LC/MS-Based Polar Metabolite Profiling Identified Unique Biomarker Signatures for Cervical Cancer and Cervical Intraepithelial Neoplasia Using Global and Targeted Metabolomics
Abstract
:1. Introduction
2. Results
2.1. General Characteristics of Study Participants
2.2. Global Metabolic Profiling of Plasma by UPLC-QTOF-MS
2.3. Differential Mapping of Metabolites in Pathway Analysis
2.4. Altered Metabolites in Patients with CINs and Cervical Cancer
2.5. Validation and Diagnostic Performance of Selected Metabolites
2.6. Association of Metabolites with CINs and Cervical Cancer Risk
2.7. Combined Effects of Targeted Metabolites with HPV Status
2.8. Pathway Analysis for Quantitative Metabolites
3. Discussion
4. Materials and Methods
4.1. Study Population and Sample Collection
4.2. Global Metabolite Profiling Using UPLC-QTOF-MS
4.3. Metabolite Quantification Using UPLC-TQ-MS
4.4. Statistical Analysis
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Conflicts of Interest
Abbreviations
AMP | Adenosine monophosphate |
AUC | Area under the curve |
BMI | Body mass index |
CI | Confidence interval |
CIN | Cervical intraepithelial neoplasia |
CV | Coefficients of variation |
FDR | False discovery rate |
HCA | Hierarchical cluster analysis |
HPV | Human papillomavirus |
OR | Odds ratio |
PCA | Principal component analysis |
QC | Quality control |
UPLC-QTOF-MS | Ultra-performance liquid chromatography-quadrupole-time-of-flight mass spectrometry |
UPLC-TQ-MS | Ultra-performance liquid chromatography-triple-quadrupole mass spectrometry |
References
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Variables | Normal, n = 69 | CIN1, n = 55 | CIN2/3, n = 42 | CX CAN, n = 60 | pa | |
---|---|---|---|---|---|---|
Age (years) | 48 (43, 51) | 35 (31, 40) | 39.5 (33, 49) | 50 (42, 51) | <0.0001 | |
BMI (Kg/m2) | 21.64 (20.5, 23.2) | 20.6 (19.4, 21.9) | 20.8 (19.8, 23.4) | 23.2 (20.6, 25.7) | 0.0003 | |
HPV | Positive | 30 (43.5) | 30 (54.6) | 30 (71.4) | 47 (78.3) | 0.0002 |
Marital status | Single | 4 (5.8) | 21 (38.2) | 7 (20) | 4 (6.67) | <0.0001 |
Married | 59 (85.5) | 29 (52.7) | 24 (68.6) | 47 (78.3) | ||
Divorce, bereavement | 6 (8.7) | 5 (9.1) | 4 (11.4) | 9 (15) | ||
Education | ≤9 y | 12 (17.4) | 2 (3.6) | 6 (17.1) | 30 (50) | <0.0001 |
9–12 y | 24 (34.8) | 19 (34.6) | 13 (37.1) | 21 (35) | ||
≥12 y | 33 (47.8) | 34 (61.8) | 16 (45.7) | 9 (15.0) | ||
Postmenopausal | Yes | 28 (40.6) | 4 (7.3) | 8 (22.9) | 34 (56.7) | <0.0001 |
Pregnancy | No | 4 (5.8) | 21 (38.2) | 9 (25.7) | 5 (8.3) | <0.0001 |
Yes | 65 (94.2) | 34 (61.8) | 26 (74.3) | 55 (91.7) | ||
Oral contraceptive | Yes | 11 (15.9) | 8 (14.8) | 12 (34.3) | 9 (17.7) | 0.0949 |
Smoking status | Yes, include past | 8 (11.8) | 18 (32.7) | 7 (20) | 7 (11.7) | 0.0097 |
Metabolite | N vs. CIN2/3 | N vs. CX CAN | CIN1 vs. CIN2/3 | CIN1 vs. CX CAN | N+CIN1 vs. CIN2/3 + CX CAN |
---|---|---|---|---|---|
AMP | 0.53 | 0.71 | <0.50 | 0.68 | 0.62 |
