Single nucleotide polymorphisms of the haptoglobin gene in non-small cell lung cancer treated with personalized peptide vaccination

  • Authors:
    • Kayoko Waki
    • Teppei Yamada
    • Koichi Yoshiyama
    • Yasuhiro Terazaki
    • Shinjiro Sakamoto
    • Shunichi Sugawara
    • Shinzo Takamori
    • Kyogo Itoh
    • Akira Yamada
  • View Affiliations

  • Published online on: December 7, 2016     https://doi.org/10.3892/ol.2016.5467
  • Pages: 993-999
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Abstract

The present study analyzed polymorphisms of the 5' flanking region (from nt ‑840 to +151) of the haptoglobin gene in 120 patients with advanced non-small cell lung cancer (NSCLC) receiving personalized peptide vaccinations. In the region, six single nucleotide polymorphisms (SNPs) were confirmed, of which two, rs5472 and rs9927981, were completely linked to each other. The minor allele frequencies of rs5472/rs9927981 and rs4788458 were higher than those of the other three SNPs. The genotype frequencies of rs5472 or rs9927981 were A/A or C/C (42.5%, n=51), A/G or C/T (40.8%, n=49), and G/G or T/T (16.7%, n=20), respectively; and those of rs4788458 were T/T (34.2%, n=41), T/C (40.0%, n=48), and C/C (25.8%, n=31). The association between polymorphism rs5472/rs9927981 and prognosis, or between rs4788458 and prognosis, was analyzed further. However, no correlation was found between these SNPs and overall survival, regardless of subgroup analysis of gender, histology or concurrent therapy. These results suggest that the polymorphisms rs5472/rs9927981 and rs4788458 are not useful prognostic tools for patients with NSCLC treated with personalized peptide vaccination.

Introduction

Lung cancer is the most commonly diagnosed cancer in the world and a leading cause of cancer-associated mortality (1). Diagnoses of non-small cell lung cancer (NSCLC) make up ~80% of all lung cancer cases (2). Surgery is the standard treatment modality for patients with early stage NSCLC, however, this may not be appropriate for the majority of patients with NSCLC (>65%) who have already progressed to the advanced stages (stages IIIb/IV) at the time of diagnosis (3).

Improved knowledge of tumor biology has facilitated the development of molecular targeted therapies, including those against epidermal cell growth factor receptor mutations and the abnormal fusion of anaplastic lymphoma kinase, which has improved prognoses for patients with advanced NSCLC (4,5). However, prognosis remains inadequate and new treatment modalities are required.

Cancer immunotherapies have attracted great interest as promising novel therapeutic modalities for NSCLC. The personalized peptide vaccine (PPV), which was developed by the authors of the current study, is one such approach. PPV is designed to boost the patient's anti-cancer immunity by administering vaccine peptides matched to the patient's human leukocyte antigen (HLA)-A types and selected based on the pre-existing immunity of the patient prior to vaccination (6). PPV vaccine peptides are cytotoxic T-lymphocyte (CTL) epitopes derived from a number of tumor-associated antigens. The current list of 31 vaccine peptides consists of 12, 9, 14, and 4 epitopes for HLA-A2, -A3 super-type (A3, A11, A31, or A33), -A24 and -A26, respectively (several epitopes are recognized by >1 type of HLA allele) (6,7). Patients were subcutaneously injected weekly or bi-weekly with ISA51VG along with ≤4 peptides selected from the 31 peptide candidates. Clinical studies of small cell and non-small cell lung cancers have indicated that PPV does not cause severe side effects but demonstrates potential immunological efficacy to some extent (8,9). However, only a proportion of patients experience clinical benefits from such vaccines. Therefore, it is crucial to identify appropriate biomarkers to predict overall survival (OS). It has been suggested that PD-1+ T-cell subsets in the peripheral blood may be developed as a prognostic marker for NSCLC patients treated with PPV (10). However, its prediction of patient prognosis remains insufficient and novel effective biomarkers are required.

