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抽血检测三大癌,准确度均高于90%!新标志物值得期待!

2021-10-17 MedSci原创 MedSci原创

Nature子刊:肾癌、乳腺癌和前列腺癌患者的血浆脂质谱与健康对照组不同

由于人口老龄化和其他危险因素的改变,全世界癌症发病率和死亡率都在上升。其中前列腺癌是男性第二大癌症乳腺癌则是女性癌症相关主要死因之一,另一方面,肾癌是男性第九大常见癌症,女性最常见的第14种癌症检测前列腺癌的测试包括外周血液中前列腺特异性抗原 (PSA) 水平和经直肠数字检查 (DRE),乳房X光检查则是乳腺癌筛查的主要方法,而肾癌通常在体检中偶然发现。一般来说,所有成像方式都受肿瘤大小限制而使早期敏感性较低,但癌症早诊早治能增加患者存活和治愈的机会。

癌症筛查方法旨在为高危人群早期发现癌症目前,人们更加关注在外周血液(包括液体活检)检查的基础上开发癌症筛查方法,如血液中循环细胞、血小板、细胞外囊泡、mRNA、miRNA、蛋白质、无细胞DNA(cfDNA)和血液中循环肿瘤DNA(ctDNA),代谢学也吸引了癌症筛查的研究关注脂质是重要的生物分子,脂质浓度的变化可以反映病理紊乱。

本研究旨在是定量测定肾癌、乳腺癌和前列腺癌患者的血浆脂质,并将其与健康对照组的脂质进行比较。

从289名癌症(乳腺癌、前列腺癌或肾癌)患者和192名没有恶性疾病史的志愿者中获得了肝素血浆样本。样本集分为训练和验证组,训练组包括135个健康对照组、209个癌症患者(77个乳腺癌、82个肾脏和50个前列腺癌),验证组包括57个健康对照组和80个癌症患者(26个乳腺癌、37个肾脏癌和17个前列腺癌)。所有样本的概况以及临床信息汇总在图1中。

样品顺序被随机化,用于提取和 UHPSFC/MS 测量,以排除任何可能的偏差。在发现阶段对人血浆进行脂质体分析,结果定量了138种脂类,属于甘油脂、甘油磷脂和鞘脂。所有培训集样本均应用了非监督PCA和受监督的OPLS-DA,以可视化所研究的三种癌症类型的样本组(健康对照组和癌症患者)之间的差异(图2A-D)。单个模型的特异性、灵敏度和准确值如下:肾癌男性 91%、73% 和 82%:肾癌女性88%,71%,84%:乳腺癌女性88%、63%和76%:前列腺癌-90%,82%,和87%。

图3总结了不同癌症阶段的特异性和敏感性值以及不同癌症类型的准确性值。在预测性能上训练集仅略高于验证集,对健康对照和癌症患者样本进行分类的诊断能力的ROC曲线如图3I-L所示。不同类型的癌症类型的 AUC 值从 0.917 到 0.967 不等,验证集的 AUC 值从 0.868 到 0.953 不等。

UHPSFC/MS测量在几个月后重复进行,以验证结果的重复性,这些重复的测量称为确认阶段。总共有138种脂质在鉴定阶段被定量(补充表S6a),其中126种脂质(91%)在发现阶段和鉴定阶段都被定量。图4A,B比较了UHPSFC/MS测量的PCA评分图。两个数据集都显示了PCA得分图中的质量控制(QC)样本(绿色)聚类,表明在测量序列中方法的稳定性令人满意。

在非监督PCA评分图中已经观察到癌症(红色)组和对照组(蓝色)组之间的部分组分离,这证实脂质组缺失具有较高的重现性,如图4A,B中所选样本的数量所示。总共有65%的值有RSD<20%,每个脂质和所有样品的所有RSD的平均值为19%。图4C-E进一步说明了在发现和鉴定阶段所选择的失调脂质定量结果的可重复性。此外盒状图还显示,与对照组相比,在所有癌症类型中,所选脂类均下调(图4C-E)。这两个阶段的预测结果具有可比性。

