MUC1 in lung adenocarcinoma: cross-sectional genetic and serological study
© The Author(s). 2017
Received: 26 May 2016
Accepted: 7 April 2017
Published: 12 April 2017
Mucin 1 (MUC1) contributes to the growth and metastasis of various cancers, including lung cancer, and MUC1 gene length polymorphisms are associated with susceptibility to lung cancer and its prognosis. In contrast, the association between rs4072037, a single nucleotide polymorphism in MUC1, and lung cancer has not been well studied.
In the present study, we determined the rs4072037 genotype and measured serum KL-6 levels to evaluate the association between lung adenocarcinoma (ADC) and rs4072037 or serum KL-6 levels. DNA samples were available for 172 patients and these were included in the genomic analyses. In addition, 304 patients were included in the serum analyses. Furthermore, 276 healthy volunteers were included in both genomic and serum analyses.
The rs4072037 genotype was not associated with susceptibility to lung ADC or its prognosis. Interestingly, serum KL-6 levels significantly differed according to rs4072037 genotype in those with T1 or T2 (P < 0.001), N0 or N1 (P = 0.002) and M0 (P < 0.001), but not in those with T3 or T4 (P = 0.882), N2 or N3 (P = 0.616) and M1a or M1b (P = 0.501). Serum KL-6 levels were significantly associated with the presence of lung ADC, as well as with its progression and prognosis, indicating the crucial involvement of KL-6/MUC1 in the development of lung cancer and its progression.
Based on these findings, we conclude that rs4072037 does not have a significant impact on the pathogenesis or prognosis of lung ADC, whereas serum KL-6 levels, which might reflecting the molecular length of MUC1, are significantly associated with lung ADC.
KeywordsKL-6 MUC1 rs4072037 Lung adenocarcinoma
Lung cancer is one of the most common malignant tumors worldwide. Adenocarcinoma (ADC) is the most common histological type of lung cancer in the United States, Europe, and East Asia, including Japan . Although novel therapeutic targets and molecular-targeted agents have been identified and applied in clinical settings, lung cancer remains the leading cause of cancer death in the majority of developed countries . Thus, the identification of novel diagnostic biomarkers and potential therapeutic target molecules is urgently needed.
Several types of mucins, including mucin 1 (MUC1), are known to contribute to the growth and metastatic properties of various tumors. In addition to their anti-adhesion functions, mucins can affect the transcriptional profile of various gene products involved in cancer cell invasion and metastasis by mediating signal-transduction [3, 4]. These findings indicate the potential utility of MUC1 as a diagnostic biomarker and/or therapeutic target in lung cancer. We have previously demonstrated that MUC1 variable numbers of tandem repeats (VNTR) polymorphism was significantly associated with susceptibility to lung ADC and its prognosis . However, it would be very difficult to identify MUC1 gene length polymorphisms in clinical practice. Thus, in the current study, we focused on alternative potential biomarkers which can reflect the VNTR polymorphism and are more easily detectable in the clinical setting: rs4072037, a single nucleotide polymorphism (SNP) in the MUC1 gene, and serum KL-6 levels.
rs4072037, a functional SNP in exon 2 of the MUC1 gene, regulates splicing site selection during the post-transcriptional regulation process . It has also been reported that rs4072037 is in linkage disequilibrium with VNTR in MUC1 . Furthermore, several studies have reported an association between rs4072037 and susceptibility to gastric cancer [8–10]. Although no significant association has been demonstrated between rs4072037 and lung cancer, these previous studies suggest that rs4072037 may play a role in the development of lung ADC and its progression, and that rs4072037 may have utility as a diagnostic and/or prognostic biomarker in lung ADC.
We previously developed a murine IgG1 monoclonal antibody (mAb), designated KL-6, by immunizing a mouse with lung ADC VMRC-LCR cells . The anti-KL-6 mAb recognizes sialylated carbohydrates attached to the core protein of MUC1 through the glycosylation process . KL-6 has been well investigated as a useful diagnostic and prognostic biomarker for various interstitial lung diseases [11, 13, 14]. Additionally, we have demonstrated that KL-6 may be a prognostic biomarker for non-small cell lung cancer patients who have been treated with epidermal growth factor receptor tyrosine kinase inhibitors or surgical resection [15, 16]. While these findings were promising, the number of patients evaluated in these two studies was relatively small. Furthermore, the combined contribution of serum KL-6 with the other important prognostic predictors of lung ADC, such as EGFR gene mutation status , was not sufficiently evaluated in the previous studies.
The two aims of the present study were as follows: 1) to assess whether rs407247, a SNP in the MUC1 gene, is associated with lung ADC development or prognosis, and 2) to assess whether KL-6, a carbohydrate associated with MUC1, improves the predictive power of the other predictive factors in patients with lung ADC. In this study, we evaluated the different rs4072037 genotypes and the serum levels of KL-6 in 354 patients with lung ADC and 276 healthy volunteers (HVs).
