Correlation between Serum Valine and Methionine Levels and Clinical Features and Risk of Breast Cancer
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摘要:
目的 比较健康人群、乳腺良性肿瘤患者和乳腺癌患者的血清Val、Met浓度差异，探究血清缬氨酸和甲硫氨酸与乳腺癌临床特征及风险的关系。 方法 采用液相色谱-串联质谱法测定38名乳腺良性肿瘤患者，87名乳腺癌患者的血清Val、Met浓度，同时选择91名健康人群作为对照组。经Kruskal-Wallis H检验比较不同分组间的血清Val、Met浓度差异，分析不同化疗方案及手术方式对乳腺癌患者血清Val、Met浓度的影响。再通过二元Logistic回归分析、计算优势比和95%置信区间（CI）来评估血清Val、Met与乳腺癌的风险关系并绘制ROC曲线评估血清Val及Met对乳腺癌的诊断效能。 结果 与健康对照组相比，乳腺癌（BC）组的血清Val浓度水平高于乳腺良性肿瘤（BE）组和健康对照组，BC组和BE组的Met水平都高于健康对照组，差异有统计学意义（P < 0.05）。不同TNM分期及接受不同化疗方案的乳腺癌患者血清Val、Met浓度，差异无统计学意义（ P > 0.05），但不同分子分型组间乳腺癌患者的血清Val浓度，差异有统计学意义（ P < 0.05）。另外，血清Val浓度水平和乳腺癌风险无明显关系，但血清Met会显著影响乳腺癌的发生（ P < 0.001），血清Met的浓度越高，乳腺癌的患病风险就越高，并且Met的浓度水平每增加一个单位，乳腺癌患病风险就增加24%（ OR = 1.24 95% CI：1.15～1.34）。并且血清Met（P < 0.001）对乳腺癌的诊断具有统计学意义。其AUC为0.83、敏感度及特异性分别为69%和90.1%，临界值为19.76 μmol/L。 结论 乳腺癌患者的血清Val浓度高于乳腺良性肿瘤患者及健康人群；与健康人群相比，乳腺癌患者及乳腺良性肿瘤患者的血清Met浓度水平也有所升高。血清Val浓度水平和乳腺癌风险无明显关系，但血清Met与乳腺癌风险呈负相关，并且血清Met对乳腺癌诊断具有一定的诊断效能。 Abstract:Objective To compare the differences in serum Val and Met concentrations in healthy people, patients with benign breast tumors and breast cancer patients, and explore the relationship between serum valine and methionine and the clinical characteristics and risk of breast cancer. Methods The serum Val and Met concentrations of 38 patients with benign breast tumors and 87 patients with breast cancer were determined by liquid chromatography-tandem mass spectrometry, and 91 healthy participants were selected as the control group. The Kruskal-Wallis H-test was used to compare the differences in serum Val and Met concentrations between different groups, and the effects of different chemotherapy regimens and surgical methods on serum Val and Met concentrations in breast cancer patients were analyzed. Binary Logistic regression analysis, calculation of odds ratio and 95% confidence interval （CI） were used to evaluate the relationship between serum Val, Met and breast cancer risk, and ROC curve was drawn to evaluate the diagnostic performance of serum Val and Met for breast cancer. Results Compared with healthy control group, the serum Val concentration in breast cancer （BC） group was higher than that in benign breast tumor （BE） group and healthy control group, and the Met level in BC and BE groups was higher than that in healthy control group, and the differences were statistically significant （P < 0.05）. There were no significant differences in serum Val and Met concentrations among breast cancer patients with different TNM stages and chemotherapy regimens, but there were differences in serum Val concentrations among breast cancer patients with different molecular types. In addition, there was no significant relationship between serum Val concentration level and breast cancer risk, but serum Met significantly affected the occurrence of breast cancer （ P < 0.001）. The higher serum Met concentration was, the higher the risk of breast cancer was; and for every one-unit increase in Met levels, the risk of breast cancer increased by 24 percent （ OR = 1.24 95%CI: 1.15-1.34）. Serum Met （P < 0.001） was statistically significant in the diagnosis of breast cancer. The AUC was 0.83, the sensitivity and specificity were 69% and 90.1%, respectively, and the critical value was 19.76 μmol/L. Conclusion The serum Val concentration of breast cancer patients was higher than that of benign breast tumor patients and healthy population. Serum Met levels were also elevated in patients with breast cancer and benign breast tumors compared with healthy subjects. There was no significant correlation between serum Val concentration and breast cancer risk, but serum Met was negatively correlated with breast cancer risk, and serum Met had certain diagnostic efficacy for breast cancer diagnosis. -
Key words:
- Amino acid /
- Valine /
- Methionine /
- Breast cancer /