所有癌症类型的ROC曲线如图5A-D所示。AUC值范围为0.888~0.994。单个模型的特异性、灵敏度和准确值如下:肾癌男性 62%、91% 和 76%:肾癌男性86%,72%,83%:乳腺癌女性94%,57%,76%:前列腺癌 88%、75% 和 82%。图5E-H为所有类型癌症的所有样本的ROC曲线汇总,AUC 值范围 0.864 -0.901。

图5I-L总结了所有类型癌症的训练集和验证集的ROC曲线。AUC的取值范围为0.841 ~ 1.00。对于两种调控最显著的脂类,所有病理状态的盒图如图5M,N所示,UHPSFC/MS(1,2)和shotgun MS (SG)两个阶段的数据集如图5M,N所示

考虑到所有癌症类型、方法和测量,15个数据子集中的至少10个在Bonferroni校正后,29种脂类具有统计学意义。准确性随研究肿瘤类型和方法的不同,用于MDA的脂质数量的减少而略有下降(补充表S4和S11)。但是,由于预测性能的下降不是很明显,我们研究了MDA中脂质的进一步减少对正确分配样本类型的预测性能的影响。根据邦费罗尼校正,考虑所有癌症类型、方法和测量的 15 个数据子集中至少有 14 个数据子集具有显著意义。为这7个脂质物种进行了MDA,并评估了预测性能。考虑到所有方法和性别,计算了不同数量脂质的灵敏度、特异性和准确性值的平均值(图6)。

一般来说,敏感性,因此精度下降,用于MDA的脂质数量减少。这种特异性不受脂质物种数量的影响,与癌症类型无关。在所有类型的癌症中,没有观察到癌症阶段对最重要脂类浓度的影响(补充图S2)。

数据的统计评价。

通过评估Bonferroni校正后具有统计学意义的脂质种类,倍数变化在±20%和VIP值>1的脂质种类,对不同血浆脂质特征进行了研究。根据图7A-D中不同癌症类型的饼状图,计算出属于符合定义标准的脂类的脂类物种百分比。非极性脂类,三酰甘油和胆固醇酯,在肾癌中有更大的相关性,而甘油磷脂和鞘脂的影响在乳腺癌和前列腺癌中似乎占主导地位。

如图7E-G所示,在癌症患者的血浆样本中,所有方法和数据集中最重要的脂类均下调,且与癌症类型无关。通过MDA研究健康对照样品和不同类型癌症样品中所有定量脂类的差异,UHPSFC/MS和shotgun MS中91种脂类的差异,29种脂类的差异,最后,所有数据集中7种最显著的脂类。健康男性对照组和前列腺癌、肾癌男性患者样本以及健康女性对照组和肾癌、乳腺癌女性患者样本的OPLS-DA模型如图8A、B所示。问题是,使用UHPSFC/MS是否可能对癌症类型和健康对照样本进行分化和预测。

对于培训和验证集和不同数量的脂质(138、91、29和7种脂类),特异性范围从97%到67,平均为83%,肾癌敏感度为49 - 74%的平均值61%;前列腺癌敏感性从0到66%,平均43%,精度从57 74%平均65%,以构建男性样本的MDA模型(图8A)。特异性范围从96%到80,平均为90%,肾癌敏感性为从0到44%的均值为24%,乳腺癌敏感度60 - 83%均值73%,精度从78%到66的均值为74%的培训构建女性样本MDA模型(图8B)。由于从女性供体中获得的样本成分数量不足,无法使用7种脂类作为变量来进行MDA模型。OPLS-DA模型对男性的肾癌和前列腺癌进行了分类(图8C),对女性的肾癌和乳腺癌进行了分类(图8D)。

