3-dependent pathways driving M2 macrophage polarization and regulatory T cell differentiation; IGF–immune crosstalk varies considerably across molecular subtypes, with microsatellite-stable tumors exhibiting high reliance on IGF-I receptor-mediated immune silencing; and local paracrine IGF production increasingly dominates over systemic regulation as disease progresses. These bidirectional connections establish self-reinforcing circuits that determine whether tumors remain immunologically responsive or develop immune exclusion. Multi-marker panels incorporating IGFBP-2 alongside complementary biomarkers have shown improved diagnostic performances for early CRC detection, underscoring the need for the large-scale prospective clinical evaluation of IGF network components as biomarkers for CRC in diverse populations. The convergence of IGF signaling with checkpoint regulation suggests that combined targeting warrants investigation for resistance in tumors lacking effective immunotherapy options.

Supplementary Figure S3 shows boxplots of gastric mucosal cytokine and chemokine concentrations (IL-8, TNFα, and IP-10) changes between baseline and 6 months stratified by treatment arm and presented separately for antrum and corpus specimens.