Haptoglobin (Hp) is a plasma protein able to bind with high affinity to the free hemoglobin released from destroyed erythrocytes (10,11). It contributes to the salvaging and recycling of hemoglobin and to antioxidation against hemoglobin-stimulated lipid peroxidation (11,12). High levels of plasma Hp have been observed in a number of malignancies (1318). In patients with NSCLC, plasma Hp levels are higher than those of healthy donors and correlate with aspects of disease progression, including clinical stage (19,20). The presence of single nucleotide polymorphisms (SNPs) in the 5′ flanking region of the Hp gene has been reported and some SNPs may affect plasma Hp levels (21,22). However, to the best of our knowledge, an association between SNPs and the prognosis of patients with malignant diseases has not yet been reported.

The present study aimed to analyze the allele/genome frequency of six SNPs of the 5′ flanking region of Hp genes in patients with NSCLC and investigate any associations Hp SNPs and patient prognosis.

Materials and methods

Clinical samples

A total of 120 patients with advanced NSCLC were subjected to analyses in the current study, which was conducted with the approval of the Kurume University Ethics Committee (Kurume, Japan). Patients were enrolled in phase II studies of PPV between December 2008 and January 2014 (clinical trial registry ID: UMIN1839 and UMIN2984) at Cancer Vaccine Center at Kurume University Medical Center; Department of Surgery, Kurume University Hospital; and Department of Pulmonary Medicine, Sendai Kousei Hospital. The designs of the clinical trials have been described in a previous report (9). Peripheral blood samples were obtained prior to and following one vaccination cycle that consisted of 6 or 8 peptide vaccinations. Peripheral blood mononuclear cells (PBMCs) were isolated by Ficoll density gradient separation, frozen and stored in the liquid nitrogen until later use.

Single nucleotide polymorphism analysis

The Hp polymorphism was determined by sequencing polymerase chain reaction (PCR) products of genomic DNA. Genomic DNA was extracted from PBMCs of 120 patients enrolled with a NucleoSpin® Blood kit (Macherey-Nagel, Düren, Germany), following the manufacturer's instructions. The target template was amplified using KOD-Plus (TOYOBO, Osaka, Japan) with the following thermocycling conditions: Initial denaturation at 94°C for 2 mins, followed by 35 cycles of 15 sec denaturation at 94°C, the 30 sec annealing at 56°C, and the one min elongation at 68°C, and the 7 min final extension at 68°C. A set of primers, forward 5′-TCAGTGTCACCATGATTATCCA-3′ and reverse, 5′-GATTTAACACACTAAGCCCTTTGG-3′, amplified a 991 bp DNA fragment, consisting of the 5′-flanking region [840 bp upstream from the transcriptional start site (+1)], the starting codon, and the first intron ≤151 bp downstream from the transcriptional start site of the Hp gene. The PCR products were purified by the NucleoSpin Gel PCR Clean-up kit (Macherey-Nagel) and subjected to sequence analyses performed by Eurofins Genomics (Tokyo, Japan). In addition to the PCR primers named above, a third forward primer, 5′-GCAATAGGGAGATGGCCACA-3′ was used for the sequence analyses. The section of the current study regarding human genome analysis was approved by the Ethics Committee of Kurume University.

Statistical analysis

Possible associations between patient prognoses and the SNPs were examined using survival curves constructed by the Kaplan-Meier method and evaluated by the log-rank test. JMP software ver. 11 (SAS Institute, NC) was used for all analyses. P<0.05 was considered to indicate a statistically significant difference.

