Funding information This study is supported by the AACI Fellowship for Translational Cancer Research and DOD Prostate Cancer Research Program PRTA (DVW) and the Chicago Cancer Genomes Project (KPW).
Low-grade prostate cancer diverges early from high grade and metastatic disease
Article first published online: 27 AUG 2014
© 2014 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
Volume 105, Issue 8, pages 1079–1085, August 2014
How to Cite
Cancer Sci 105 (2014) 1079–1085
- Issue published online: 27 AUG 2014
- Article first published online: 27 AUG 2014
- Accepted manuscript online: 31 MAY 2014 05:12AM EST
- Manuscript Accepted: 23 MAY 2014
- Manuscript Revised: 16 MAY 2014
- Manuscript Received: 8 JAN 2014
- genetic heterogeneity;
- multiple primary neoplasms;
- prostatic neoplasms
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.