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Novel blood-based FUT7 DNA methylation is associated with lung cancer: especially for lung squamous cell carcinoma

Clinical Epigenetics volume 14, Article number: 167 (2022) Cite this article

Abstract

Background

The death rate of lung cancer (LC) ranks first in the world. Changes of DNA methylation in peripheral blood may be related to malignant tumors. It is necessary to explore blood-based biomarkers of methylation to detect LC.

Methods

Mass spectrometry assays were conducted to measure DNA methylation levels of seven CpG sites within FUT7 gene in the peripheral blood of 428 patients with LC, 233 patients with benign pulmonary nodule (BPN) and 862 normal controls (NC). The odds ratios (ORs) of all CpG sites were evaluated for their risk to LC using per SD change and tertiles analyses by logistic regression. The predictive ability of the seven FUT7 CpG sites and risk factors were evaluated by receiver operating characteristic curve (ROC).

Results

The methylation levels of seven CpG sites of FUT7 in LC were significantly lower than that in NC (P < 0.05). The per SD decrement of methylation level in CpG_1-7 was significantly associated with 65%, 38%, 59%, 46%, 23%, 20% and 68% higher risk for LC versus NC, respectively, and the adjusted ORs (95% CI) were 2.92 (2.17–3.96), 1.76 (1.29–2.38), 2.83 (2.09–3.82), 3.00 (2.17–4.16), 1.81 (1.35–2.43), 1.48 (1.11–1.97) and 3.04 (2.23–4.16) for the lowest tertiles of methylation level in CpG_1-7 compared with the top tertiles, respectively. The area under the curve (AUC) of FUT7_CpG_1-7 was 0.659 (CI 0.626–0.693), 0.792 (CI 0.736–0.848) and 0.729 (CI 0.665–0.792) in distinguishing LC versus NC, LUSC versus NC and LUSC versus BPN.

Conclusions

Our study revealed an association between FUT7 hypomethylation and LC, especially for LUSC, which provides novel support for the blood-based methylation signatures as potential marker for assessing lung cancer risk.

Background

Lung cancer (LC) is the leading cause of death from cancer, with 1.8 million deaths worldwide in 2020 [1]. The mortality rate of LC in China is among the highest globally, and it remains on the rise [2]. The 5-year relative survival rate for LC is only 6%, mainly due to diagnosis at late stages of 57% patients, and the 5-year survival rate for localized stage disease is 59% [1]. Therefore, initial diagnosis and proper treatment are efficient way to improve the survival of LC patients. Low-dose computed tomography (LDCT) screening has been proven to reduce LC mortality by 20% in high-risk populations, but the high false positives rate and overdiagnosis should also be concerned [3, 4]. In addition, the sensitivity of LDCT may be severely affected by tumor size and location, varying in a wide range (60–80%) [5, 6].

Epigenetics plays a vital role in the occurrence and development of many diseases, and its characteristic is to regulate gene expression without changing the DNA sequence. DNA methylation performs a vital epigenetic mechanism that involves the regulation of X chromosome inactivation, genomic imprinting, tissue-specific gene expression and a variety of disorders [7, 8].

Genome-wide hypomethylation and hypermethylation changes were found in LC, which may be used as markers [9]. For example, hypermethylation of SHOX2 and p16/CDKN2A was reported for early detection of LC [10,11,12]. Fucosyltransferases (FUTs), catalyzing the transfer of GDP-fucose residues to the receptor molecules to complete fucosylation, participate in various biological processes, including tumor progression, cell adhesion and differentiation [13,14,15]. As far as we know, there are 13 genes in FUT family, divided into four subfamilies based on glycosidic bonds, namely α1,2-, α1,3/4-, α1,6- and protein O-fucosylation [16]. FUT7 belongs to the α1,3/4-fucosyltransferase family and catalyzes the synthesis of α1,3-fucose [17]. Evidence is mounting that the expression of FUT7 is increased in liver cancer, lung cancer, breast cancer and other solid tumors [18, 19]. According to previous studies, FUT7 may promote the process of cancers via EGFR/AKT/mTOR signaling pathway and MAPK and PI3K/Akt signaling pathway [19, 20]. However, there is rare report about the association between blood-based FUT7 methylation and lung cancers. The purpose of our study is to explore the relationship of lung cancer with FUT7 methylation in peripheral blood and the detection value of FUT7 methylation in LC patients.

