Background/Objectives: The incidence of early-onset colorectal cancer (EOCRC), defined as diagnosis before age 50, has been rising at an alarming rate, with Hispanic/Latino (H/L) individuals experiencing the most significant increases in both incidence and mortality. Despite this growing public health concern, the molecular mechanisms driving EOCRC disparities remain poorly understood. Oncogenic pathways such as WNT, TGF-beta, and RTK/RAS are critical in colorectal cancer (CRC) progression, yet their specific roles in EOCRC across diverse populations have not been extensively studied. This research seeks to identify molecular alterations within these pathways by comparing EOCRC cases in H/L and non-Hispanic White (NHW) individuals. Furthermore, we explore the clinical significance of these findings to inform precision medicine strategies tailored to high-risk populations. Methods: To investigate mutation frequencies in genes associated with the WNT, TGF-beta, and RTK/RAS pathways, we conducted a bioinformatics analysis using publicly available CRC datasets. The study cohort consisted of 3412 patients, including 302 H/L and 3110 NHW individuals. The patients were categorized based on age (EOCRC: <50 years; late-onset CRC [LOCRC]: ≥50 years) and population group (H/L vs. NHW) to assess variations in mutation prevalence. Statistical comparisons of mutation rates between the groups were conducted using chi-squared tests, while Kaplan–Meier survival analysis was employed to evaluate overall survival differences associated with pathway alterations. Results: Notable molecular distinctions in the RTK/RAS pathway were identified between EOCRC and LOCRC among the H/L patients, with EOCRC exhibiting a lower frequency of RTK/RAS alterations compared to LOCRC (66.7% vs. 79.3%,p= 0.01). Within this pathway, mutations in CBL (p< 0.05) and NF1 (p< 0.05) were significantly more prevalent in the EOCRC cases (5.8% vs. 1.2% and 11.6% vs. 3.7%, respectively), whereas BRAF mutations were notably less frequent in EOCRC than in LOCRC (5.1% vs. 18.3%,p< 0.05). Comparisons between the EOCRC patients from the H/L and NHW populations revealed distinct pathway-specific alterations that were more common in the H/L individuals. These included RNF43 mutations (12.3% vs. 6.7%,p< 0.05) in the WNT pathway, BMPR1A mutations (5.1% vs. 1.8%,p< 0.05) in the TGF-beta pathway, and multiple RTK/RAS pathway alterations, such as MAPK3 (3.6% vs. 0.7%,p< 0.05), CBL (5.8% vs. 1.4%,p< 0.05), and NF1 (11.6% vs. 6.1%,p< 0.05). Survival analysis in the H/L EOCRC patients did not reveal statistically significant differences based on pathway alterations. However, in the NHW EOCRC patients, the presence of WNT pathway alterations was associated with significantly improved survival outcomes, suggesting potential ethnicity-specific prognostic implications. Conclusions: This study highlights the substantial molecular heterogeneity present in EOCRC, particularly among high-risk populations. The H/L EOCRC patients exhibited distinct genetic alterations, with a higher prevalence of CBL, NF1, RNF43, BMPR1A, and MAPK3 mutations compared to their NHW counterparts. Additionally, RTK/RAS pathway alterations were less frequent in EOCRC than in LOCRC. Despite these molecular differences, pathway alterations did not significantly impact survival outcomes in the H/L EOCRC patients. However, in the NHW EOCRC patients, the presence of WNT pathway alterations was associated with improved survival. These findings emphasize the necessity for further research to clarify the molecular mechanisms driving EOCRC disparities in high-risk populations and to inform precision medicine strategies for underrepresented groups.
**背景/目的：** 早发性结直肠癌（定义为50岁前确诊）的发病率正以惊人的速度上升，其中西班牙裔/拉丁裔人群的发病率和死亡率增幅最为显著。尽管这一公共卫生问题日益严峻，但驱动EOCRC差异的分子机制仍知之甚少。WNT、TGF-β和RTK/RAS等致癌通路在结直肠癌进展中至关重要，但它们在EOCRC中于不同人群中的具体作用尚未得到广泛研究。本研究旨在通过比较西班牙裔/拉丁裔与非西班牙裔白人个体的EOCRC病例，识别这些通路内的分子改变。此外，我们探讨了这些发现的临床意义，以期为针对高危人群的精准医疗策略提供信息。 **方法：** 为研究与WNT、TGF-β和RTK/RAS通路相关基因的突变频率，我们利用公开可用的CRC数据集进行了生物信息学分析。研究队列包括3412名患者，其中西班牙裔/拉丁裔302人，非西班牙裔白人3110人。根据年龄（EOCRC：<50岁；晚发性结直肠癌：≥50岁）和人群分组（西班牙裔/拉丁裔 vs. 非西班牙裔白人）对患者进行分类，以评估突变流行率的差异。组间突变率的统计比较采用卡方检验，而通路改变相关的总生存期差异则采用Kaplan-Meier生存分析进行评估。 **结果：** 在西班牙裔/拉丁裔患者中，EOCRC与LOCRC之间在RTK/RAS通路上发现了显著的分子差异，EOCRC的RTK/RAS改变频率低于LOCRC（66.7% vs. 79.3%，p=0.01）。在该通路内，CBL（p<0.05）和NF1（p<0.05）突变在EOCRC病例中显著更普遍（分别为5.8% vs. 1.2% 和 11.6% vs. 3.7%），而BRAF突变在EOCRC中的频率则显著低于LOCRC（5.1% vs. 18.3%，p<0.05）。对西班牙裔/拉丁裔与非西班牙裔白人EOCRC患者的比较显示，西班牙裔/拉丁裔个体中存在更常见的、通路特异性的独特改变。这些改变包括WNT通路中的RNF43突变（12.3% vs. 6.7%，p<0.05），TGF-β通路中的BMPR1A突变（5.1% vs. 1.8%，p<0.05），以及RTK/RAS通路中的多种改变，如MAPK3（3.6% vs. 0.7%，p<0.05）、CBL（5.8% vs. 1.4%，p<0.05）和NF1（11.6% vs. 6.1%，p<0.05）。在西班牙裔/拉丁裔EOCRC患者中，生存分析未显示基于通路改变的统计学显著差异。然而，在非西班牙裔白人EOCRC患者中，WNT通路改变的存在与生存结局的显著改善相关，提示可能存在种族特异性的预后意义。 **结论：** 本研究强调了EOCRC中存在显著的分子异质性，尤其是在高危人群中。与非西班牙裔白人EOCRC患者相比，西班牙裔/拉丁裔EOCRC患者表现出独特的遗传改变，CBL、NF1、RNF43、BMPR1A和MAPK3突变更为普遍。此外，EOCRC中RTK/RAS通路改变的发生频率低于LOCRC。尽管存在这些分子差异，通路改变并未显著影响西班牙裔/拉丁裔EOCRC患者的生存结局。然而，在非西班牙裔白人EOCRC患者中，WNT通路改变的存在与生存改善相关。这些发现强调了有必要开展进一步研究，以阐明驱动高危人群EOCRC差异的分子机制，并为代表性不足群体的精准医疗策略提供信息。
肿瘤(癌症)患者之家