Aspartate | 0.80 | 0.76 | 0.71 | 0.67 | 0.74 |
Glutamate | 0.76 | 0.81 | 0.69 | 0.73 | 0.76 |
Hypoxanthine | 0.68 | 0.77 | 0.72 | 0.80 | 0.74 |
Lactate | 0.74 | 0.74 | 0.67 | 0.69 | 0.71 |
Proline | 0.68 | 0.71 | 0.51 | 0.54 | 0.62 |
Pyroglutamate | 0.72 | 0.74 | 0.68 | 0.69 | 0.71 |
Aspartate,Glutamate | 0.80 | 0.81 | 0.70 | 0.71 | 0.76 |
Aspartate,Hypoxanthine | 0.82 | 0.76 | 0.73 | 0.73 | 0.73 |
Glutamate,Hypoxanthine | 0.76 | 0.81 | 0.67 | 0.76 | 0.76 |
Aspartate,Glutamate,Hypoxanthine | 0.81 | 0.81 | 0.73 | 0.74 | 0.75 |
AMP,Aspartate,Glutamate,Hypoxanthine | 0.82 | 0.82 | 0.71 | 0.73 | 0.75 |
Aspartate,Glutamate,Hypoxanthine,Lactate | 0.80 | 0.80 | 0.73 | 0.73 | 0.76 |
Aspartate,Glutamate,Hypoxanthine,Proline | 0.82 | 0.81 | 0.72 | 0.72 | 0.75 |
Aspartate,Glutamate,Hypoxanthine,Pyroglutamate | 0.80 | 0.81 | 0.74 | 0.76 | 0.76 |
AMP,Aspartate,Glutamate,Hypoxanthine,Lactate | 0.81 | 0.82 | 0.71 | 0.73 | 0.75 |
AMP,Aspartate,Glutamate,Hypoxanthine,Proline | 0.82 | 0.83 | 0.72 | 0.72 | 0.75 |
AMP,Aspartate,Glutamate,Hypoxanthine,Pyroglutamate | 0.81 | 0.82 | 0.73 | 0.77 | 0.78 |
Aspartate,Glutamate,Hypoxanthine,Lactate,Proline | 0.82 | 0.81 | 0.72 | 0.72 | 0.75 |
Aspartate,Glutamate,Hypoxanthine,Lactate,Pyroglutamate | 0.81 | 0.80 | 0.74 | 0.76 | 0.77 |
AMP,Aspartate,Glutamate,Hypoxanthine,Lactate,Proline | 0.82 | 0.83 | 0.71 | 0.72 | 0.75 |
AMP,Aspartate,Glutamate,Hypoxanthine,Lactate,Pyroglutamate | 0.81 | 0.82 | 0.72 | 0.78 | 0.78 |
Aspartate,Glutamate,Hypoxanthine,Lactate,Proline,Pyroglutamate | 0.82 | 0.82 | 0.73 | 0.77 | 0.78 |
AMP,Aspartate,Glutamate,Hypoxanthine,Lactate,Proline,Pyroglutamate | 0.82 | 0.83 | 0.72 | 0.78 | 0.78 |
Metabolite | N | CIN2/3 | N vs. CIN2/3 | CX CAN | N vs. CX CAN | CIN1 | CIN23 | CIN1 vs. CIN2/3 | CX CAN | CIN1 vs. CX CAN | N + CIN1 | CIN23 + CX CAN | N + CIN1 vs. CIN23 + CX CAN |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
n = 69 | n = 42 | mOR (95% CI) | n = 60 | mOR (95% CI) | n = 55 | n = 42 | mOR (95% CI) | n = 60 | mOR (95% CI) | n = 124 | n = 102 | mOR (95% CI) | |
AMP | |||||||||||||
Low | 49.3 | 38.1 | ref | 25 | ref | 40.1 | 35.7 | ref | 25 | ref | 50 | 30.4 | ref |
High | 50.7 | 61.9 | 2.11 (0.79–5.63) | 75 | 1.52 (0.54–4.28) | 50.9 | 64.3 | 4.34 (1.29–14.6) | 75 | 0.62 (0.12–3.28) | 50 | 69.6 | 2.34 (1.13–4.83) |
Aspartate | |||||||||||||
Low | 50.7 | 11.9 | ref | 21.7 | ref | 49.1 | 14.3 | ref | 25 | ref | 50 | 20.6 | ref |
High | 49.3 | 88.1 | 4.31 (1.38–13.5) | 78.3 | 1.64 (0.59–4.58) | 50.9 | 85.7 | 8.92 (2.38–33.4) | 75 | 0.81 (0.15–4.24) | 50 | 79.4 | 2.80 (1.36–5.78) |
Glutamate | |||||||||||||
Low | 50.7 | 11.9 | ref | 8.3 | ref | 50.9 | 28.6 | ref | 20 | ref | 50.8 | 14.7 | ref |
High | 49.3 | 88.1 | 7.99 (2.31–27.6) | 91.7 | 6.31 (1.74–22.9) | 49.1 | 71.4 | 2.68 (0.87–8.20) | 80 | 0.60 (0.10–3.71) | 49.2 | 85.3 | 4.49 (2.05–9.82) |
Hypoxanthine | |||||||||||||
