Turriff Amy E, Annunziata Christina M, Malayeri Ashkan A, Redd Bernadette, Pavelova Miroslava, Goldlust Ian S, Rajagopal Padma Sheila, Lin Jielu, Bianchi Diana W
From the Prenatal Genomics and Therapy Section, Center for Precision Health Research (A.E.T., D.W.B.), and the Section on Social Network Methods, Social and Behavioral Research Branch (J.L.), National Human Genome Research Institute, the Women's Malignancies Branch (C.M.A., I.S.G., P.S.R.) and the Cancer Data Science Laboratory (P.S.R.), Center for Cancer Research, National Cancer Institute, Radiology and Imaging Sciences, Clinical Center (A.A.M., B.R.), and the Office of the Director, Eunice Kennedy Shriver National Institute of Child Health and Human Development (D.W.B.), National Institutes of Health, Bethesda, and Leidos Biomedical Research, Frederick (M.P.) - both in Maryland.
N Engl J Med. 2024 Dec 5;391(22):2123-2132. doi: 10.1056/NEJMoa2401029.
Cell-free DNA (cfDNA) sequence analysis to screen for fetal aneuploidy can incidentally detect maternal cancer. Additional data are needed to identify DNA-sequencing patterns and other biomarkers that can identify pregnant persons who are most likely to have cancer and to determine the best approach for follow-up.
In this ongoing study we performed cancer screening in pregnant or postpartum persons who did not perceive signs or symptoms of cancer but received unusual clinical cfDNA-sequencing results or results that were nonreportable (i.e., the fetal aneuploidy status could not be assessed) from one of 12 different commercial laboratories in North America. We used a uniform cancer-screening protocol including rapid whole-body magnetic resonance imaging (MRI), laboratory tests, and standardized cfDNA sequencing for research purposes with the use of a genomewide platform. The primary outcome was the presence of cancer in participants after the initial cancer-screening evaluation. Secondary analyses included test performance.
Cancer was present in 52 of the 107 participants in the initial cohort (48.6%). The sensitivity and specificity of whole-body MRI in detecting occult cancer were 98.0% and 88.5%, respectively. Physical examination and laboratory tests were of limited use in identifying participants with cancer. Research sequencing showed that 49 participants had a combination of copy-number gains and losses across multiple (≥3) chromosomes; cancer was present in 47 of the participants (95.9%) with this sequencing pattern. Sequencing patterns of cfDNA in which there were only chromosomal gains (multiple trisomies) or only chromosomal losses (one or more monosomies) were found in participants with nonmalignant conditions, such as fibroids.
In this study, 48.6% of participants who received unusual or nonreportable clinical cfDNA-sequencing results had an occult cancer. Further study of DNA-sequencing patterns that are suggestive of occult cancer during prenatal screening is warranted. (Funded by the NIH Intramural Research Programs; ClinicalTrials.gov number, NCT04049604.).
用于筛查胎儿非整倍体的游离DNA（cfDNA）序列分析可能会偶然检测出母体癌症。需要更多数据来确定DNA测序模式和其他生物标志物，以识别最有可能患癌症的孕妇，并确定最佳的后续随访方法。
在这项正在进行的研究中，我们对未察觉到癌症体征或症状，但从北美12家不同商业实验室之一获得异常临床cfDNA测序结果或无法报告的结果（即无法评估胎儿非整倍体状态）的孕妇或产后女性进行了癌症筛查。我们使用了统一的癌症筛查方案，包括快速全身磁共振成像（MRI）、实验室检查，以及为研究目的使用全基因组平台进行标准化的cfDNA测序。主要结局是初始癌症筛查评估后参与者中是否存在癌症。次要分析包括检测性能。
初始队列的107名参与者中有52名患有癌症（48.6%）。全身MRI检测隐匿性癌症的敏感性和特异性分别为98.0%和88.5%。体格检查和实验室检查在识别癌症患者方面作用有限。研究测序显示，49名参与者在多条（≥3条）染色体上存在拷贝数增加和减少的组合；具有这种测序模式的参与者中有47名患有癌症（95.9%）。在患有非恶性疾病（如子宫肌瘤）的参与者中发现了cfDNA的测序模式，其中仅存在染色体增加（多个三体）或仅存在染色体减少（一个或多个单体）。
在本研究中，48.6%收到异常或无法报告的临床cfDNA测序结果的参与者患有隐匿性癌症。有必要进一步研究产前筛查期间提示隐匿性癌症的DNA测序模式。（由美国国立卫生研究院内部研究项目资助；ClinicalTrials.gov编号，NCT04049604。）
