USING SIZE AND NUMBER ABERRATIONS IN PLASMA DNA FOR DETECTING CANCER

摘要

Analysis of tumor-derived circulating cell-free DNA opens up new possibilities for performing liquid biopsies for solid tumor assessment or cancer screening. However, many aspects of the biological characteristics of tumor-derived cell-free DNA remain unclear. Regarding the size profile of plasma DNA molecules, some studies reported increased integrity of tumor-derived plasma DNA while others reported shorter tumor-derived plasma DNA molecules. We performed an analysis of the size profiles of plasma DNA in patients with cancer using massively parallel sequencing at single base resolution and in a genomewide manner. Tumor-derived plasma DNA molecules were further identified using chromosome arm-level z-score analysis (CAZA). We showed that populations of aberrantly short and long DNA molecules co-existed in the plasma of patients with cancer. The short ones preferentially carried the tumor-associated copy number aberrations. These results show the ability to use plasma DNA as a molecular diagnostic tool.

主权项

1. A method of analyzing a biological sample of an organism, the biological sample including nucleic acid molecules originating from normal cells and potentially from cells associated with cancer, wherein at least some of the nucleic acid molecules are cell-free in the biological sample, the method comprising:
identifying a plurality of chromosomal regions of the organism, each chromosomal region including a plurality of loci; for each of a plurality of the nucleic acid molecules in the biological sample:
measuring a size of the nucleic acid molecule; andidentifying a location of the nucleic acid molecule in a reference genome of the organism; for each of the plurality of chromosomal regions:
identifying a respective group of nucleic acid molecules as being from the chromosomal region based on the identified locations, the respective group including at least one nucleic acid molecule located at each of the plurality of loci of the chromosomal region;calculating, with a computer system, a respective amount of the respective group of nucleic acid molecules; andcomparing the respective amount to a count reference value to determine a count classification of whether the chromosomal region exhibits an aberration, the count classification for a first chromosomal region of the plurality of chromosomal regions indicating a first aberration; identifying a first group of nucleic acid molecules as being from the first chromosomal region based on the identified locations; calculating, with a computer system, a first statistical value of a first size distribution of the first group of nucleic acid molecules; and comparing the first statistical value to a size reference value to determine a size classification of whether the first chromosomal region exhibits the first aberration; and determining a final classification of whether the first chromosomal region exhibits the first aberration using the count classification and the size classification of the first chromosomal region.