Material and methods

Study population

A total of 1523 patients were included in the study, of which 428 patients with LC, 233 patients with BPN, and 862 unrelated self-reported healthy individuals were consecutively recruited from the First Affiliated Hospital of Zhengzhou University between January 2018 and January 2021, and approved by the Ethics Committee of the First Affiliated Hospital of Zhengzhou University (2021-KY-1057-002). The diagnosis of LC and BPN was confirmed by thoracic surgery or pneumocentesis followed by histopathological diagnosis, and the blood samples of these patients were collected before surgery and any cancer-related treatments. The detailed characteristics of participants are shown in Table 1.

Table 1 Characteristics of study participants
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Sample processing

All the peripheral blood samples were collected by EDTA blood collection tubes and kept at 4 °C for less than 24 h before the storage at − 80 °C for future usage. DNA Extraction Kit (TANTICA, Nanjing, China) was used to extract DNA from whole blood and further bisulfite-converted utilized EZ-96 DNA Methylation Gold Kit according to standard protocol (Zymo Research, Orange, U.S.). All the samples were processed in parallel.

MALDI-TOF mass spectrometry

Bisulfite converted DNA of all participants was amplified by bisulfite-specific primers. The sequence of target region is shown in Additional file 1: S1. There is no single nucleotide polymorphism (SNP) nor CpG site in the primers. Forward primer: 5′-aggaagagagTAAAATGTTGGGATTATAGTTTGGG-3′, reverse primer: 5′-cagtaatacgactcactatagggagaaggctAAAACCAAATTCCTTCTTCTACACC-3′. Upper case letters presented the sequence specific regions, and the unspecific tags were shown in lower case letters. The PCR products were analyzed by a matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometry for the semi-quantitative measurements of the DNA methylation intensity at the single CpG resolution (Agena Bioscience, California, U.S.). Briefly, the PCR amplified products were incubated with Shrimp Alkaline Phosphatase (SAP) and further transcribed to RNA by T7 transcriptase according to the standard protocol of Agena EpiTyper assay (Agena Bioscience, California, U.S.). The RNA was digested by RNase into small fragments and then cleaned the ions by resin. The final products were dispensed on a 384 SpectroCHIP. The DNA methylation levels were semi-quantitatively determined by comparing the intensities of methylated and non-methylated segments. The data were collected by SpectroACQUIRE v3.3.1.3 software and visualized by EpiTyper v1.3 software.

Statistical analysis

All statistical data were analyzed by SPSS Statistics 23.0 software and GraphPad Prism 9.0. The mean ± SD or the median (25th percentile, 75th percentile) and the number (%) were utilized to describe continuous data and categorical data, respectively. Mann–Whitney U test was adopted to compare the methylation level in different clinical categories due to the non-normal distribution of the data and the Z value was calculated to make the results adequate and convincing. Chi-squared test was applied for categorical data. By presenting the 95% confidence interval (CI) and the odds ratios (ORs) with adjustment for covariates (age, sex, smoking, alcohol drinking, history of chronic lung diseases and personal tumor history), the association between FUT7 methylation and LC were assessed via logistic regression analyses. In the assessing of FUT7 methylation, we established models for both continuous data per SD decrement and categorical data by utilizing tertiles with the highest tertile (T3) as the reference group. The tests for linear trend were performed by entering the tertiles of each category of seven FUT7 CpG sites as continuous data in the models. The predictive ability of seven FUT7 CpG sites (FUT7_CpG_1-7) was evaluated via the corresponding area under curve (AUC) of receiver operating characteristic curve (ROC) with 95% CI. A two-sided P < 0.05 was statistically significant.

