PDF(Pubmed)
Abstract：
BACKGROUND: A better understanding of lung cancer etiology and the development of screening biomarkers have important implications for lung cancer prevention.
METHODS: We included 623 matched case-control pairs from the Cancer Prevention Study (CPS) cohorts. Pre-diagnosis blood samples were collected between 1998 and 2001 in the CPS-II Nutrition cohort and 2006 and 2013 in the CPS-3 cohort and were sent for metabolomics profiling simultaneously. Cancer-free controls at the time of case diagnosis were 1:1 matched to cases on date of birth, blood draw date, sex, and race/ethnicity. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using conditional logistic regression, controlling for confounders. The Benjamini-Hochberg method was used to correct for multiple comparisons.
RESULTS: Sphingomyelin (d18:0/22:0) (OR: 1.32; 95% CI: 1.15, 1.53, FDR = 0.15) and taurodeoxycholic acid 3-sulfate (OR: 1.33; 95% CI: 1.14, 1.55, FDR = 0.15) were positively associated with lung cancer risk. Participants diagnosed within 3 years of blood draw had a 55% and 48% higher risk of lung cancer per standard deviation increase in natural log-transformed sphingomyelin (d18:0/22:0) and taurodeoxycholic acid 3-sulfate level, while 26% and 28% higher risk for those diagnosed beyond 3 years, compared to matched controls. Lipid and amino acid metabolism accounted for 47% to 80% of lung cancer-associated metabolites at P < 0.05 across all participants and subgroups. Notably, ever-smokers exhibited a higher proportion of lung cancer-associated metabolites (P < 0.05) in xenobiotic- and lipid-associated pathways, whereas never-smokers showed a more pronounced involvement of amino acid- and lipid-associated metabolic pathways.
CONCLUSIONS: This is the largest prospective study examining untargeted metabolic profiles regarding lung cancer risk. Sphingomyelin (d18:0/22:0), a sphingolipid, and taurodeoxycholic acid 3-sulfate, a bile salt, may be risk factors and potential screening biomarkers for lung cancer. Lipid and amino acid metabolism may contribute significantly to lung cancer etiology which varied by smoking status.
METHODS: We included 623 matched case-control pairs from the Cancer Prevention Study (CPS) cohorts. Pre-diagnosis blood samples were collected between 1998 and 2001 in the CPS-II Nutrition cohort and 2006 and 2013 in the CPS-3 cohort and were sent for metabolomics profiling simultaneously. Cancer-free controls at the time of case diagnosis were 1:1 matched to cases on date of birth, blood draw date, sex, and race/ethnicity. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using conditional logistic regression, controlling for confounders. The Benjamini-Hochberg method was used to correct for multiple comparisons.
RESULTS: Sphingomyelin (d18:0/22:0) (OR: 1.32; 95% CI: 1.15, 1.53, FDR = 0.15) and taurodeoxycholic acid 3-sulfate (OR: 1.33; 95% CI: 1.14, 1.55, FDR = 0.15) were positively associated with lung cancer risk. Participants diagnosed within 3 years of blood draw had a 55% and 48% higher risk of lung cancer per standard deviation increase in natural log-transformed sphingomyelin (d18:0/22:0) and taurodeoxycholic acid 3-sulfate level, while 26% and 28% higher risk for those diagnosed beyond 3 years, compared to matched controls. Lipid and amino acid metabolism accounted for 47% to 80% of lung cancer-associated metabolites at P < 0.05 across all participants and subgroups. Notably, ever-smokers exhibited a higher proportion of lung cancer-associated metabolites (P < 0.05) in xenobiotic- and lipid-associated pathways, whereas never-smokers showed a more pronounced involvement of amino acid- and lipid-associated metabolic pathways.
CONCLUSIONS: This is the largest prospective study examining untargeted metabolic profiles regarding lung cancer risk. Sphingomyelin (d18:0/22:0), a sphingolipid, and taurodeoxycholic acid 3-sulfate, a bile salt, may be risk factors and potential screening biomarkers for lung cancer. Lipid and amino acid metabolism may contribute significantly to lung cancer etiology which varied by smoking status.