Patients and clinical samples
Patients with lung adenocarcinoma
65.9 ± 0.6
63.8 ± 0.9
66.6 ± 0.6
49.9 ± 0.4
Gender, Male / Female
195 / 159
95 / 77
164 / 140
228 / 48
Smoking, Yes / No
211 / 143
103 / 69
179 / 125
158 / 118
PS, ≤1 / ≥2
319 / 35
149 / 23
274 / 30
EGFR, Mutant / Wild / ND
122 / 182 / 50
55 / 67 / 50
122 / 182 / 0
T factor, ≤2 / ≥3
237 / 117
105 / 67
207 / 97
N factor, ≤1 / ≥2
180 / 174
72 / 100
156 / 148
M factor, 0 / 1
189 / 165
78 / 94
160 / 144
EGFR mutation status
EGFR mutation status was evaluated in 304 patients, for whom serum samples were available, in one of the following sample types: cytology liquid samples derived from bronchoscopy or thoracentesis, paraffin-embedded transbronchial lung biopsy samples, or surgically resected tumor tissues. To evaluate EGFR mutations, the peptide nucleic acid-locked nucleic acid polymerase chain reaction clamp test that detects the G719C, G719S, G719A, L858R, L861Q, and T790 M mutations and seven different exon 19 deletions was used, as previously described .
DNA preparation and rs4072037 genotyping
DNA was extracted from peripheral venous whole blood samples using the phenol-chloroform extraction and ethanol precipitation methods, as previously described [24–26]. The rs4072037 genotype was determined by real-time polymerase chain reaction (PCR) using a commercially available SNP genotyping assay (TaqMan SNP Genotyping Assay C 27532642–10; Life Technologies Corp. Carlsbad, CA, USA) and the Applied Biosystems 7500 Fast RT-PCR System (Life Technologies Corp.)
Measurement of serum KL-6 levels
The numerical data were presented as the mean ± standard error of the mean. The Mann–Whitney U-test was used to analyze data between 2 groups; for 3 or more groups, the Kruskal-Wallis test followed by multiple comparisons using rank sums was performed . When dividing patients into clinical subgroups according to performance status (PS) or TNM factors, we performed receiver operating characteristic (ROC) analysis and determined the appropriate cut-off point to predict the prognosis of the patients. Survival analysis was performed using the log-rank test and Cox proportional hazards models. Concordance (C)-statistics were used to evaluate and compare the Cox models. To test for deviations from Hardy-Weinberg equilibrium, genotype frequencies were determined by direct counting and the chi-square test or Fisher’s exact test were used as appropriate. Allelic frequencies were calculated based on the genotype frequencies, and the association between the minor G allele of rs4072037 and lung ADC was tested using the chi-square test or Fisher’s exact test. All statistical analyses were performed using SPSS for Windows, version 18.0 (SPSS Inc. Chicago, USA).
The rs4072037 genotype was not associated with susceptibility to lung ADC or its prognosis
Genotype distributions of rs4072037
limited to ≥T3
limited to ≥N2
limited to ≥M1a
rs4072037 genotype and the risk of lung adenocarcinoma
OR (95% CI)
OR (95% CI)
limited to ≥T3
limited to ≥N2
limited to ≥M1a
Serum KL-6 levels varied according to the rs4072037 genotype in HVs and patients with early stage ADC, but not in those with advanced disease
Serum KL-6 levels were significantly elevated in patients with lung ADC
Serum KL-6 levels significantly correlated with survival in patients with lung ADC
Impact of serum KL-6 on the prognosis of lung adenocarcinoma
A. Multivariate Cox proportional hazards regression model
EGFR, wild type / mutant
N factor, ordinal
M factor, yes / no
Serum KL-6, ≥600 / <600 U/mL
B. Comparison of C statistics for each prediction model
Covariates + serum KL-6
In the present study, no significant association was found between the rs4072037 genotype and susceptibility to lung ADC or its prognosis. rs4072037 genotype significantly affected serum KL-6 levels in patients with early stage ADC, but not in those with advanced disease. Furthermore, we demonstrated that serum KL-6 levels were significantly associated with the presence of lung ADC and its prognosis.