Results

The methylation levels of FUT7 in LC were lower than that in NC and BPN

As shown in Table 2 and Fig. 1, the methylation levels of seven sites of FUT7 in LC were significantly lower than that in NC (P < 0.05). The methylation levels of CpG-4 and CpG-7 were lower in LC than in BPN (P < 0.05), and no significant differences in other sites (Table 2; Fig. 1).

Table 2 The methylation levels of FUT7_CpG_1-7 in LC, BPN and NC
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Fig. 1
figure 1

The methylation levels of FUT7 in LC, BPN and NC. LC lung cancer, BPN benign pulmonary nodule, NC normal control. *P < 0.05; ***P < 0.001. P: Mann–Whitney-U test was used to continuous data

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Association between FUT7 methylation and LC patients

The per SD decrement and tertiles were conducted to evaluate the ORs of seven CpG sites in FUT7 for the risk of LC by multivariate logistic regression. In adjusted model (adjusted age and sex), the per SD decrement of methylation level in CpG_1-7 was significantly associated with 65%, 38%, 59%, 46%, 23%, 20% and 68% higher risk for LC versus NC, respectively, and the adjusted OR (95% CI) was 2.92 (2.17–3.96), 1.76 (1.29–2.38), 2.83 (2.09–3.82), 3.00 (2.17–4.16), 1.81 (1.35–2.43), 1.48 (1.11–1.97) and 3.04 (2.23–4.16) for the lowest tertile of methylation level in CpG_1-7 compared with the top tertile, respectively (P for trend < 0.05) (Table 3). After adjustment for age, gender smoking, alcohol drinking, history of chronic lung diseases and personal tumor history in adjusted model, the per SD decrement of methylation level in CpG_4 was significantly associated with 32% higher risk for LC versus BPN (Table 3). To explore the value of FUT7 methylation in the detection of LC, the combination analyses of seven CpG sites were performed. ROC analysis showed AUC of 0.659 (95% CI 0.626–0.693) and 0.658 (CI 0.614–0.701) in distinguishing LC from NC (Fig. 2A) and LC versus BPN (Fig. 2B).

Table 3 Odds ratio of LC versus NC or BPN according to continuous or tertiles of FUT7_CpG_1-7
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Fig. 2
figure 2

The diagnostic capability of FUT7_CpG_1-7. A ROC for LC versus NC. B ROC for LC versus BPN. C ROC for LUAD versus NC. D ROC for LUSC versus NC. E ROC for LUAD versus BPN. F ROC for LUSC versus BPN. ROC receiver operating characteristic curve, AUC area under the curve, NC normal control, BPN benign pulmonary nodule, LC lung cancer, LUAD lung adenocarcinoma, LUSC lung squamous cell carcinoma

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The predictive ability of FUT7_CpG_1-7 in LUAD and LUSC patients

There are 291 LUAD and 81 LUSC patients in our study as shown in Table 4. Compared with LUAD patients, LUSC patients were older and more likely to be men. Besides, patients in LUSC had higher rates of smoking, alcohol drinking and history of chronic lung diseases. What’s more, patients with LUSC have longer nodule length and later stages than LUAD. The levels of FUT7 methylation were higher in LUAD patients than that in LUSC patients (Table 4; Fig. 3).

Table 4 Comparison between LUAD and LUSC
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Fig. 3
figure 3

The methylation levels of FUT7_CpG_1-7 in LUAD and LUSC. LUAD lung adenocarcinoma, LUSC lung squamous cell carcinoma. **P < 0.01; ***P < 0.001. P: Mann–Whitney-U test was used to continuous data