摘要：
背景：对肺癌病因学的更好理解和筛选生物标志物的发展对肺癌的预防具有重要意义。
方法：我们纳入了来自癌症预防研究（CPS）队列的623个匹配的病例对照对。在1998年至2001年期间在CPS-II营养队列和2006年和2013年在CPS-3队列中收集诊断前血液样本，并同时送去进行代谢组学分析。病例诊断时的无癌对照与出生日期的病例1:1匹配，抽血日期,性别,和种族/民族。使用条件逻辑回归估计赔率(ORs)和95%置信区间(CIs)，控制混杂因素。Benjamini-Hochberg方法用于校正多重比较。
结果：神经鞘磷脂（d18：0/22：0）（OR：1.32；95％CI：1.15，1.53，FDR=0.15）和牛磺去氧胆酸3-硫酸盐（OR：1.33；95％CI：1.14，1.55，FDR=0.15）与肺癌风险呈正相关。在抽血后3年内诊断的参与者在自然对数转化的鞘磷脂（d18：0/22：0）和牛磺去氧胆酸3-硫酸盐水平每标准偏差增加，患肺癌的风险分别增加55％和48％。而那些被诊断超过3年的人的风险增加26%和28%，与匹配的对照相比。在所有参与者和亚组中，脂质和氨基酸代谢占肺癌相关代谢物的47％至80％，P<0.05。值得注意的是,曾吸烟者在异源生物和脂质相关途径中表现出更高的肺癌相关代谢物比例（P<0.05），而从不吸烟者表现出更明显的氨基酸和脂质相关代谢途径参与.
结论：这是一项关于肺癌风险的非靶向代谢谱的最大的前瞻性研究。神经鞘磷脂(d18:0/22:0),一种鞘脂,和牛磺脱氧胆酸3-硫酸盐，胆汁盐，可能是肺癌的危险因素和潜在的筛查生物标志物。脂质和氨基酸代谢可能对肺癌的病因有重要贡献，肺癌的病因因吸烟状况而异。
方法：我们纳入了来自癌症预防研究（CPS）队列的623个匹配的病例对照对。在1998年至2001年期间在CPS-II营养队列和2006年和2013年在CPS-3队列中收集诊断前血液样本，并同时送去进行代谢组学分析。病例诊断时的无癌对照与出生日期的病例1:1匹配，抽血日期,性别,和种族/民族。使用条件逻辑回归估计赔率(ORs)和95%置信区间(CIs)，控制混杂因素。Benjamini-Hochberg方法用于校正多重比较。
结果：神经鞘磷脂（d18：0/22：0）（OR：1.32；95％CI：1.15，1.53，FDR=0.15）和牛磺去氧胆酸3-硫酸盐（OR：1.33；95％CI：1.14，1.55，FDR=0.15）与肺癌风险呈正相关。在抽血后3年内诊断的参与者在自然对数转化的鞘磷脂（d18：0/22：0）和牛磺去氧胆酸3-硫酸盐水平每标准偏差增加，患肺癌的风险分别增加55％和48％。而那些被诊断超过3年的人的风险增加26%和28%，与匹配的对照相比。在所有参与者和亚组中，脂质和氨基酸代谢占肺癌相关代谢物的47％至80％，P<0.05。值得注意的是,曾吸烟者在异源生物和脂质相关途径中表现出更高的肺癌相关代谢物比例（P<0.05），而从不吸烟者表现出更明显的氨基酸和脂质相关代谢途径参与.
结论：这是一项关于肺癌风险的非靶向代谢谱的最大的前瞻性研究。神经鞘磷脂(d18:0/22:0),一种鞘脂,和牛磺脱氧胆酸3-硫酸盐，胆汁盐，可能是肺癌的危险因素和潜在的筛查生物标志物。脂质和氨基酸代谢可能对肺癌的病因有重要贡献，肺癌的病因因吸烟状况而异。
