Abstract A08: Extensive subclonal mutations in human colorectal cancers detected by Duplex Sequencing

Abstract

Abstract The accumulation of somatic mutations is a defining hallmark of cancer. The genomes of solid tumors contain thousands of mutations that are present in most or all of the malignant cells in that tumor. In addition to these clonal mutations, subclonal mutations, those occurring only in a fraction of malignant cells, likely contribute to the phenotypic and morphologic heterogeneity of cancer cells within a tumor. The extent of subclonal mutations in cancer, however, has been difficult to quantify, as the high error rate of next-generation sequencing precludes reliable detection of mutations present in fewer than 5% of cells. Here, we apply the highly accurate Duplex Sequencing methodology to quantify the extent of subclonal mutations in colorectal cancer (CRC) and paired normal mucosa. By sequencing known CRC driver and non-driver genes, we find that colorectal cancers without known DNA repair deficits harbor an extensive complement of subclonal mutations, in addition to the large number of clonal mutations previously identified. We show that normal colonic mucosa also accumulates substantial numbers of subclonal mutations in an age-dependent manner. The frequency of tumor-associated subclonal mutations, however, does not correlate with age, and has a spectrum distinct from that seen in normal tissue, indicating different mechanisms of mutation accumulation are operative in normal and tumor tissue. The frequency of tumor cells harboring unique subclonal mutations is so high that it is likely that every possible neutral somatic point mutation is present by the time a tumor is clinically detectable. We propose that these subclonal mutations likely accumulate in a series of punctuated bursts, making it highly likely that resistant subclones will emerge during chemotherapy. Citation Format: Edward John Paul Fox, Michael W. Schmitt, Kate S. Reid-Bayliss, Robert A. Beckman, Lawrence A. Loeb. Extensive subclonal mutations in human colorectal cancers detected by Duplex Sequencing. [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer: From Initiation to Outcomes; 2016 Sep 17-20; Tampa, FL. Philadelphia (PA): AACR; Cancer Res 2017;77(3 Suppl):Abstract nr A08.