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Under the condition that BPN was a control group, multivariate logistic regression analyses of adjusted model (adjusted age, sex, smoking, alcohol drinking, history of chronic lung diseases, personal tumor history) demonstrated that each SD decrement of methylation level in CpG_4 and CpG_5 was significantly associated with 24% and 31% higher risk for LUAD. Compared with the top tertiles, the adjusted OR (95% CI) was 1.62 (1.03, 2.55) and 1.74 (1.08, 2.81) for the lowest tertiles of methylation level in CpG_4 and CpG_5 (P for trend < 0.05) (Table 5). Meanwhile, the per SD decrement of methylation level in CpG_1, 2, 3, 4 and 7 was significantly associated with a 57%, 72%, 75%, 115% and 115% higher risk for LUSC, respectively (Table 5). Compared with the top tertiles, the adjusted ORs (95% CI) were 2.66 (1.16, 6.09), 2.97 (1.21, 7.29), 2.90 (1.31, 6.43), 5.19 (2.26, 11.92) and 4.52 (1.93, 10.57) for the lowest tertiles of methylation level in CpG_1, 2, 3, 4 and 7, respectively, after assessing the seven FUT7 CpG sites as tertiles in model 2 (all P for trend < 0.05). ROC curves demonstrated the AUC was 0.617 (CI 0.577–0.657), 0.792 (CI 0.736–0.848), 0.669 (CI 0.622–0.716) and 0.729 (CI 0.665–0.792) for seven FUT7 CpG sites in the discrimination of LUAD versus NC (Fig. 2C), LUSC versus NC (Fig. 2D), LUAD versus BPN (Fig. 2E) and LUSC from BPN (Fig. 2F). The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), positive likelihood ratio (+ LR), and negative likelihood ratio (-LR) are shown in Table 6.

Table 5 Odds ratio of LUAD or LUSC versus BPN according to continuous or tertiles of FUT7_CpG_1-7
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Table 6 Diagnostic value of CpG1-7 in distinguishing LC from NC or BPN
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The association of methylation levels of FUT7 with clinical characteristics in LC patients

To understand the methylation patterns in 428 LC patients, the methylation levels of FUT7 stratified by different clinical characteristics were further analyzed. FUT7_CpG_1-7 were significant different in tumor length. Compared to the patients with smaller nodules (tumor length ≤ 3 cm), the LC patients with more than 3 cm tumor length have significantly lower methylation at FUT7_CpG_1-7 (P < 0.05; Table VII). The methylation levels of FUT7_CpG_2,3,5,6,7 groups were lower in terms of clinical stage III and IV, lymph nodes and metastasis than the corresponding control group (P < 0.05; Table 7), which indicated that hypomethylation of FUT7_CpG_2,3,5,6,7 might be associated with the progress of LC.

Table 7 FUT7_CpG_1-7 methylation levels in LC patients with different clinical characteristics
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Discussion

Lung cancer is a high malignant carcinoma leading cause of cancer death worldwide. There is an urgent need to search for the sensitive and specific biomarkers of LC to improve the diagnosis, treatment and prognosis assessment. Our results revealed that the methylation level in all CpG sites in FUT7 was significantly and negatively associated with LC in the presence of NC as control group. In the case of BPN as control group, the hypomethylation levels of FUT7_CpG_4,5 were associated with increasing risk of LUAD. Furthermore, the increased risk of LUSC was associated with the decreased methylation levels of FUT7_CpG_1,2,3,4,7, and FUT7_CpG_1-7 showed good predictive ability in LUSC. In addition, the hypomethylation of FUT7_CpG_2,3,5,6,7 may associate with the progress of lung cancer.

FUT7 belongs to the α1,3/4-fucosyltransferase family, which includes FUT3, 4, 5, 6, 7, 9, 10, and 11, and catalyzes the last step in the synthesis of fucosylated glycoconjugates [17, 21]. Aberrant fucosylation has been implicated in tumor proliferation, metastasis and angiogenesis [22, 23]. Qin et al. reported that FUT7 was expressed in follicular thyroid carcinoma (FTC) cells at higher level than in the paracancerous thyroid tissue, and it promoted the migration and invasion of FTC cells by activating MAPK and PI3K/Akt signaling pathways [20]. Liang et al. found that the expression of FUT7 was elevated in A549 cells, and it played a vital role in cell growth and proliferation via triggering EGFR/AKT/mTOR signaling pathway [24]. In the study of Liu et al., FUT7 promoted the proliferation, migration, invasion and epithelial–mesenchymal transition (EMT) of bladder cancer cells [25]. The methylation level of FUT7 was decreased in bladder cancer tissues and reduced in patients with high stage status and nodal metastasis [25], indicating that FUT7 methylation level might be a potential indicator reflecting clinical features of bladder urothelial carcinoma.

