Low-grade prostate cancer diverges early from high grade and metastatic disease

Understanding the developmental relationship between indolent and aggressive tumors is central to understanding disease progression and making treatment decisions. For example, most men diagnosed with prostate cancer have clinically indolent disease and die from other causes. Overtreatment of prostate cancer remains a concern. Here we use laser microdissection followed by exome sequencing of low- and high-grade prostate cancer foci from four subjects, and metastatic disease from two of those subjects, to evaluate the molecular relationship of coincident cancer foci. Seventy of 79 (87%) high-confidence somatic mutations in low-grade disease were private to low-grade foci. In contrast, high-grade foci and metastases harbored many of the same mutations. In cases in which there was a metastatic focus, 15 of 80 (19%) high-confidence somatic mutations in high-grade foci were private. Seven of the 80 (9%) were shared with low-grade foci and 65 (82%) were shared with metastatic foci. Notably, mutations in cancer-associated genes and the p53 signaling pathway were found exclusively in high-grade foci and metastases. The pattern of mutations is consistent with early divergence between low- and high-grade foci and late divergence between high-grade foci and metastases. These data provide insights into the development of high-grade and metastatic prostate cancer. The overwhelming majority of somatic mutations in coincident low and high grade prostate cancer foci are private, suggesting these foci diverge early from a common progenitor. In contrast, synchronous metastatic disease contains few mutations not already present in high grade prostate cancer foci.