Low | 49.3 | 23.8 | ref | 15 | ref | 50.9 | 14.3 | ref | 8.3 | ref | 50.8 | 17.7 | ref |
High | 50.7 | 76.2 | 5.30 (1.64–17.1) | 85 | 4.33 (1.30–14.5) | 49.1 | 85.7 | 7.90 (2.00–31.3) | 91.7 | 2.36 (0.42–13.3) | 49.2 | 32.3 | 4.26 (1.95–9.28) |
Lactate | |||||||||||||
Low | 50.7 | 14.3 | ref | 13.3 | ref | 50.9 | 33.3 | ref | 25 | ref | 50 | 20.6 | ref |
High | 49.3 | 85.7 | 5.18 (1.74–15.4) | 86.7 | 3.93 (1.24–12.5) | 49.1 | 66.7 | 1.98 (0.68–5.78) | 75 | 0.96 (0.17–5.50) | 50 | 79.4 | 2.30 (1.13–4.69) |
Proline | |||||||||||||
Low | 50.7 | 23.8 | ref | 20 | ref | 50.9 | 54.8 | ref | 53.3 | ref | 50 | 30.4 | ref |
High | 49.3 | 76.2 | 5.13 (1.71–15.4) | 80 | 5.23 (1.50–18.3) | 49.1 | 45.2 | 1.04 (0.35–3.09) | 46.7 | 0.69 (0.12–3.94) | 50 | 69.6 | 2.12 (1.02–4.43) |
Pyroglutamate | |||||||||||||
Low | 50.7 | 23.8 | ref | 10 | ref | 49.1 | 23.8 | ref | 11.7 | ref | 50.8 | 16.7 | ref |
High | 49.3 | 76.2 | 2.94 (1.10–7.84) | 90 | 8.02 (2.13–30.3) | 50.9 | 76.2 | 5.46 (1.63–18.4) | 88.3 | 4.54 (0.65–32.0) | 49.2 | 83.3 | 4.14 (1.92–8.92) |
Metabolite | HPV | N vs. CIN2/3 | N vs. CX CAN | CIN1 vs. CIN2/3 | CIN1 vs. CX CAN | N+CIN1 vs. CIN2/3 + CX CAN |
---|---|---|---|---|---|---|
mOR (95% CI) | mOR (95% CI) | mOR (95% CI) | mOR (95% CI) | mOR (95% CI) | ||
AMP | ||||||
Low | Neg | ref | ref | ref | ref | ref |
Low | Pos | 6.56 (0.99–43.2) | 5.36 (0.99–29.0) | 5.32 (0.79–35.9) | 5.31 (0.98–28.8) | 3.36 (1.02–11.1) |
High | Neg | 1.90 (0.27–13.3) | 0.87 (0.12–6.06) | 1.82 (0.26–12.8) | 0.85 (0.12–5.94) | 1.24 (0.32–4.82) |
High | Pos | 12.19 (2.21–67.1) | 8.54 (1.63–44.8) | 12.78 (2.31–70.7) | 8.46 (1.61–44.6) | 9.33 (2.94–29.6) |
p interaction 1 | 0.0022 | 0.0184 | 0.0008 | 0.0184 | <0.0001 | |
p trend 2 | 0.0065 | 0.0489 | 0.0034 | 0.0513 | 0.0002 | |
Aspartate | ||||||
Low | Neg | ref | ref | ref | ref | ref |
Low | Pos | 2.52 (0.31–20.5) | 3.58 (0.67–19.2) | 3.45 (0.47–25.3) | 4.67 (0.93–23.4) | 2.47 (0.73–8.34) |
High | Neg | 1.64 (0.24–11.2) | 0.46 (0.06–3.46) | 1.74 (0.25–12.0) | 0.50 (0.07–3.76) | 1.08 (0.28–4.13) |
High | Pos | 13.93 (2.62–74.0) | 7.71 (1.60–37.1) | 13.52 (2.55–71.7) | 6.97 (1.45–33.4) | 9.15 (2.96–28.3) |
p interaction | <0.0001 | 0.0067 | 0.0002 | 0.0236 | <0.0001 | |
p trend | 0.0009 | 0.041 | 0.0013 | 0.0802 | <0.0001 | |
Glutamate | ||||||
Low | Neg | ref | ref | ref | ref | ref |
Low | Pos | 0.98 (0.11–9.18) | 1.14 (0.11–12.3) | 3.62 (0.69–18.9) | 3.28 (0.60–18.0) | 2.76 (0.68–11.3) |
High | Neg | 1.49 (0.20–11.3) | 1.33 (0.16–10.7) | 1.51 (0.21–10.6) | 0.92 (0.12–7.06) | 2.29 (0.56–9.40) |
High | Pos | 27.18 (4.23–175) | 24.52 (3.61–167) | 17.01 (3.38–85.6) | 14.33 (2.64–77.8) | 14.85 (4.27–51.7) |
p interaction | <0.0001 | <0.0001 | 0.0002 | 0.001 | <0.0001 | |
p trend | <0.0001 | 0.0005 | 0.0006 | 0.0047 | <0.0001 | |
Hypoxanthine | ||||||
Low | Neg | ref | ref | ref | ref | ref |
Low | Pos | 7.59 (0.93–61.9) | 3.35 (0.45–24.9) | 46.45 (2.11–999) | 10.83 (0.73–161) | 2.11 (0.56–8.04) |