Epigenetic modifications are involved in the regulation of gene expression and the control of many cellular processes in both normal and cancer cells. UALCAN (http://ualcan.path.uab.edu/index.html), which could evaluate the potential role of DNA promoter methylation, showed that the methylation levels of FUT7 in LUAD and LUSC were significantly lower than that in normal tissues (P < 0.05) (Additional file 1: Fig. S2). The dataset from Wanderer (http://maplab.imppc.org/wanderer/) demonstrated that the mean methylation level of each CpG site in the FUT7 gene (chr9: 139927000–139928000) was significantly decreased in LUAD and LUSC compared to normal tissues (P < 0.05) (Additional file 1: Fig. S3). In general, our results were consistent with those of the database. We found seven CpG sites in chr9:139,927,462–139,927,771 by EpiTyper assay, and the results illustrated that the methylation levels of seven FUT7 CpG sites in the blood of lung cancer were significantly lower than those in normal control (Table 2), and the hypomethylation of FUT7 was associated with increased risk of lung cancer (Table 3). Moreover, the methylation levels of FUT7_CpG_2,3,5,6,7 decreased in terms of advanced stage (stage III and IV) and nodal metastasis of LC patients (Table 7). We speculated that various cancer types may share the same blood-based DNA methylation genes, but there are differences in methylation levels and specific sites due to changes in cancer types. Previous studies were performed mostly in the context of comparing cancers and healthy controls, while our study included benign pulmonary nodule. The hypomethylation levels of FUT7_CpG_4,5 were associated with increasing risk of LUAD, while the increased risk of LUSC was associated with the decreased methylation levels of FUT7_CpG_1,2,3,4,7 (Table 5). These results suggested that FUT7 methylation could be used to differentiate lung cancer subtypes from BPN. Therefore, the specific molecular mechanisms between FUT7 methylation and LC might be the subject for further research. The expression of FUT7 in LC patients could provide additional hints for the regulation of DNA methylation. We suggested that the hypomethylation of FUT7 may upregulate the function of FUT7 and subsequently accelerate downstream pathways.

LUAD and LUSC are the largest non-small cell lung cancer (NSCLC) subgroups. In our present study, the levels of FUT7 methylation were lower in LUSC patients than that in LUAD patients (Table 4; Fig. 3), and FUT7 methylation indicated good diagnostic accuracy in the discrimination of LUSC versus NC or BPN (Fig. 2D, F). Experimental evidence suggested that LUAD and LUSC were vastly different in molecular, pathological and clinical levels. Genes differentially expressed between LUAD and LUSC contain main Gene Ontology subgroups [26,27,28,29,30], including the regulatory network of cell proliferation, DNA replication, DNA repair and RNA splicing. Different driver gene changes are related to different tumor diseases and distinct cell control pathways [31, 32]. In lung cancer, the types of mutated oncogenes and cells of origin decide the formation of LUAD versus LUSC, tumor invasiveness and aggressiveness. For instance, mutations in receptor tyrosine kinases are usual in LUAD but rare in LUSC [33]. The overexpression of keratins is connected with tumor progression in LUAD [34]. It is found that driving the p53/p63/p73 axis is closely associated with LUSC [35, 36], but not with LUAD. In histopathology, LUAD and LUSC have different origins. LUAD originates from cells secreting surfactant components, while LUSC originates from cells lining inside of the lung airways. LUAD is the most common type of lung cancer seen in nonsmokers and is more general in women than in men. Our results showed that LUAD patients were younger and more likely to be women compared with LUSC. LUAD has replaced LUSC as the most common histological subtype for unknown reasons in the past 25 years. LUSC is linked to a history of smoking and is frequently found in the main bronchus of the lungs. As the genetic drivers and tumor control networks are obviously different in LUAD and LUSC, further research works are needed to explain the specific mechanism for FUT7 methylation in the progress of LUAD and LUSC.

