Overweight and obesity constitute a major public health emergency, presenting a grave and imminent threat to global health progress. In 2021 alone, these conditions contributed to 71 million deaths and 129 million disability-adjusted life years (DALYs). Over the past two decades, the global age-standardized DALY rates linked to overweight and obesity have risen by more than 15%, making them one of the foremost risk factors and showcasing the steepest increase in disease burden attributable to any cause (1, 2).

Lung cancer is the most common malignancy worldwide, with an estimated 2.48 million new cases and 1.82 million deaths reported globally in 2022. By 2050, projections suggest that China alone will see approximately 1.12 million new cases and 960,000 deaths among males, alongside 680,000 new cases and 450,000 deaths among females (3, 4). Non-small cell lung cancer (NSCLC) accounts for roughly 85% of all lung cancers, with EGFR mutations occurring in 40% to 60% of Asian patients diagnosed with ADC (5).

Obesity is closely linked to tumor development, with cancer cases attributed to obesity projected to surpass 2 million globally by 2070, accounting for 7% of all cancer cases (6). Another study have demonstrated that the obesity-related gene ABCC8 may promote the development of hepatocellular carcinoma (HCC) (7). However, previous studies analyzing molecular data from human and mouse samples revealed that obesity-induced microenvironmental changes, rather than novel driver gene mutations, drive the progression of pancreatic ductal ADC (8). A critical discovery was the remarkable adaptation of islet cells within tumors associated with obesity. Moreover, the tumor microenvironment plays a key role in the development and progression of tumors, and its interaction with genetic mutations directly affects the invasiveness and metastatic potential of the tumor (9–11). Microenvironmental factors are universal across various types of tumors (12–14). In ADC, microenvironmental components such as immune cell infiltration, angiogenesis, and extracellular matrix remodeling often synergize with specific mutations to exacerbate the malignant phenotype of the tumor (15, 16).

However, research on the link between obesity and the gene mutation rate in ADC remains limited. The main goal of this study is to comprehensively investigate the relationship between obesity and gene mutation rate in ADC patients. To achieve this objective, genetic testing data from 404 clinically confirmed ADC cases were analyzed. The results indicate that higher BMI levels are associated with a reduced likelihood of gene mutations. This research is expected to offer new insights and potential avenues for future research into tumor gene mutations.

Our study identified a significant linear association between BMI and ADC gene mutation rates, particularly notable within the BMI range of 21.08 to 22.86kg/m². ROC prediction models for ADC gene mutations, based on BMI, yielded AUC values of 0.533 (all BMI) and 0.625 (BMI range: 21.08-22.86 kg/m²). Spearman correlation analysis further confirmed a significant negative correlation between BMI and ADC gene mutation rate in the range of 21.08 to 22.86 kg/m². Additionally, gene mutation rates were relatively higher among patients younger than 60, women, and those without a history of smoking or drinking.

Obesity is intricately linked to tumorigenesis, with underlying mechanisms that are notably complex. In obese individuals, dysfunctional adipocytes overproduce free fatty acids (FFAs) and pro-inflammatory cytokines, such as tumor necrosis factor-α (TNF-α) and Interleukin-6 (IL-6) (21). This excessive production activates the JNK/TLR/NF-κB signaling pathway, impairing insulin receptor function. Hyperinsulinemia subsequently promotes tumor cell proliferation through the PI3K-AKT-mTOR and RAS-MAPK pathways, while simultaneously reducing insulin-like growth factor-binding proteins (IGFBPs) and increasing the bioavailability of free Insulin-like growth factor-1/2 (IGF-1/IGF-2)—key factors for sustaining tumor stem cells (22–24). CD36, a crucial fatty acid transporter, is significantly upregulated in obesity and hypercholesterolemia, enabling gastric cancer cells to aggressively absorb lipids, thereby fueling rapid tumor growth and invasion (25). Notably, CD36 serves as the only shared genetic link between obesity, hypercholesterolemia, and gastric cancer, with its expression levels strongly correlating with advanced cancer staging and poor prognosis (26). Within obese adipose tissue, macrophages form a “crown-like structure”, continuously secreting pro-inflammatory factors that induce DNA damage and impair repair mechanisms. Furthermore, adipose tissue itself generates reactive oxygen species (ROS), further elevating mutation risks. Macrophages also polarize into the M2 phenotype, releasing inhibitory factors like Interleukin-10 (IL-10) and transforming growth factor-β (TGF-β), which suppress CD8⁺ T cell function and help cancer cells evade immune surveillance (27, 28).

