Background/Objectives:Early-onset colorectal cancer (EOCRC), defined as colorectal cancer (CRC) diagnosed before the age of 50, has been increasing in incidence, particularly among Hispanic/Latino (H/L) populations. Despite this trend, the underlying molecular mechanisms driving EOCRC disparities remain poorly understood. The MAPK and JAK/STAT pathways play critical roles in tumor progression, proliferation, and treatment response; however, their involvement in ethnicity-specific differences in EOCRC remains unclear. This study aims to characterize molecular alterations in MAPK and JAK/STAT pathway genes among EOCRC patients, focusing on differences between H/L and Non-Hispanic White (NHW) patients. Additionally, we assess whether these pathway-specific alterations contribute to survival outcomes in H/L EOCRC patients.Methods:We conducted a bioinformatics analysis using publicly available CRC datasets to assess mutation frequencies in MAPK and JAK/STAT pathway genes. A total of 3412 patients were included in the study, comprising 302 H/L patients and 3110 NHW patients. Patients were stratified by age (EOCRC: <50 years, late-onset colorectal cancer—LOCRC: ≥50 years) and ethnicity (H/L vs. NHW) to evaluate differences in mutation prevalence. Chi-squared tests were performed to compare mutation rates between groups, and Kaplan–Meier survival analysis was used to assess overall survival differences based on pathway alterations among both H/L and NHW EOCRC patients.Results:Significant differences were observed in MAPK pathway-related genes when comparing EOCRC and LOCRC in H/L patients. NF1 (11.6% vs. 3.7%,p= 0.01), ACVR1 (2.9% vs. 0%,p= 0.04), and MAP2K1 (3.6% vs. 0%,p= 0.01) were more prevalent in EOCRC, while BRAF mutations (18.3% vs. 5.1%,p= 9.1 × 10−4) were significantly more frequent in LOCRC among H/L patients. Additionally, when comparing EOCRC in H/L patients to EOCRC in NHW patients, key MAPK pathway genes such as AKT1 (5.1% vs. 1.8%,p= 0.03), MAPK3 (3.6% vs. 0.7%,p= 6.83 × 10−3), NF1 (11.6% vs. 6.1%,p= 0.02), and PDGFRB (5.8% vs. 2.1%,p= 0.02) were significantly enriched in H/L EOCRC patients. However, no significant differences were observed in JAK/STAT pathway-related genes when comparing EOCRC and LOCRC in H/L patients, nor when comparing EOCRC in H/L vs. NHW patients. Survival analysis revealed borderline significant differences in H/L EOCRC patients, whereas NHW EOCRC patients with no alterations in the JAK/STAT pathway exhibited significant survival differences. In contrast, MAPK pathway alterations were not associated with significant survival differences. These findings suggest that MAPK and JAK/STAT pathway alterations may have distinct prognostic implications in H/L EOCRC patients, justifying further investigation into their potential role in cancer progression and treatment response.Conclusions:These findings suggest that MAPK pathway dysregulation plays a distinct role in EOCRC among H/L patients, potentially contributing to disparities in CRC development and treatment response. The higher prevalence of MAPK alterations in H/L EOCRC patients compared to NHW patients underscores the need to explore ethnicity-specific tumor biology and therapeutic targets. Conversely, the lack of significant differences in JAK/STAT pathway alterations suggests that this pathway may not play a major differential role in EOCRC vs. LOCRC within this population. Survival analysis highlighted the prognostic relevance of pathway-specific alterations. These insights emphasize the importance of precision medicine approaches that consider genetic heterogeneity and pathway-specific alterations to improve outcomes for H/L CRC patients.
**背景/目的：** 早发性结直肠癌（EOCRC）指50岁前确诊的结直肠癌（CRC），其发病率呈上升趋势，尤其在西班牙裔/拉丁裔（H/L）人群中更为显著。尽管存在这一趋势，驱动EOCRC差异的潜在分子机制仍不清楚。MAPK和JAK/STAT通路在肿瘤进展、增殖及治疗反应中发挥关键作用，但其在EOCRC种族特异性差异中的作用尚不明确。本研究旨在分析EOCRC患者中MAPK和JAK/STAT通路基因的分子改变，重点关注H/L与非西班牙裔白人（NHW）患者间的差异，并评估这些通路特异性改变是否影响H/L EOCRC患者的生存结局。 **方法：** 本研究利用公开的CRC数据集进行生物信息学分析，评估MAPK和JAK/STAT通路基因的突变频率。共纳入3412例患者，包括302例H/L患者和3110例NHW患者。按年龄（EOCRC：<50岁；晚发性结直肠癌—LOCRC：≥50岁）和种族（H/L vs. NHW）分层，比较突变发生率的差异。采用卡方检验比较组间突变率，并使用Kaplan-Meier生存分析评估H/L与NHW EOCRC患者中通路改变对总生存期的影响。 **结果：** 在H/L患者中，比较EOCRC与LOCRC时，MAPK通路相关基因存在显著差异：NF1（11.6% vs. 3.7%，p=0.01）、ACVR1（2.9% vs. 0%，p=0.04）和MAP2K1（3.6% vs. 0%，p=0.01）在EOCRC中更常见，而BRAF突变（18.3% vs. 5.1%，p=9.1×10⁻⁴）在H/L患者的LOCRC中显著更高。此外，比较H/L与NHW患者的EOCRC时，关键MAPK通路基因如AKT1（5.1% vs. 1.8%，p=0.03）、MAPK3（3.6% vs. 0.7%，p=6.83×10⁻³）、NF1（11.6% vs. 6.1%，p=0.02）和PDGFRB（5.8% vs. 2.1%，p=0.02）在H/L EOCRC患者中显著富集。然而，在H/L患者中比较EOCRC与LOCRC，或比较H/L与NHW患者的EOCRC时，JAK/STAT通路相关基因均未发现显著差异。生存分析显示，H/L EOCRC患者的生存差异处于临界显著水平，而NHW EOCRC患者中JAK/STAT通路未发生改变者生存差异显著。相比之下，MAPK通路改变与显著生存差异无关。这些结果表明，MAPK和JAK/STAT通路改变在H/L EOCRC患者中可能具有不同的预后意义，值得进一步研究其在癌症进展和治疗反应中的潜在作用。 **结论：** 本研究表明，MAPK通路失调在H/L患者的EOCRC中具有独特作用，可能影响CRC发生和治疗反应的差异。与NHW患者相比，H/L EOCRC患者MAPK改变的高发生率凸显了探索种族特异性肿瘤生物学及治疗靶点的必要性。相反，JAK/STAT通路改变缺乏显著差异，提示该通路在该人群的EOCRC与LOCRC中可能无主要差异作用。生存分析强调了通路特异性改变的预后相关性。这些发现强调了精准医学方法的重要性，需结合遗传异质性和通路特异性改变，以改善H/L CRC患者的临床结局。
肿瘤(癌症)患者之家