In present cohort study, the sample size was large and diverse, covering normal control, benign pulmonary nodule and lung cancer patients. Moreover, multiple logistic regression was utilized to analyze the relationship between FUT7 methylation level and lung cancer. There is no doubt that there are some limitations in our study. The sample size of each subtype of LC is small, and more LC patients of different subtypes are needed to determine the detection ability of FUT7 methylation in them. Meanwhile, further functional studies are needed to explain the molecular mechanism for FUT7 methylation in the progress of LC.

Conclusions

In conclusion, this study disclosed a significant correlation between altered blood-based FUT7 methylation and lung cancer, especially in LUSC. Our results provide novel evidence that changes DNA methylation in peripheral blood might be a potential biomarker for the evaluation of lung cancer risk.

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

Not applicable.

Funding

This research was funded by National Natural Science Foundation of China (No. U1804195) and National Natural Science Foundation of China (No. 81800091).

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Authors and Affiliations

  1. Department of Respiratory and Sleep Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China

    Yifei Fang, Jiao Su & Songyun Ouyang

  2. Department of Clinical Laboratory, The First Affiliated Hospital of Zhengzhou University and Key Clinical Laboratory of Henan Province, Zhengzhou, 450052, Henan, China

    Yunhui Qu

  3. Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450052, Henan, China

    Longtao Ji, Yutong Zhao, Feifei Liang, Zhi Wang, Jingjing Liu & Liping Dai

  4. BGI College, Zhengzhou University, Zhengzhou, 450052, Henan, China

    Longtao Ji, Jiaqi Li, Feifei Liang, Zhi Wang, Jingjing Liu & Liping Dai

  5. Henan Key Medical Laboratory of Tumor Molecular Biomarkers, Zhengzhou University, Zhengzhou, 450052, Henan, China

    Longtao Ji, Jiaqi Li, Yutong Zhao, Feifei Liang, Zhi Wang, Jingjing Liu & Liping Dai

  6. Department of Radiotherapy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China

    Hao Sun

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  1. Yifei Fang
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Contributions

YFF, YHQ and LTJ performed the majority of the experiments, analyzed the data and managed the clinical information, and were also involved in the conception and design of the study. HS, JQL and YTZ were involved in data curation. FFL, ZW and JS were involved in formal analysis. JJL made contribution to the improvement of the article. YFF, YHQ and LPD reviewed and revised the manuscript. LPD and SYOY provided clinical insight, secured funding and supervised the research. YFF, YHQ, LPD and SYOY confirmed the authenticity of all the raw data. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Liping Dai or Songyun Ouyang.

Ethics declarations

Ethics approval and consent to participate

Plasma samples presented in this study were collected from the First Affiliated Hospital of Zhengzhou University upon approval of institutional ethics committees (2021-KY-1057-002). All participants provided written informed consent.

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All authors have reviewed and agreed on the contents of the manuscript.

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The authors declare no competing financial interests.

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Supplementary Information

Additional

file 1. Fig. S1: The sequence of the FUT7 amplicon. The FUT7 amplicon examined by EpiTyper assay (chr9:139,927,462-139,927,771, antisense strand, build 37/hg19, in the UCSC Genome Browser). The measurable seven CpG sites by EpiTyper assay were in light gray. The numbers (50, 100,150, etc.) denoted number of bases per line. Fig. S2: Promoter methylation level of FUT7 in LUAD and LUSC in UALCAN. (A) Promoter methylation level of FUT7 in LUAD. (B) Promoter methylation level of FUT7 in LUSC.LUAD lung adenocarcinoma, LUSC lung squamous cell carcinoma. Fig. S3: Mean methylation of FUT7 in LUAD and LUSC in chr9: 139927000-139928000. (A) Mean methylation of FUT7 in LUAD. (B) Mean methylation of FUT7 in LUSC. LUAD lung adenocarcinoma, LUSC lung squamous cell carcinoma.

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Fang, Y., Qu, Y., Ji, L. et al. Novel blood-based FUT7 DNA methylation is associated with lung cancer: especially for lung squamous cell carcinoma. Clin Epigenet 14, 167 (2022). https://doi.org/10.1186/s13148-022-01389-2

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Keywords

Clinical Epigenetics

ISSN: 1868-7083

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