Although the MUC1 VNTR polymorphism is associated with susceptibility to lung ADC and its prognosis , we found that rs4072037, a SNP in the MUC1 gene, was not associated with susceptibility to lung ADC or with its prognosis. MUC1 is known to inhibit E-cadherin-mediated cell-cell adhesion and integrin-mediated cell-extracellular matrix adhesion [30, 31]. It is also known that MUC1 is involved in the growth and metastasis of various tumors, mainly due to its anti-adhesion and signal-transduction functions [3, 4]. We have previously reported that lung ADC cells expressed high levels of KL-6/MUC1 [16, 32] and that an anti-KL-6 mAb induced capping of MUC1, thereby interfering with its anti-adhesion function and inhibiting tumor proliferation . On the basis of these previous findings, we hypothesized that the rs4072037 genotype in MUC1 was associated with susceptibility to lung ADC and/or its prognosis. However, we failed to verify our hypothesis. The link between rs4072037 and the VNTR polymorphism, which was reported in 1996 , has actually been challenged by several recent studies. Imbert et al. reported that the MUC1 VNTR polymorphism correlated with the rs4072037 genotype in only 80% of dry eye cases . A similar result in patients with sarcoidosis was also reported by Shigemura et al. . Based on these findings, we speculate that the VNTR polymorphism in MUC1, but not the rs4072037 genotype, has a significant impact on the pathogenesis and progression of lung ADC.
Interestingly, we found that the correlation between the rs4072037 genotype and serum KL-6 levels, which was previously reported [24, 29, 35], was significant in HVs and in patients with early stage ADC, but not in those with advanced ADC (Fig. 2). Serum KL-6 in patients with lung ADC, especially in those with advanced disease, is considered to be predominantly derived from lung cancer cells with a minor contribution from normal type II pneumocytes, which are known to be major source of serum KL-6 under normal conditions [16, 32]. In addition, serum KL-6 levels have been reported to be influenced by the molecular size of MUC1 in healthy controls or in patients with sarcoidosis . However, such a correlation has not been reported in patients with lung cancer. Therefore, we can speculate that the rs4072037 genotype has a significant impact on serum KL-6 derived from normal type II pneumocytes, but not on serum KL-6 derived from lung ADC cells. In cancer cells, alterations in the glycosylation properties of mucins, which encompass aberrant glycosylation of O-linked glycans, are known to play an important role in tumorigenesis, tumor progression, and metastasis [36–41]. Serum KL-6 levels in patients with lung ADC may be influenced by the aberrant glycosylation of O-linked glycans in MUC1 and also by the depolarized expression pattern of MUC1 in lung ADC [12, 16]. The influence of these epigenetic factors may diminish the association between the rs4072037 genotype and serum KL-6 levels in patients with advanced ADC.
In the present study, we successfully confirmed that serum KL-6 levels are independently associated with prognosis in patients with lung ADC. Although the correlation between serum KL-6 levels and disease progression or prognosis in patients with lung ADC has already been reported [11, 15, 16], the results from the present study are still of pivotal importance; we have demonstrated that serum KL-6 is a significant prognostic factor for lung ADC, independent of the other known prognostic factors, including EGFR mutation status . Based on these data, it is clear that KL-6/MUC1 plays an important role in tumor cell growth, proliferation, and metastasis. Therefore serum KL-6 may be an alternative and useful biomarker; it can reflect the VNTR polymorphism in MUC1 and is more easily detectable in the clinical setting.
This study had some limitations. First, the patient sample size was small, especially for the genomic analysis. Considering the low frequency of the rs4072037 G allele, we cannot exclude the possibility that the small number of patients harboring the G allele influenced the results. Second, age and sex distributions differed between patients and HVs. Despite these limitations, the results from our study are quite evocative and provide important insight into the crucial involvement of KL-6/MUC1 in the development of lung cancer and its progression.
In conclusion, we demonstrated that rs4072037, a SNP in MUC1 gene, does not affect lung ADC development or its prognosis. We also demonstrated that serum KL-6 levels were significantly associated with the presence of lung ADC and its progression and prognosis, indicating the crucial role of KL-6/MUC1 in the development of lung cancer and its progression.
Polymerase chain reaction
Receiver operating characteristic
Single nucleotide polymorphism
Variable numbers of tandem repeats
This work was partly supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan. The funders had no role in study design, collection, analysis and interpretation of data and in writing the manuscript.
Availability of data and materials
The dataset supporting the conclusions of this article is included within the Additional file 2 “datasheet. Xls”.
YH drafted the manuscript, performed serum measurements, genotyping and statistical analyses. NI, SO, HH, NH and NK conceived the study and helped drafting the manuscript. ST and CH performed a part of serum measurements and genotyping. HI and KF participated in study design, coordination, and recruitment of the participants. All authors participated in the process of revision and finalizing the manuscript. All authors read and approved the final manuscript.
All authors declare that they have no competing interest.
Consent for publication
Ethics approval and consent to participate
This study was approved by the Ethics Committee of Hiroshima University Hospital (IRB M33 and 326) and conducted in accordance with the ethical standards established by the Helsinki Declaration of 1975. All participants presented their written informed consents for using their samples and publishing the data.
Previous presentation as congress abstract
The outline of this study have been previously presented at European Respiratory Society International Congress 2015 in Amsterdam, Netherlands (Abstract number: PA4237).
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