回顾NIPT披露母体肿瘤的案例,展望未来NIPT的切入点
2016/01/15
近年来,越来越多的研究报道了NIPT不仅可告知胎儿的遗传信息,偶尔还会披露母亲的健康状况,母体肿瘤使得NIPT筛查结果变得更加复杂。本文回顾了Nature等杂志上报道的揭露母体肿瘤的NIPT筛查案例,并对NIPT未来的研究进行展望。


1997年孕妇血浆中胎儿游离DNA的发现开辟了无创产前检测(NIPT)的新纪元,自2011年以来,世界范围内已有200多万名孕妇使用NIPT技术来进行染色体三倍体筛查,目前对该技术使用较普遍的地区有美国、中国及欧洲部分国家。

数据回顾: Nature等报道的NIPT披露母体肿瘤的案例

随着对NIPT的使用越来越广泛,越来越多的研究报道了NIPT不仅可告知胎儿的遗传信息,偶尔还会披露母亲的健康状况,同时很多出版物也报道了NIPT可揭示孕妇恶性肿瘤的存在。例如,2013年Osborne在《Prenat. Diagn》杂志上报道了NIPT检测出孕妇转移性恶性肿瘤的案例。在这个案例中,NIPT筛查结果显示胎儿染色体出现13三体与18单体,然而羊膜穿刺结果发现胎儿染色体核型均为正常,随后临床调查发现,该孕妇体内存在转移性小细胞癌,且可能起源于阴道。

现在回想起来,这也许不足为奇,NIPT揭示母体恶性肿瘤在Osborne报道之前,就已经被一组血浆DNA全基因组大规模平行测序所披露。据估计,孕妇母体恶性肿瘤发生的概率为1/1000,因此人们会认为NIPT技术能揭示母体恶性肿瘤只是时间问题。

2015年,Amant在《JAMA Oncol》杂志上报道了4000多例孕妇使用NIPT的现状,其中有三名孕妇血浆基因组分析结果出现异常,且无法在胎儿中追溯到相应的结果,通过全身磁共振成像检测,三名孕妇分别患有卵巢癌、滤泡淋巴瘤和霍奇金淋巴瘤。

2015年Bianchi在《Nature》上报道了一组更庞大的数据,报道中共有125426名孕妇接受了NIPT,其中3757名受试者的血浆DNA检测结果异常,随后进一步诊断并自愿报道的母体瘤有10例,包括3例B细胞淋巴瘤(分别为I期,II期和IVB期),1例T细胞白血病(阶段未知),1例霍金淋巴瘤(IIA),1例腺癌(未指定),1例平滑肌肉瘤,1例神经内分泌癌(IV阶段,转移性)1例结肠癌(IIIC阶段)和1例肛门癌(IIIB阶段);此外研究人员对8名孕妇进行额外的测序和生物学分析,结果发现其中7名孕妇血浆DNA出现异常。

作为一个整体,NIPT能够检测到孕妇的恶性肿瘤,且研究发现似乎大多数的母体癌症病例均属于相对晚期阶段,即III期和IV期。因此这些信息应当告知参与NIPT的临床医生与遗传咨询师,并且写入NIPT知情同意表中。

NIPT识别母体肿瘤的敏感度还需要更多的探索

尽管,NIPT披露母体癌症的出版物频频出现,但NIPT识别母体肿瘤的敏感度还需要更多的探索。2015年Amant在《JAMA Oncol》中表明他们能够检测到母体癌症的灵敏度为0.1%,该比例与妊娠期恶性肿瘤发病率相似。另外,Bianchi在《Nature》上的报道数据显示,母体癌症病例概率为0.008%,远低于Amant所报道的数据。

然而,值得注意的是,这两位作者的研究设计是不同的。例如,Bianchi团队的数据依赖于医生的病例报告,孕产妇癌症在研究的时间里可能未被识别,此外值得注意的是,不同的测序和生物信息学方法的差异对观察结果的差异性有重要的影响。