对于训练集和验证集以及男性样本的UHPSFC/MS数据集,对前列腺癌的敏感性为71-88%,平均为81%,对肾癌的敏感性为57-82%,平均为72%。对于训练集和验证集以及女性样本的UHPSFC/MS数据集,乳腺癌的灵敏度介于100%至94之间,平均为98%,敏感性为肾癌14 - 86%不等的均值57%,和准确性介于97%至80之间,平均88%。

总的来说,本研究通过超高效超临界流体色谱和质谱联用研究了人血浆的脂质组分析,目的是区分乳腺癌、肾癌和前列腺癌患者与健康对照组。脂质定位方法对肾癌的平均敏感性、特异性和准确性分别为85%、95%和92%;乳腺癌分别为91%、97%和94%;前列腺癌分别是87% 95%和92%,统计模型与肿瘤分期无相关性。统计上对癌型分化最显著的脂类是CE 16:0, Cer 42:1, LPC 18:2, PC 36:2, PC 36:3, SM 32:1,和SM 41:1,这7种脂类是肾脏、乳腺和前列腺癌筛查的潜在生物标志物,但还需要在前瞻性研究中进行进一步验证,以验证临床效用。

 

原文来源:

DeniseWolrab, et al. Plasma lipidomic profles of kidney,breast and prostate cancer patients difer from healthy controls.

Scientifc Reports | (2021) 11:20322 | https://doi.org/10.1038/s41598-021-99586-1

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    2021-11-18 ms9000001664046218

    作为筛查,还是希望价格能控制在一个合理的范围

    0

  4. [GetPortalCommentsPageByObjectIdResponse(id=1841755, encodeId=1f941841e55c6, content=<a href='/topic/show?id=18bf61953d3' target=_blank style='color:#2F92EE;'>#标志物#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=74, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=61953, encryptionId=18bf61953d3, topicName=标志物)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=6ab940, createdName=hukaixun, createdTime=Thu Jan 06 12:32:39 CST 2022, time=2022-01-06, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=2056694, encodeId=cd312056694a2, content=<a href='/topic/show?id=e20f312062d' target=_blank style='color:#2F92EE;'>#准确度#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=100, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=31206, encryptionId=e20f312062d, topicName=准确度)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=742793, createdName=zutt, createdTime=Sun Jan 09 16:32:39 CST 2022, time=2022-01-09, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1071346, encodeId=af5210e13460e, content=作为筛查,还是希望价格能控制在一个合理的范围, beContent=null, objectType=article, channel=null, level=null, likeNumber=104, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=83be5719217, createdName=ms9000001664046218, createdTime=Thu Nov 18 10:42:24 CST 2021, time=2021-11-18, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1061769, encodeId=8dcb1061e69b7, content=1, beContent=null, objectType=article, channel=null, level=null, likeNumber=108, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=0ccf5537117, createdName=ms7000001309583260, createdTime=Tue Oct 19 10:48:05 CST 2021, time=2021-10-19, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1447047, encodeId=53db144e0474d, content=<a href='/topic/show?id=549489135c5' target=_blank style='color:#2F92EE;'>#血检#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=117, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=89135, encryptionId=549489135c5, topicName=血检)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=cc1f5300484, createdName=Luyuxie_11, createdTime=Tue Oct 19 06:32:39 CST 2021, time=2021-10-19, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1061438, encodeId=4a4e1061438cf, content=希望价格不要太高,早日用于临床, beContent=null, objectType=article, channel=null, level=null, likeNumber=112, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=c8441297975, createdName=wuleilei, createdTime=Mon Oct 18 11:29:20 CST 2021, time=2021-10-18, status=1, ipAttribution=)]
    2021-10-19 ms7000001309583260