- Benign breast tumor
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图 1 血清Val、Met与乳腺癌的风险关系
*P < 0.05。
Figure 1. The relationship between serum Val，Met and breast cancer risk
图 2 乳腺癌组和健康对照组的血清Val、Met ROC曲线
Figure 2. Serum Val and Met ROC curves of breast cancer group and healthy control group
表 1 不同分组的血清Val、Met浓度的比较（n = 216）
Table 1. Comparison of serum Val and Met concentrations in different groups （n=216）（M±IQR）
类别 健康对照组（n = 91） BE组（n = 38） BC组（n = 87） H P Val（μmlo/L） 161.32 ± 52.64 157.09 ± 42.35 185.63 ± 56.44 13.05 0.001* Met（μmlo/L） 14.03 ± 6.11 20.39 ± 6.45 24.28 ± 56.44 67.60 < 0.001 * *P < 0.05。 
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表 2 不同Val、Met浓度水平的乳腺癌患者基线特征
Table 2. Baseline characteristics of breast cancer patients with different concentrations of Val and Met
分组 Val（μmlo/L） χ² P Met（μmlo/L） χ² P < 188.66（ n=46） ≥188.66（n=41） < 27.74（ n=53） ≥27.74（n=34） 年龄（岁） 0.100 0.752 3.400 0.065 < 50 22 21 22 21 ≥50 24 20 31 13 停经 是 12 12 0.116 0.733 19 5 4.557 0.033* 否 33 28 33 28 未知 1 1 1 1 初潮年龄（岁） 2.018 0.155 1.886 0.170 < 14 15 18 16 17 ≥14 26 16 27 15 未知 5 7 10 2 乳腺癌家族史 3.295 0.069 1.966 0.161 有 6 1 6 1 无 40 40 47 33 BIM 3.172 0.205 0.526 0.769 < 18.5 4 2 4 2 ≤18.5 < 24 28 19 27 20 ≥24 14 20 22 12 TNM分期 5.616 0.060 0.059 0.971 I-II 33 25 36 22 III 7 13 12 8 IV 3 0 2 1 未知 3 3 3 3 肿块大小（cm） 1.415 0.234 2.966 0.397 Tx 5 6 8 3 ≤2 21 15 25 11 < 2≤5 15 19 17 17 ≥5 1 1 1 1 T4 4 0 2 2 淋巴结转移 7.590 0.006* 0.011 0.915 （+） 27 12 24 15 （−） 19 29 29 19 ER 2.769 0.096 0.041 0.839 （+） 31 34 40 25 （−） 15 7 13 9 PR 2.305 0.129 0.079 0.778 （+） 36 37 44 29 （−） 10 4 9 5 ki-67 0.123 0.726 0.311 0.577 < 14% 13 13 17 9 ≥14% 33 28 36 25 HER-2b 0.774 0.379 1.576 0.209 （+） 14 9 17 6 （−） 28 28 33 23 未知 4 4 3 5 AR 0.289 0.591 0.429 0.513 （+） 28 29 34 23 （−） 8 6 7 7 未知 10 6 12 4 病理分型 0.006 0.002* 0.062 0.803 浸润性导管癌 35 39 44 30 浸润性小叶癌 1 2 2 1 其他 10 0 7 3 化疗史 0.346 0.557 8.746 0.003* 有 31 30 31 30 无 15 11 22 4 经手术治疗 1.276 0.259 7.130 0.008* 是 26 28 27 27 否 20 13 26 7 *P < 0.05。
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表 3 不同分期乳腺癌患者的Val、Met浓度水平比较（n = 81）
Table 3. Comparison of levels of Val and Met in breast cancer patients in different stages （n = 81）
类别 I期 II期 III期 IV期 F P n = 26（32%） n = 32（39%） n = 20（25%） n = 3（4%） Val（μmlo/L） 183.34 ± 54.03 186.37 ± 47.67 199.33 ± 45.91 158.01 ± 35.61 0.814 0.490 Met（μmlo/L） 25.67 ± 10.90 29.73 ± 14.29 27.23 ± 18.06 23.95 ± 10.12 0.465 0.707
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表 4 不同分子分型的乳腺癌患者Val、Met浓度水平比较（n = 80）
Table 4. Comparison of Val and Met concentrations in breast cancer patients with different molecular types （n = 80）
类别 Luminal A型 Luminal B型 三阴型 HER-2阳性（HR阳性） HER-2阳性（HR阴性） F P n = 15（19%） n = 34（42%） n = 10（12.5%） n = 10（12.5%） n = 11（14%） Val（μmlo/L） 211.81 ± 81.40 191.81 ± 37.75 186.81 ± 58.75 193.05 ± 44.98 153.69 ± 30.13 3.403 0.023* Met（μmlo/L） 27.58 ± 13.03 29.35 ± 16.45 30.81 ± 21.23 26.53 ± 10.25 20.72 ± 7.36 0.822 0.515 *P < 0.05。
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表 5 不同化疗方案乳腺癌患者的Val、Met浓度水平比较（n = 61）
Table 5. Comparison of levels of Val and Met in breast cancer patients with different chemotherapy regimens （n = 61）
类别 TC方案 AC方案 AC-T方案 其他方案 F P n = 11（18%） n = 22（36%） n = 22（36%） n = 6（10%） Val（μmlo/L） 187.45 ± 72.52 204.54 ± 54.89 193.71 ± 37.95 161.95 ± 51.19 1.084 0.363 Met（μmlo/L） 26.12 ± 14.33 29.15 ± 10.57 35.76 ± 18.43 23.18 ± 11.59 1.836 0.151 TC：紫衫醇 + 环磷酰胺；AC：蒽环类药物+环磷酰胺；AC-T：蒽环类药物+环磷酰胺序贯紫杉醇；其他：除以上化疗方案的其他方案。
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表 6 乳腺癌组和健康对照组血清Met的ROC曲线下面积（AUC）、敏感度（%）和特异性（%）及 95% CI参数
Table 6. Area under the ROC curve （AUC），sensitivity （%），specificity （%） and 95% CI parameters of serum Met in breast cancer group and healthy control group
氨基酸 P AUC 临界值
（μmlo/L）敏感度（%） 特异性（%） 95% CI Met < 0.001 * 0.83 19.76 69 90.1 0.76~0.89 *P < 0.05。
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