未来的NIPT或可识别血浆中基因畸形的组织来源,新技术随理念的进步问世

在技术发展方面,未来的NIPT将有可能识别血浆中基因畸变的组织起源。2015年,Sun研究团队在《Proc. Natl Acad. Sci.》上阐述了他们开发的新技术,该技术基于不同组织中含有不同的DNA甲基化模式,因此利用亚硫酸氢-全基因组测序的方法对血浆DNA进行测序,可在超过5800个DNA甲基化标记的帮助下进行数据分析。通过反褶积过程可推断出将DNA释放到血浆中的组织的贡献比例,这种方法被称为血浆DNA组织图谱( plasma DNA tissue mapping)。在研究中,Sun证明了白细胞、肝、胎盘是孕妇血浆循环DNA的主要组织来源。

Sun进一步推断,释放DNA进入血浆中的肿瘤细胞拷贝数增加将导致血浆中肿瘤组织基因组比例增加,否则反之。因此通过系统比较血浆中与组织相关的区域(可揭示血浆中不同组织类型基因组的增减情况),可确定血浆DNA畸变的来源。研究人员通过将该技术应用于NIPT结果为染色体异常的孕妇身上证实了该原则。使用血浆DNA组织图谱,研究人员发现B细胞扩散到血浆DNA池的概率很高,证实了B细胞可能是血浆拷贝数异常的来源,这些数据均符合滤泡淋巴瘤的临床和组织学诊断,然而这些数据需要更大的群体来验证。

血浆DNA组织图谱被视为是衔接液体活检信息生成与组织切片技术的纽带。通过在不同临床情况下使用血浆DNA组织图谱,可获得不同临床血浆DNA中不同组织贡献率的变化等,另外,这种方法有助于提高研究人员使用血浆DNA来进行癌症非侵入性检测分析的兴趣。目前,血浆组织DNA图谱还比较昂贵,并涉及到亚硫酸氢-全基因组测序,因而对于临床效应而言,开发低成本的、更有针对性的方法是有必要的。

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  • Presymptomatic Identification of Cancers in Pregnant Women During Noninvasive Prenatal Testing

    Importance Noninvasive prenatal testing (NIPT) for fetal aneuploidy by scanning cell-free fetal DNA in maternal plasma is rapidly becoming a major prenatal genetic test. Similar to placental DNA, tumor DNA can be detected in the plasma, and analysis of cell-free tumor DNA can be used to characterize and monitor cancers. We show that plasma DNA profiling allows for presymptomatic detection of tumors in pregnant women undergoing routine NIPT. Observations During NIPT in over 4000 prospective pregnancies by parallel sequencing of maternal plasma cell-free DNA, 3 aberrant genome representation (GR) profiles were observed that could not be attributed to the maternal or fetal genomic constitution. A maternal cancer was suspected, and those 3 patients were referred for whole-body diffusion-weighted magnetic resonance imaging, which uncovered an ovarian carcinoma, a follicular lymphoma, and a Hodgkin lymphoma, each confirmed by subsequent pathologic and genetic investigations. The copy number variations in the subsequent tumor biopsies were concordant with the NIPT plasma GR profiles. Conclusions and Relevance We show that maternal plasma cell-free DNA sequencing for noninvasive prenatal testing also may enable accurate presymptomatic detection of maternal tumors and treatment during pregnancy.

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  • Noninvasive Prenatal Testing and Incidental Detection of Occult Maternal Malignancies