Results

Patient characteristics

The characteristics of the 120 patients with advanced (stages IIIb and V) or recurrent NSCLC receiving PPV treatment are presented in Table I. There were 59 females and 61 males, with a median age of 63 years (range, 29–84 years) at the time of enrollment. The clinical stages of the patients were determined according to the TNM classification of malignant tumors (7th ed.) provided by Union for International Cancer Control, and were as follows: 12 cases in stage IIIb, 66 in stage IV, and 42 with recurrence. Tumor histology consisted of adenocarcinoma (n=100), squamous cell carcinoma (n=15), adenosquamous carcinoma (n=2), large cell carcinoma (n=2) and pleomorphic carcinoma (n=1). By the time PPV treatment began, 111 of the 120 patients had failed ≥1 chemotherapy regimen: 25, 32, 19, and 35 patients had failed 1, 2, 3, or 4–12 regimens, respectively. A total of 9 patients were naïve to any chemotherapy regimens prior to treatment with PPV.

Table I.

Characteristics of 120 patients with advanced non-small cell lung cancer treated with personalized peptide vaccines.

Table I.

Characteristics of 120 patients with advanced non-small cell lung cancer treated with personalized peptide vaccines.

rs5472 (rs9927981)rs4788458


CharacteristicTotalA/A (C/C) n=51A/G (C/T) n=49G/G (T/T) n=20T/T n=41T/C n=48C/C n=31
OS, days120  
  Median6746676461182692639753
  (95% CI)(452–870)(357–870)(361–997)(231-NR)(411–1200)(302–996)(234-NR)
Age, years120
  Median  63636661.56366.562
  (Range)(29–84)(29–84)(42–84)(37–82)(29–84)(42–84)(37–82)
Gender
  Female/male59/6127/2424/258/1221/2023/2515/16
Stage
  IIIb  12  5  4  3  4  5  3
  IV  66272811222420
  Recurrence  421917  61519  8
Histology
  Adeno100444115383923
  SCC  15  6  6  3  3  6  6
  AdSq  2  1  1  0  0  2  0
  LCC  2  0  1  1  0  1  1
  Pleomorph  1  0  0  1  0  0  1
Pre-vaccination regimen
  0–2  66282612232518
  ≥3  542323  8182313

[i] OS, overall survival; CI, confidence interval; Adeno, adenocarcinoma; SCC, squamous cell carcinoma; AdSq, adenosquamous carcinoma; LCC, large cell carcinoma; Pleomorph, pleomorphic carcinoma; NR, not reached.

Polymorphism of 5′ flanking region of haptoglobin gene

A total of six SNPs were identified from the genomic DNA samples of NSCLC patients: rs5467 (−242C>T), rs5468 (−191T>G), rs190482744 (−102A>G), rs5472 (−55A>G), rs9927981 (+131C>T) and rs4788458 (+154T>C). Minor alleles of rs5467, rs5468, and rs190482744 were rarely detected. By contrast, those of rs5472, rs9927981, and rs4788458 were abundant. The detected number and frequency of each allele and genotype of the SNPs are presented in Table II. Allele frequencies of rs5472A>G and rs9927981C>T were the same and all patients with rs5472A possessed the rs9927981C allele. These results suggest that the rs5472 and rs992798 are completely linked to each other. By contrast, no such linkage was observed between rs4788458 and rs5472/rs9927981.

Table II.

SNPs of the 5′ flanking region of the haptoglobin gene.

Table II.

SNPs of the 5′ flanking region of the haptoglobin gene.

SNPsPosition from transcription startAllelesAllele frequencyGenotypesn(Total=120)Genotype frequency
rs5467−242C0.9167C/C1020.85
T0.0833C/T  160.1333
T/T     20.0167
rs5468−191T0.9708T/T1150.9583
G0.0292T/G     30.025
G/G     20.0167
rs190482744−102A0.9917A/A1180.9833
G0.0083A/G     20.0167
G/G     00
rs5472   −55A0.6292A/A  510.425
G0.3708A/G  490.4083
G/G  200.1667
rs9927981+131C0.6292C/C  510.425
T0.3708C/T  490.4083
T/T  200.1667
rs4788458+154T0.5417T/T  410.3417
C0.4583T/C  480.4
C/C  310.2583

[i] SNPs, small nuclear polymorphisms.