Current understanding of modifiable risk factors for EGFR/KRAS-mutant ADC remains notably scarce. Prior research indicates that obese ADC patients have higher rates of KRAS mutations, and that KRAS-mutant tumors demonstrate increased responsiveness to immune checkpoint inhibitors, which partly explains the enhanced efficacy of immunotherapy in this group. Among East Asian populations, obesity exerts a more pronounced negative effect on EGFR mutations (29). Our study further uncovers a significant inverse relationship between BMI and ADC gene mutation rates, likely attributable to the high frequency of EGFR mutations within our cohort, underscoring the pivotal role of gene-environment interactions in ADC pathogenesis. Moreover, these findings highlight the potential clinical implications of incorporating BMI evaluations into genetic screening protocols for ADC patients, especially in populations with a high prevalence of EGFR mutations. Future investigations should explore the underlying biological mechanisms, such as hormonal or metabolic pathways, that facilitate the interaction between obesity and EGFR mutation prevalence. Such insights could pave the way for personalized prevention and treatment strategies. Additionally, longitudinal studies are needed to determine whether weight management interventions can mitigate mutation-associated risks and enhance immunotherapy outcomes in this specific patient subgroup.

Previous research has revealed significant differences in the mutation profiles of NSCLC, including alterations in genes such as ALK, Rearranged during Transfection (RET), MET, EGFR, serine/threonine kinase 11(STK11), Kelch-like ECH-associated protein 1 (KEAP1), BRAF, and KRAS, as well as in Tumor Mutation Burden (TMB)-High status, between patients under 40 and those aged 40 or older (30). Our study similarly demonstrates that ADC patients aged 60 or older have a significantly lower probability of gene mutations compared to those under 60. Furthermore, our findings indicate that women exhibit a lower rate of gene mutations than men, and patients with a smoking history have a markedly reduced mutation rate compared to non-smokers, which is consistent with the majority of prior studies (31–36). These observations underscore the substantial impact of age, gender, and smoking history on the likelihood of ADC gene mutations, providing a basis for optimizing screening and treatment strategies tailored to different age, gender, and smoking status groups. Further research should delve into the biological mechanisms associated with these factors, such as changes in DNA repair capacity, immune responses, or cell proliferation rates, which may influence the accumulation of gene mutations across diverse age, gender, and smoking contexts.

Various gene mutation types in ADC are strongly associated with a notably poor clinical prognosis. Patients with EGFR-sensitive mutations, such as exon 19 deletions or L858R, who are treated with first-generation EGFR tyrosine kinase inhibitors (TKIs), typically achieve a median progression-free survival (PFS) of 9 to 18 months (37). In contrast, first-line therapy with the third-generation TKI osimertinib extends median PFS to 18.9 months and overall survival (OS) beyond 3 years. Moreover, patients with exon 19 deletions have a more favorable prognosis than those with L858R mutations, with median PFS of 14.7 months versus 9.8 months, respectively. However, the presence of concurrent TP53 mutations significantly worsens prognosis, with a hazard ratio (HR) ranging from 1.6 to 2.3 (38). In the context of ALK fusion gene-targeted therapy, median OS exceeds 7 years, marking this subtype as having the most favorable prognosis (39). For MET exon 14 skipping mutations, targeted therapy yields an objective response rate (ORR) of 68% and a median PFS of 12.4 months (40). Nevertheless, the precise mechanisms contributing to the poor prognosis associated with distinct genetic mutation types remain incompletely understood. Future research should focus on multicenter prospective studies that incorporate single-cell sequencing and functional experiments to clarify the regulatory roles of signaling pathways, such as PI3K/AKT or MAPK, in various mutant subtypes, while these studies should evaluate the impact of the tumor immune microenvironment. A comprehensive analysis of multiple factors will provide a theoretical foundation for the development of personalized treatment strategies.

This study has notable strengths and limitations. Significantly, A key strength is that it is the first to explore the association between BMI and ADC gene mutations, including EGFR, KRAS, and TP53, potentially providing clinicians with fresh insights to inform evidence-based decision-making. However, several limitations warrant consideration. Firstly, as a single-center retrospective study with a relatively small sample size, it was not feasible to conduct a longitudinal analysis of the relationship between BMI and tumor gene mutations. Secondly, our research did not differentiate among specific gene mutations but rather examined the correlation between BMI and tumor gene mutation in a general sense. Thirdly, potential selection bias in the study data may affect the accuracy of the findings. Fourthly, the study population lacked racial diversity, which may limit the generalizability of the results. Finally, errors in data collection could introduce bias into the outcomes.

In summary, this retrospective real-world study reveals a significant inverse correlation between BMI and ADC gene mutations. Specifically, within the BMI range of 21.08 to 22.86 kg/m², higher BMI levels are associated with a reduced risk of such mutations. Furthermore, the mutation frequency appears to be elevated among female patients under 60 who have no history of smoking or alcohol consumption. These findings offer clinicians preliminary insights for assessing the likelihood of ADC mutations in patients.