    Importance Understanding the relationship between aneuploidy detection on noninvasive prenatal testing (NIPT) and occult maternal malignancies may explain results that are discordant with the fetal karyotype and improve maternal clinical care. Objective To evaluate massively parallel sequencing data for patterns of copy-number variations that might prospectively identify occult maternal malignancies. Design, Setting, and Participants Case series identified from 125 426 samples submitted between February 15, 2012, and September 30, 2014, from asymptomatic pregnant women who underwent plasma cell-free DNA sequencing for clinical prenatal aneuploidy screening. Analyses were conducted in a clinical laboratory that performs DNA sequencing. Among the clinical samples, abnormal results were detected in 3757 (3%); these were reported to the ordering physician with recommendations for further evaluation. Exposures NIPT for fetal aneuploidy screening (chromosomes 13, 18, 21, X, and Y). Main Outcomes and Measures Detailed genome-wide bioinformatics analysis was performed on available sequencing data from 8 of 10 women with known cancers. Genome-wide copy-number changes in the original NIPT samples and in subsequent serial samples from individual patients when available are reported. Copy-number changes detected in NIPT sequencing data in the known cancer cases were compared with the types of aneuploidies detected in the overall cohort. Results From a cohort of 125 426 NIPT results, 3757 (3%) were positive for 1 or more aneuploidies involving chromosomes 13, 18, 21, X, or Y. From this set of 3757 samples, 10 cases of maternal cancer were identified. Detailed clinical and sequencing data were obtained in 8. Maternal cancers most frequently occurred with the rare NIPT finding of more than 1 aneuploidy detected (7 known cancers among 39 cases of multiple aneuploidies by NIPT, 18% [95% CI, 7.5%-33.5%]). All 8 cases that underwent further bioinformatics analysis showed unique patterns of nonspecific copy-number gains and losses across multiple chromosomes. In 1 case, blood was sampled after completion of treatment for colorectal cancer and the abnormal pattern was no longer evident. Conclusions and Relevance In this preliminary study, a small number of cases of occult malignancy were subsequently diagnosed among pregnant women whose noninvasive prenatal testing results showed discordance with the fetal karyotype. The clinical importance of these findings will require further research.

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  • Plasma DNA tissue mapping by genome-wide methylation sequencing for noninvasive prenatal, cancer, and transplantation assessments

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    Noninvasive prenatal testing (NIPT) for fetal aneuploidy is clinically available for women at an increased risk of fetal aneuploidy. At the time of the present case report, detection of aneuploidy through NIPT was only available for Down syndrome, trisomy 18, and trisomy 13. NIPT has been quoted to have a detection rate for trisomies 21 and 18 of approximately 99%, and a detection rate for trisomy 13 of between 79 to 92%. The false positive rate for all autosomal aneuploidies is reported to be 1% or less.

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  • Noninvasive Prenatal Testing and Incidental Detection of Occult Maternal Malignancies

    Importance Understanding the relationship between aneuploidy detection on noninvasive prenatal testing (NIPT) and occult maternal malignancies may explain results that are discordant with the fetal karyotype and improve maternal clinical care. Objective To evaluate massively parallel sequencing data for patterns of copy-number variations that might prospectively identify occult maternal malignancies. Design, Setting, and Participants Case series identified from 125 426 samples submitted between February 15, 2012, and September 30, 2014, from asymptomatic pregnant women who underwent plasma cell-free DNA sequencing for clinical prenatal aneuploidy screening. Analyses were conducted in a clinical laboratory that performs DNA sequencing. Among the clinical samples, abnormal results were detected in 3757 (3%); these were reported to the ordering physician with recommendations for further evaluation. Exposures NIPT for fetal aneuploidy screening (chromosomes 13, 18, 21, X, and Y). Main Outcomes and Measures Detailed genome-wide bioinformatics analysis was performed on available sequencing data from 8 of 10 women with known cancers. Genome-wide copy-number changes in the original NIPT samples and in subsequent serial samples from individual patients when available are reported. Copy-number changes detected in NIPT sequencing data in the known cancer cases were compared with the types of aneuploidies detected in the overall cohort. Results From a cohort of 125 426 NIPT results, 3757 (3%) were positive for 1 or more aneuploidies involving chromosomes 13, 18, 21, X, or Y. From this set of 3757 samples, 10 cases of maternal cancer were identified. Detailed clinical and sequencing data were obtained in 8. Maternal cancers most frequently occurred with the rare NIPT finding of more than 1 aneuploidy detected (7 known cancers among 39 cases of multiple aneuploidies by NIPT, 18% [95% CI, 7.5%-33.5%]). All 8 cases that underwent further bioinformatics analysis showed unique patterns of nonspecific copy-number gains and losses across multiple chromosomes. In 1 case, blood was sampled after completion of treatment for colorectal cancer and the abnormal pattern was no longer evident. Conclusions and Relevance In this preliminary study, a small number of cases of occult malignancy were subsequently diagnosed among pregnant women whose noninvasive prenatal testing results showed discordance with the fetal karyotype. The clinical importance of these findings will require further research.

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