High | Neg | 5.25 (0.61–45.3) | 1.82 (0.24–13.6) | 9.76 (0.70–135) | 1.27 (0.18–9.21) | 1.58 (0.42–6.05) |
High | Pos | 21.89 (3.36–142) | 14.88 (2.57–86.2) | 33.48 (2.83–396) | 8.19 (1.44–46.6) | 11.18 (3.55–35.2) |
p interaction | 0.0005 | 0.0009 | 0.003 | 0.0076 | <0.0001 | |
p trend | 0.0006 | 0.0023 | 0.0024 | 0.0216 | <0.0001 | |
Lactate | ||||||
Low | Neg | ref | ref | ref | ref | ref |
Low | Pos | 2.33 (0.31–17.8) | 5.35 (0.69–41.7) | 10.40 (1.80–60.0) | 3.30 (0.71–15.4) | 4.24 (1.23–14.6) |
High | Neg | 1.86 (0.27–12.8) | 2.79 (0.36–21.4) | 3.57 (0.50–25.3) | 0.34 (0.03–3.8) | 1.63 (0.42–6.36) |
High | Pos | 17.99 (3.31–97.8) | 26.84 (3.69–196) | 16.54 (2.86–95.7) | 12.01 (2.35–61.3) | 9.93 (3.05–32.4) |
p interaction | <0.0001 | 0.0006 | 0.0105 | 0.0022 | <0.0001 | |
p trend | 0.0002 | 0.0013 | 0.0058 | 0.0139 | 0.0003 | |
Proline 3 | ||||||
Low | Neg | ref | ref | ref | ref | ref |
Low | Pos | – | 4.16 (0.52–33.5) | 6.61 (1.53–28.6) | 4.83 (1.07–21.8) | 7.65 (1.95–29.9) |
High | Neg | – | 2.79 (0.35–22.2) | 4.29 (0.63–29.2) | 1.38 (0.18–10.7) | 3.10 (0.73–13.2) |
High | Pos | - | 34.22 (3.96–296) | 66.90 (8.82–507) | 22.04 (3.60–135) | 13.46 (3.51–51.7) |
p interaction | - | 0.0003 | 0.0004 | 0.0028 | <.0001 | |
p trend | - | 0.0009 | 0.0001 | 0.0029 | <.0001 | |
Pyroglutamate | ||||||
Low | Neg | ref | ref | ref | ref | ref |
Low | Pos | 6.76 (0.92–49.9) | 3.81 (0.39–37.7) | 6.90 (0.94–50.5) | 6.71 (0.75–60.2) | 4.23 (1.07–16.8) |
High | Neg | 2.68 (0.34–21.0) | 4.59 (0.56–37.4) | 2.83 (0.36–22.0) | 4.76 (0.60–37.7) | 3.15 (0.77–12.9) |
High | Pos | 15.50 (2.79–86.0) | 27.93 (4.03–194) | 15.79 (2.86–87.1) | 22.76 (3.47–149) | 16.17 (4.55–57.5) |
p interaction | 0.001 | 0.0004 | 0.001 | 0.0013 | <0.0001 | |
p trend | 0.0019 | 0.0005 | 0.0017 | 0.0011 | <0.0001 |
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Share and Cite
Khan, I.; Nam, M.; Kwon, M.; Seo, S.-s.; Jung, S.; Han, J.S.; Hwang, G.-S.; Kim, M.K. LC/MS-Based Polar Metabolite Profiling Identified Unique Biomarker Signatures for Cervical Cancer and Cervical Intraepithelial Neoplasia Using Global and Targeted Metabolomics. Cancers 2019, 11, 511. https://doi.org/10.3390/cancers11040511
Khan I, Nam M, Kwon M, Seo S-s, Jung S, Han JS, Hwang G-S, Kim MK. LC/MS-Based Polar Metabolite Profiling Identified Unique Biomarker Signatures for Cervical Cancer and Cervical Intraepithelial Neoplasia Using Global and Targeted Metabolomics. Cancers. 2019; 11(4):511. https://doi.org/10.3390/cancers11040511
Chicago/Turabian StyleKhan, Imran, Miso Nam, Minji Kwon, Sang-soo Seo, Sunhee Jung, Ji Soo Han, Geum-Sook Hwang, and Mi Kyung Kim. 2019. "LC/MS-Based Polar Metabolite Profiling Identified Unique Biomarker Signatures for Cervical Cancer and Cervical Intraepithelial Neoplasia Using Global and Targeted Metabolomics" Cancers 11, no. 4: 511. https://doi.org/10.3390/cancers11040511