    1

    0

  5. [GetPortalCommentsPageByObjectIdResponse(id=1841755, encodeId=1f941841e55c6, content=<a href='/topic/show?id=18bf61953d3' target=_blank style='color:#2F92EE;'>#标志物#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=74, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=61953, encryptionId=18bf61953d3, topicName=标志物)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=6ab940, createdName=hukaixun, createdTime=Thu Jan 06 12:32:39 CST 2022, time=2022-01-06, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=2056694, encodeId=cd312056694a2, content=<a href='/topic/show?id=e20f312062d' target=_blank style='color:#2F92EE;'>#准确度#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=100, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=31206, encryptionId=e20f312062d, topicName=准确度)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=742793, createdName=zutt, createdTime=Sun Jan 09 16:32:39 CST 2022, time=2022-01-09, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1071346, encodeId=af5210e13460e, content=作为筛查,还是希望价格能控制在一个合理的范围, beContent=null, objectType=article, channel=null, level=null, likeNumber=104, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=83be5719217, createdName=ms9000001664046218, createdTime=Thu Nov 18 10:42:24 CST 2021, time=2021-11-18, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1061769, encodeId=8dcb1061e69b7, content=1, beContent=null, objectType=article, channel=null, level=null, likeNumber=108, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=0ccf5537117, createdName=ms7000001309583260, createdTime=Tue Oct 19 10:48:05 CST 2021, time=2021-10-19, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1447047, encodeId=53db144e0474d, content=<a href='/topic/show?id=549489135c5' target=_blank style='color:#2F92EE;'>#血检#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=117, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=89135, encryptionId=549489135c5, topicName=血检)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=cc1f5300484, createdName=Luyuxie_11, createdTime=Tue Oct 19 06:32:39 CST 2021, time=2021-10-19, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1061438, encodeId=4a4e1061438cf, content=希望价格不要太高,早日用于临床, beContent=null, objectType=article, channel=null, level=null, likeNumber=112, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=c8441297975, createdName=wuleilei, createdTime=Mon Oct 18 11:29:20 CST 2021, time=2021-10-18, status=1, ipAttribution=)]
  6. [GetPortalCommentsPageByObjectIdResponse(id=1841755, encodeId=1f941841e55c6, content=<a href='/topic/show?id=18bf61953d3' target=_blank style='color:#2F92EE;'>#标志物#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=74, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=61953, encryptionId=18bf61953d3, topicName=标志物)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=6ab940, createdName=hukaixun, createdTime=Thu Jan 06 12:32:39 CST 2022, time=2022-01-06, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=2056694, encodeId=cd312056694a2, content=<a href='/topic/show?id=e20f312062d' target=_blank style='color:#2F92EE;'>#准确度#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=100, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=31206, encryptionId=e20f312062d, topicName=准确度)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=742793, createdName=zutt, createdTime=Sun Jan 09 16:32:39 CST 2022, time=2022-01-09, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1071346, encodeId=af5210e13460e, content=作为筛查,还是希望价格能控制在一个合理的范围, beContent=null, objectType=article, channel=null, level=null, likeNumber=104, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=83be5719217, createdName=ms9000001664046218, createdTime=Thu Nov 18 10:42:24 CST 2021, time=2021-11-18, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1061769, encodeId=8dcb1061e69b7, content=1, beContent=null, objectType=article, channel=null, level=null, likeNumber=108, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=0ccf5537117, createdName=ms7000001309583260, createdTime=Tue Oct 19 10:48:05 CST 2021, time=2021-10-19, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1447047, encodeId=53db144e0474d, content=<a href='/topic/show?id=549489135c5' target=_blank style='color:#2F92EE;'>#血检#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=117, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=89135, encryptionId=549489135c5, topicName=血检)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=cc1f5300484, createdName=Luyuxie_11, createdTime=Tue Oct 19 06:32:39 CST 2021, time=2021-10-19, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1061438, encodeId=4a4e1061438cf, content=希望价格不要太高,早日用于临床, beContent=null, objectType=article, channel=null, level=null, likeNumber=112, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=c8441297975, createdName=wuleilei, createdTime=Mon Oct 18 11:29:20 CST 2021, time=2021-10-18, status=1, ipAttribution=)]
    2021-10-18 wuleilei

    希望价格不要太高,早日用于临床

    0

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