The minor allele frequencies of rs5472/rs9927981 and rs4788458 were higher than those of the other three SNPs. The genotype frequencies of rs5472 or rs9927981 were A/A or C/C (42.5%, n=51), A/G or C/T (40.8%, n=49), and G/G or T/T (16.7%, n=20), respectively, and those of rs4788458 were T/T (34.2%, n=41), T/C (40.0%, n=48), and C/C (25.8%, n=31), respectively. The genotype frequencies of rs5472 observed in the current study are similar to those documented in a previous report on a Japanese population (140/385: 36.4%, 197/385: 51.2%, and 48/385: 12.4%, respectively) (22), with no significant differences.

Hp SNP rs5472/rs9927981 and prognosis in NSCLC

Associations between the Hp SNPs rs5472/rs9927981 and the OS of NSCLC patients were assessed by a Kaplan-Meier plot (Fig. 1). Genotypes A/A, A/G, and G/G of rs5472 are compatible with C/C, C/T, and T/T of rs9927981 therefore, only results from SNP rs5472 genotype are presented in Fig. 1. The median survival times (MST) from the date of the first vaccination in the A/A, A/G, and G/G groups of rs5472 were 667, 646, and 1182 days, respectively (Fig. 1A). No significant differences in MST were observed among the genotype groups.

Subgroup analyses by gender and tumor histology type were subsequently performed. The histology type of the majority of patients was adenocarcinoma, thus only the adenocarcinoma group (n=100) was subjected to subgroup analysis by tumor histology type. Kaplan-Meier plots for male, female, and all adenocarcinoma patients were constructed (Fig. 1B-D). Statistical analyses of the subgroups revealed no correlations between SNP rs5472/rs9927981 and OS among male, female, or adenocarcinoma patients. In addition, possible associations between the rs5472/rs9927981 genotypes and OS in the patients with bone metastasis were examined. No significant correlations, however, were observed (data not shown).

Previous studies have suggested that patients concurrently treated with PPV and chemotherapy (concurrent therapy) exhibit better prognosis compared to those treated with PPV alone (monotherapy), in castration-resistant prostate cancer, pancreatic cancer, colorectal cancer, and NSCLC (2326). Similar results were observed in the present study; patients treated with concurrent therapy had a significantly longer MST (n=75, 736 days) than patients treated with PPV monotherapy (n=45, 367 days; P=0.038; data not shown). However, the OS did not differ among patients with SNP rs5472/rs9927981 treated with either concurrent therapy or PPV monotherapy (Fig. 1E and F, respectively).

Hp SNP rs4788458 and prognosis in NSCLC

The possible association between Hp SNP rs4788458 and OS was assessed (Fig. 2A). The MST of OS in the T/T, T/C, and C/C groups of rs4788458 were 692, 639, and 753 days, respectively. Similar to the case with rs5472/rs9927981, there were no significant differences among the genotype groups of rs4788458. In addition, subgroup analyses of gender, histology, or concurrent therapy were performed (Fig. 2B-F). Again, however, there were no significant differences among the genotype groups of rs4788458.

Discussion

A number of studies have investigated possible associations between the SNPs of various genes and disease susceptibility or prognosis. Correlations have previously been observed between the SNPs of the TNF-α gene, and susceptibility to human T-cell lymphotropic virus 1 uveitis (27) and rheumatoid arthritis (28). Furthermore, possible associations between SNPs and the prognosis of cancer patients have been previously investigated. In NSCLC, such correlations were demonstrated between prognosis and the SNPs of DNA excision repair 1/2 endonuclease non-catalytic subunit (29), xeroderma pigmentosum group D (30) and vesicular epidermal cell growth factor (31).

