identifying cancer patients from GC-patterned fragment ends of cell-free DNA
Curtis, S. D.; Summers, M.; Cohen, J.; Wang, Y.; Popoli, M.; Dobbyn, L.; Ptak, J.; Silliman, N.; Nehme, N.; Gibbs, P.; Buchanan, A.; Tran, B. N. H.; Ho-Pham, L. T.; Hruban, R.; Lennon, A. M.; Bettegowda, C.; Zhou, S.; Papadopoulos, N.; Kinzler, K. W.; Vogelstein, B.; Douville, C.
Show abstract
One of the most intriguing characteristics of cell-free DNA (cfDNA) from plasma is the sequence at the ends of the fragments. Previous studies have shown that these end-sequences are somewhat different in cancer patients than in healthy individuals. While investigating this characteristic, we noticed that the bases at the 5-ends of a double-stranded fragment were highly correlated with the GC content of that particular fragment. This led us to develop a method, called MendSeqS (Modified End-based sequencing System), that incorporates the correlation between end-motifs and GC content into the analysis of shallow (0.5x) whole genome sequencing (WGS). When applied to plasma samples, MendSeqS was able to classify patients with a sensitivity of 96% at 98% specificity in a cohort comprised of 107 individuals evaluated in our laboratory (43 with cancer and 64 without). In cohorts evaluated in three other laboratories, comprising a total of 401 individuals (193 with cancer and 208 without), MendSeqS achieved a sensitivity of 87% at 98% specificity. MendSeqS could in principle be combined with other methods of cfDNA analysis to enhance cancer detection.
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