Serum Insulin-Like Growth Factor Binding Protein 7 as a Potential Biomarker in the Diagnosis and Prognosis of Esophagogastric Junction Adenocarcinoma

In our study, IGFBP7 was significantly higher in both early- and late-stage EJA compared to normal controls (p<0.001). For diagnosis, we achieved an AUC of 0.794 (95% CI, 0.733 to 0.854) and cutoff value of 2.716 ng/mL with sensitivity of 63.3% (95% CI, 54.0% to 71.8%) and specificity of 90.9% (95% CI, 82.4% to 95.7%) in EJA. Furthermore, we found that the level of serum IGFBP7 is not associated with any clinical parameters. However, if diagnosed with EJA, lower IGFBP7 expression may lead to the worse survival.

IGF family members regulate cell proliferation, differentiation and apoptosis through the MAPK and PI3K/Akt signaling pathways.19 They have also been demonstrated to correlate with many cancers.20-22 IGFBP7, also named IGFBP-rP1, is one of the members in IGF family. Although it shares 30% structural homology with IGFBP1 to IGFBP6 at its N-terminal domain, as it binds to IGF with low affinity10,23 and its individual characteristics are different from IGFBP1 to IGFBP6. Methylation of IGFBP7 may reduce the expression of IGFBP7 in gastric cancer and prostate cancer and improve the tumor progression,13,24 and administration of IGFBP7 may be therapeutic for reducing breast cancer growth.25 However, prior studies investigated expression in mostly cells and tissues. Serum expression of IGFBP7 has only been studied in a few diseases, such as chronic obstructive pulmonary disease12 and metabolic syndrome.26 Therefore, we evaluated the potential diagnostic and prognostic value of circulating IGFBP7 in EJA.

Early detection is one of the best methods to reduce cancer mortality and cancer burden.27 In clinical practice, endoscopy contributes to the early diagnosis of EJA.28 However, it is invasive and may produce adverse effects, such as infection, perforation, and bleeding.29 A recent study on serum autoantibody panels to detect EJA aroused our interest to identify noninvasive techniques to detect IGFBP7 in EJA patient serum.16 When accounting for the early detection of IGFBP7 in EJA, through ROC curve analysis, we found an AUC of 0.749 (95% CI, 0.644 to 0.854), which led to a sensitivity of 54.3% (95% CI, 36.9% to 70.8%) and specificity of 90.9% (95% CI, 82.4% to 95.7%). Although there was no statistical correlation between late-stage and early-stage EJA (p=0.187) (Table 4), IGFBP7 might be used as a potential biomarker for the early detection of EJA. Actually, there have been several studies on serum IGFBP7 in other cancers. Overexpression of serum IGFBP7 has been observed in high-grade soft tissue sarcoma,30 and high levels of serum IGFBP7 have been associated with positive nodal status in non-small cell lung cancer.31 However, both of them have not researched on the early-stage cancer. Additionally, our recent study has showed serum IGFBP7 might serve as a diagnostic biomarker for esophageal cancer,32 and it also made sense in early-stage esophageal cancer. Herein, although IGFBP7 is not a unique biomarker for EJA, it still may be a valuable candidate for EJA, in particular for the early detection of EJA.

Although Smith et al.33 suggested that the expression of IGFBP7 is related to poor prognosis in esophageal squamous cell carcinoma, as described in many cancers, such as thyroid,34 lung,35 liver,36 and ovarian,37 a high level of IGFBP7 gene expression could be a potential protective factor to suppress the growth of tumor cells. However, all of these studies were based on IGFBP7 expression at the level of tissues or cells. Therefore, we extended these studies to serum expression. As our study shows, low serum IGFBP7 concentration is associated with poor outcome (p=0.034), and multivariate analysis suggests that the level of serum IGFBP7 protein expression is an independent prognostic factor for EJA (p=0.011), suggesting that serum IGFBP7 might be also a potential prognostic marker for EJA.

In summary, our study offers useful information regarding the diagnostic value of serum IGFBP7 in EJA and suggests that IGFBP7 might be a potential biomarker for the detection and diagnosis of EJA. Additionally, low expression of IGFBP7, acting as an independent factor, might predict the poor prognosis of EJA. However, this was a single-institution study with a small sample size, which may lead to bias. A study with large sample size in multiple institutions should be performed to further verify the diagnostic value of IGFBP7 in EJA, especially early-stage EJA.