Renal cancer currently ranks seventh among the most frequently diagnosed cancer in males and ninth in females (1). In 2020, more than 431,000 cases of renal cancer were projected to occur worldwide (2). The geographic distribution of renal cancer is highest in the Baltic countries and in Eastern European countries and lowest in most parts of Asia and Latin America (3). There is a consistent male to female excess of renal cancer observed in both low- and high-incidence regions (4). The main established risk factors of renal cancer include tobacco smoking, body size, history of hypertension and chronic kidney disease (5, 6). However, they do not sufficiently explain these geographical and ethnic differences. Additional investigation is required to identify other suspected risk factors, which can improve prevention of renal cancer.

Emerging evidence have suggested a potential relationship between cancer development and diets associated with glucose and insulin metabolism. Hyperglycemia is associated with greater cancer risk and progression (7). This cancer-promoting effect may be mediated by systemic effects of insulin/insulin-related growth factor-1 (IGF-1) and inflammatory signaling. Direct uptake of glucose by cancer cells may also lead to epigenetic and biosynthetic changes (8). Glycemic index (GI) is a scale of zero to 100 for ranking carbohydrate-rich foods based on how quickly and how much they raise blood sugar levels after eating. Glycemic load (GL), a related measure, is a ranking system that takes into account the GI of a food and the carbohydrate content in a serving. High GI or GL has been associated with an increased risk of cardiovascular disease incidence and mortality (9–11) and some types of cancer (e.g., breast cancer) (12). A few prospective studies also have examined the potential association between dietary GI or GL and risk of renal cancer, with controversial results (13–15). A previous meta-analysis reported a significant positive association between GI and the risk of renal cancer (16). Given the potential impact of glucose and insulin on cancer, and limited evidence with mixed findings regarding GI and GL in relation to renal cancer risk, we investigated the associations of GI and GL with renal cancer risk within the large prospective Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial.

In this large prospective PLCO cohort, there was a statistically significant association between dietary GI and renal cancer risk. No obvious association between GL and renal cancer risk was observed. Similar results were obtained when excluding cases diagnosed within the first two years of follow-up. Findings from continuous analyses and spline regression plots were comparable with the results in main analyses.

These results, which were based on a large prospective cohort study, were consistent with our previous findings based on a meta-analysis (16). A significant positive association was observed between GI and the risk of renal cancer (poled RR 1.16, 95% CI 1.02–1.32). GL was not significantly associated with renal cancer risk (pooled RR 1.14, 95% CI 0.81–1.60). However, only five studies (three case–control and two cohort studies) were eligible in this meta-analysis. Case–control studies were more likely to be prone to recall bias and select bias. The evidence on the association between GI or GL and renal cancer risk may be still limited and not robust. Therefore, we further performed an analysis based on a large US cohort. As a result, we also found a significant association between GI and renal cancer risk and no association was observed for GL in PLCO cohort, which further enhanced the current evidence.

In subgroup analyses for GI, a more significant association was observed in male, in white non-Hispanic population and in overweight/obese participants, which suggested a potential differential susceptibility. The incidence of renal cancer has obvious ethnic and sex differences. In addition. A high BMI is also a well-established risk factor for renal cancer.

Several mechanisms have been proposed to explain a potential association between dietary GI and human cancers. Foods with a high GI will increase the concentration of glucose and insulin in blood and thus induce hyperinsulinemia (25, 26). Hyperinsulinemia can increase the insulin-like growth factor-1 (IGF-1) expression (27). Higher IGF-1 has been reported to be modestly associated with increased risk of overall cancer risk, including kidney cancer based on a cohort study analysis from the UK Biobank (28). Previous studies have demonstrated that IGF-1 pathway plays an important role in cell proliferation and apoptosis resistance in renal cell carcinoma (29). In addition, long-term exposure of tubular cells to hyperglycemia can lead to disturbances in DNA repair mechanisms, which may drive and promote renal cancer development (30).

Several limitations of the current study should be acknowledged. First, the outcome of this study was renal cancer incidence. Although we have excluded the renal pelvis cancer, we were not able to further classify the types of renal cancer because of the limited data on original questionnaire. Second, the majority of GI values (32.97 to 79.16, median value: 53.62) centered around the middle of the theoretical range for GI (i.e., 0–100) in PLCO trial. Therefore, it was hard to evaluate the effects of different levels of GI unless it is a strong cancer risk determinant at middle values (31). Third, dietary questionnaire used in PLCO cohort was self-administrated, which may cause some measurement error (32). In addition, dietary intake was assessed only once at baseline and any changes in diet during follow-up could not be examined. Finally, although the statistical models were adjusted for various important confounders, a certain degree of residual confounding may be unavoidable because of collinearity from other nutrients, particularly macronutrients.

This study had some unique strengths. As a prospective study, the chance of reverse causality from subclinical disease-causing changes in diet was small and the recall bias was avoided as the exposure was preceding the onset of cancer. This study included almost 100,000 participants with a median of 12.2 years of follow-up, which provided strong power to detect differences in renal cancer incidence if they truly existed. Additionally, the rate of participants lost to follow up was very low in PLCO study. The large study population was recruited from institutions across the United States, which improved the generalizability. The availability of data on various potential confounders made comprehensive adjustment possible. Lastly the methods used to assign GI and GL values to foods was rigorous, which was based on American data wherever possible (21).

In summary, analysis of the PLCO cohort suggested that diets high in GI was associated with greater renal cancer risk. If confirmed in other populations and settings, dietary GI could be considered as a modifiable risk factor for renal cancer prevention.

The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found at: https://cdas.cancer.gov/datasets/plco/.

The studies involving human participants were reviewed and approved by National Cancer Institute. The patients/participants provided their written informed consent to participate in this study.

XX and DX contributed to the conception or design of the work. XX, HQ, and DX contributed to the acquisition, analysis, or interpretation of data for the work. HQ and DX drafted the manuscript. XX critically revised the manuscript. All authors gave final approval and agreed to be accountable for all aspects of work ensuring integrity and accuracy.

This study was supported by grants from the Zhejiang Provincial Natural Science Foundation (LY22H160027) and National Natural Science Foundation of China (82172597).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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