Patients with NSCLC exhibit higher plasma Hp protein levels than healthy donors and those levels correlate with aspects of disease progression, including clinical stage (19,20). Additionally, correlations between plasma Hp levels and patient prognosis have been reported in other types of cancer (32). The 5′ flanking regions of genes generally control gene transcription through the binding of transcription factors. Therefore, in the current study, the SNPs of the 5′ flanking region of the Hp gene were investigated, and six SNPs of the Hp gene in NSCLC were identified. Subsequently, possible correlations between the SNPs and OS in patients with NSCLC treated with PPV were investigated, but none were observed. Another research group have obtained different results in patients with castration-resistant prostate cancer treated with PPV; they observed a certain degree of correlation between Hp SNP rs5472 and OS (Miyazaki et al, manuscript submitted for publication). Therefore, in the current study, further subgroup analyses of gender, histology or concurrent therapy were performed, however, no correlations were observed. At present, it is unclear why such different results were obtained in patients with NSCLC and castration-resistant prostate cancer. It is noted that Motifmap analysis, an in silico analysis of transcription factor binding sites (33,34), of the Hp gene suggested that there were seven binding sites (−691, −432, −159, −148, −84, +9, and +328) for transcription factors in the 5′ flanking region of the Hp gene. These sites do not include the six SNPs (−242, −191, −102, −55, +131, and +154) identified in the present study.

The present study investigated possible correlations between the SNPs of the Hp gene and immune responses to the vaccinated peptides: responses to immunoglobulin G and CTL. Again, however, no correlation was observed (data not shown).

In conclusion, the current study investigated possible correlations between Hp polymorphisms and the prognosis of advanced NSCLC patients treated with PPV. However, no correlations between the Hp SNPs and prognosis in advanced NSCLC were identified. This suggests that the SNPs of the Hp gene are not suitable biomarkers for NSCLC.

Acknowledgements

The present study was supported in part by grants from the Private University Strategic Research Foundation Support Program of the Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT), the Regional Innovation Cluster Program of MEXT, and the Sendai Kousei Hospital (Sendai, Miyagi, Japan).

Glossary

Abbreviations

Abbreviations:

CTL

cytotoxic T-lymphocyte

Hp

haptoglobin

MST

median survival times

NSCLC

non-small cell lung cancer

OS

overall survival

PPV

personalized peptide vaccine

SNPs

single nucleotide polymorphisms

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Spandidos Publications style
Waki K, Yamada T, Yoshiyama K, Terazaki Y, Sakamoto S, Sugawara S, Takamori S, Itoh K and Yamada A: Single nucleotide polymorphisms of the haptoglobin gene in non-small cell lung cancer treated with personalized peptide vaccination. Oncol Lett 13: 993-999, 2017
APA
Waki, K., Yamada, T., Yoshiyama, K., Terazaki, Y., Sakamoto, S., Sugawara, S. ... Yamada, A. (2017). Single nucleotide polymorphisms of the haptoglobin gene in non-small cell lung cancer treated with personalized peptide vaccination. Oncology Letters, 13, 993-999. https://doi.org/10.3892/ol.2016.5467
MLA
Waki, K., Yamada, T., Yoshiyama, K., Terazaki, Y., Sakamoto, S., Sugawara, S., Takamori, S., Itoh, K., Yamada, A."Single nucleotide polymorphisms of the haptoglobin gene in non-small cell lung cancer treated with personalized peptide vaccination". Oncology Letters 13.2 (2017): 993-999.
Chicago
Waki, K., Yamada, T., Yoshiyama, K., Terazaki, Y., Sakamoto, S., Sugawara, S., Takamori, S., Itoh, K., Yamada, A."Single nucleotide polymorphisms of the haptoglobin gene in non-small cell lung cancer treated with personalized peptide vaccination". Oncology Letters 13, no. 2 (2017): 993-999. https://doi.org/10.3892/ol.2016.5467