Background
Non-invasive prenatal testing (NIPT) identifies fetal aneuploidy by sequencing cell-free DNA in the maternal plasma. Pre-symptomatic maternal malignancies have been incidentally detected during NIPT based on abnormal genomic profiles. This low coverage sequencing approach could have potential for leimoyosarcoma screening in the non-pregnant population. Our objective was to investigate whether plasma DNA sequencing with a clinical whole genome NIPT platform can detect early- and late-stage high-grade leimyosarcoma compared to their benign controls
Methods
This is a case control study of prospectively-collected biobank samples comprising preoperative plasma from 4 women with metastatic leiomyosarcoma and 20 benign controls. Plasma DNA from cases and controls were sequenced using a commercial NIPT platform and chromosome dosage measured.
Sequencing data were blindly analyzed with two methods: (1) Subchromosomal changes were called using an open source algorithm WISECONDOR (WIthin-SamplE COpy Number aberration DetectOR). Genomic gains or losses ≥ 20 Mb were prespecified as “screen positive” calls, and mapped to recurrent copy number variations reported in cancer genome atlas. (2) Selected whole chromosome gains or losses were reported using the routine NIPT pipeline for fetal aneuploidy.
Results
We detected 1/4 cancer cases using the subchromosomal analysis (specificity 86% (95% CI 0.66-0.97)) . All of the 20 benign controls did not have any subchromosomal gains ≥ 20 Mb. For the positive result in the leiomyosarcoma patient, the NIPT pipeline resulted in a gain in 1q, loss in 10p and 10q and loss of 13.
Conclusions
Low coverage plasma DNA sequencing used for prenatal testing detected 25% of all leimyosarcomas, with all benign controls screening negatives. Our findings demonstrate the potential of a high throughput sequencing platform to screen for leiomyosacoma in plasma based on characteristic multiple segmental chromosome gains and losses. The performance of this approach may be further improved by refining bioinformatics algorithms and targeting selected cancer copy number variations.
Keywords
Non-invasive prenatal testing leimyosarcaoma screening Circulating tumor DNA Low coverage sequencing Copy number variations Genomic profiling Liquid biopsy
References