Plasma-Derived Tumor DNA Analysis at Whole-Genome Resolution

Abstract

The last 2 years have witnessed an extraordinary change in our understanding of the somatic mutational landscape of solid tumors, driven by the impressive large-scale sequencing efforts from such groups as the Cancer Genome Atlas and the Cancer Genome Project. As is so often the case with such ambitious scientific endeavors, the complexities these efforts have revealed raise even greater questions for the future. These studies have exposed the scale of diversity in the mutational landscape among tumors of the same histopathologic subtype. For example, between 1 and 3 genes in high-grade serous ovarian cancer or triple-negative breast cancer are subject to somatic mutations in >10% of patients with the same histopathologic subtype of disease (1, 2). The remainder of the somatic mutational landscape is dominated by genes subject to mutations at much lower frequencies. Low-frequency but potentially targetable events challenge conventional approaches to personalized medicine, both in terms of the health-economic costs in developing therapeutics for such small numbers of patients and in terms of tumor screening to identify such low-frequency somatic events. Adding to this layer of complexity is the increasing evidence for profound heterogeneity in DNA copy number states, somatic mutational and ploidy profiles that may be distinguished within a single tumor sample (3–5) or between primary and metastatic sites (6–9). Indeed, such subclonal diversity is thought to contribute to adaptation for tumor growth at distant sites of disease (10). Increasing evidence suggests that the emergence of drug resistance in solid tumors may be predetermined by the presence of low-frequency heterogeneous tumor subclones harboring somatic mutations that confer resistance to the targeting anticancer agent (11). Finally, also emerging is clear evidence that …