A Practical Approach for Targeting Structural Variants Genome-wide in Plasma Cell-free DNA
Murata, M. M.; Igari, F.; Urbanowicz, R.; Mouakkad, L.; Kim, S.; Chen, Z.; Di Vizio, D.; Posadas, E. M.; Giuliano, A. E.; Tanaka, H.
Show abstract
Interrogating gene mutations and aberrant DNA methylation in plasma cell-free DNA (cfDNA) has become increasingly common for monitoring tumor burden in cancer patients. However, no tests currently target chromosomal structural variants (SVs) genome-wide. Here, we report a simple molecular and sequencing workflow, Genome-wide Analysis of Palindrome Formation (GAPF-seq), to probe DNA palindromes, a type of SV that often demarcates gene amplification. Low-coverage next-generation sequencing of palindrome-enriched DNA uncovered skewed chromosomal distributions of high-coverage 1-kb bins (HCBs) in tumor DNA. When combined with traditional machine learning, GAPF-seq differentiated 39 breast tumors from matched control DNA with an Area Under the Curve (AUC) of 0.955. A proof-of-concept liquid biopsy study using cfDNA from 27 prostate cancer patients and 24 control individuals yielded an average AUC of 0.896. HCBs on the X chromosome emerged as a nearly decisive feature and were linked to androgen receptor gene amplification. As a simple and agnostic liquid biopsy approach, GAPF-seq could fill this technological gap, offering unique cancer-specific SV profiles.
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