Multiregion analysis demonstrates multiple clinically significant subclonal alterations within index foci of localized prostate cancer

Authors

• DJ VanderWeele
• R Finney
• K Katayama
• M Gillard
• G Paner
• S Imoto
• R Yamaguchi
• D Wheeler
• M Cam
• K Maejima
• A Sasaki-Oku
• K Nakano
• H Tanaka
• A Pontier
• D Grigoryev
• M Kubo
• M Ratain
• S Miyano
• H Nakagawa

Abstract

Metastatic, lethal prostate cancer is typically derived from a single index focus, and the intratumoral heterogeneity of individual index foci is not well characterized. We sought to evaluate the clonal relationships of separate regions of a single contiguous index focus using exome sequencing and copy number analysis. We studied ten cases of potentially lethal, localized prostate cancer, with up to nine separate regions sampled per index focus. Exome sequencing demonstrated branched evolution characterized by marked heterogeneity among regions sampled, with 91% mutations being subclonal. Early mutations included those in known prostate cancer driver genes, SPOP, FOXA1, TP53, and PTEN. Copy number analysis also demonstrated branched evolution, and multiple examples of convergent evolution were identified, both in non-cancer and known cancer genes. Mutation and copy number analysis demonstrated subclones are comingled within multiple regions, and within an individual region branch and trunk mutations can be found in subtotal cell fractions. Importantly, index foci contain multiple subclonal populations harboring biologically and clinically significant genetic alterations (average 11.5/case) known to occur in advanced disease, including genes in androgen receptor, cell cycle, PI3K, Ras/Raf, WNT, DNA repair, and chromatin pathways. These data suggest that it is difficult to identify clinically relevant subclones, and predictions regarding targets for future therapy should be made with caution. Our research supports a model whereby advanced disease emerges from enrichment of pre-existing subclones in response to therapeutic pressure.

Scientific Focus Area: Genetics and Genomics

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