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The evolutionary history of lethal metastatic prostate cancer

An Author Correction to this article was published on 29 July 2020

Abstract

Cancers emerge from an ongoing Darwinian evolutionary process, often leading to multiple competing subclones within a single primary tumour1,2,3,4. This evolutionary process culminates in the formation of metastases, which is the cause of 90% of cancer-related deaths5. However, despite its clinical importance, little is known about the principles governing the dissemination of cancer cells to distant organs. Although the hypothesis that each metastasis originates from a single tumour cell is generally supported6,7,8, recent studies using mouse models of cancer demonstrated the existence of polyclonal seeding from and interclonal cooperation between multiple subclones9,10. Here we sought definitive evidence for the existence of polyclonal seeding in human malignancy and to establish the clonal relationship among different metastases in the context of androgen-deprived metastatic prostate cancer. Using whole-genome sequencing, we characterized multiple metastases arising from prostate tumours in ten patients. Integrated analyses of subclonal architecture revealed the patterns of metastatic spread in unprecedented detail. Metastasis-to-metastasis spread was found to be common, either through de novo monoclonal seeding of daughter metastases or, in five cases, through the transfer of multiple tumour clones between metastatic sites. Lesions affecting tumour suppressor genes usually occur as single events, whereas mutations in genes involved in androgen receptor signalling commonly involve multiple, convergent events in different metastases. Our results elucidate in detail the complex patterns of metastatic spread and further our understanding of the development of resistance to androgen-deprivation therapy in prostate cancer.

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Figure 1: n-D Dirichlet process clustering reveals widespread polyclonal seeding in A22.
Figure 2: Subclonal structure within 10 metastatic lethal prostate cancers.
Figure 3: Metastasis-to-metastasis seeding occurs either by a linear or by a branching pattern of spread.
Figure 4: Drivers of tumorigenesis are truncal while drivers of castration resistance are convergent.

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Acknowledgements

We thank the men and their families who participated in the PELICAN (Project to ELIminate lethal CANcer) integrated clinical-molecular autopsy study of prostate cancer. We thank M. A. Eisenberger, M. A. Carducci, V. Sinibaldi, T. B. Smyth and G. J. Mamo for oncologic and urologic clinical support; T. Tolonen for uropathology support; P. Martikainen, M. Vaha-Jaakkola, M. Vakkuri, K. Leinonen, T. Vormisto, M. Rohrer, A. Koskenalho, J. Silander, T. Lahtinen, C. Hardy, G. Hutchins, B. Crain, S. Jhavar, C. Talbot, L. Kasch, M. Penno, A. Warner and Y. Golubeva for technical support; and M. R. Stratton and P. A. Futreal for their comments on the manuscript. This is an ICGC Prostate Cancer study funded by: Cancer Research UK (2011-present); NIH NCI Intramural Program (2013-2014); Academy of Finland (2011-present); Cancer Society of Finland (2013-present); PELICAN Autopsy Study family members and friends (1998-2004); John and Kathe Dyson (2000); US National Cancer Institute CA92234 (2000-2005); American Cancer Society (1998-2000); Johns Hopkins University Department of Pathology (1997-2011); Women's Board of Johns Hopkins Hospital (1998); The Grove Foundation (1998); Association for the Cure of Cancer of the Prostate (1994-1998); American Foundation for Urologic Disease (1991-1994); Bob Champion Cancer Trust (2013-present); Research Foundation – Flanders (FWO) [FWO-G.0687.12] (2012-present). E.P. is a European Hematology Association Research Fellow.

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Contributions

D.E.N., C.S.C., R.A.E., U.M. and G.S.B. co-designed and co-directed the project and are Senior Principal Investigators of the Cancer Research UK funded ICGC Prostate Cancer Project. G.G., P.V.L., T.V., D.C.W., U.M. and G.S.B. designed the study and co-wrote the paper. G.G., P.V.L., B.K., L.B.A., J.M.C.T., K.J.D., M.A. and D.C.W. carried out bioinformatic analyses. K.K., V.G., C.L. and S.O.'M. carried out laboratory analysis. E.P., D.S.B., H.C.W., C.S.C., P.J.C. and all authors edited the paper. D.S.B., Z.K.-J., H.C.W., G.G. and D.C.W. coordinated the study. H.M.L.K. and G.H. performed clinical data analysis and curation. W.I. facilitated the initial development of the autopsy study. M.R.E.-B. provided pathology support. M.N. provided bioinformatics support and supported project development. The full ICGC Prostate Group created and maintains overall study direction. For this work the primary affiliation of C.S.C. is The Institute of Cancer Research.

Corresponding authors

Correspondence to Ultan McDermott, David C. Wedge or G. Steven Bova.

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The authors declare no competing financial interests.

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A list of participants and their affiliations appears in the Supplementary Information.

Extended data figures and tables

Extended Data Figure 1 Variants identified in 51 whole-genome sequenced samples from 10 patients.

ac, Number of insertion/deletions (a), high-confidence substitutions (b) and chromosomal rearrangements (c) are plotted across all the samples from the 10 patients that had their whole genome sequenced.

Extended Data Figure 2 Validation of the subclonal hierarchies in A22.

The primary means of validation was a deep sequencing validation experiment that included selected substitutions and indels from each sample, as described in Extended Data Table 2 and Supplementary Information section 2b. In addition, indels and rearrangements identified in WGS represent data sets orthogonal to the substitution data from which the subclones were identified. The subsets of samples in which validated substitutions, indels and rearrangements are found correlate strongly with the subclonal clusters identified from the clustering of substitutions from WGS, providing support for the existence of these subclones. a, b, For each patient, hierarchical clustering of the variant allele fraction (VAF) was performed separately for substitutions (a) and indels (b). VAFs are represented as a heat map with deeper shades of red indicating a higher proportion of reads reporting the mutant allele. Above each heat map, mutations are colour-coded according to the subclone they were assigned to by Dirichlet process clustering of WGS data in the case of substitutions or by VAF for indels. Indels that could not be assigned to any cluster are annotated with black. For A22, additional samples not subject to WGS were included in the validation experiment. c, For these patients the phylogenetic tree from Fig. 2 was modified to incorporate these additional samples. df, Number of substitutions assigned to each subclone (d) and numbers of indels (e) and rearrangements (f) present in different subsets of samples are plotted as bar charts. g, VAFs from whole-genome sequencing and validation data, plotted as scatter plots, are very highly correlated. h, Subclone colour key.

Extended Data Figure 3 Validation of the subclonal hierarchies in A31 and A32.

Validation strategy as described in Extended Data Fig. 2. For A31 and A32, hierarchical clustering of the VAF was performed separately for substitutions (a) and (j) and indels (b) and (k). Heat maps are annotated as described in Extended Data Fig. 2. Additional samples for A31 and A32 are incorporated into the phylogenetic trees (c) and (l). Subclones for A31 CD and A32 CE are annotated in the corresponding 2d-DP plots (d) and (m). Numbers of substitutions in WGS data assigned to each subclone are plotted in (e) and (n). VAFs from WGS and validation data, plotted as scatter plots (f) and (o), are very highly correlated. Number of indels (g) and (p) and rearrangements (h) and (q) present in different subsets of samples are plotted as bar charts. Subclone Colour keys for A31 and A32 (i and r) respectively.

Extended Data Figure 4 Validation of the subclonal hierarchies in A24 and A34.

Validation strategy as described in Extended Data Fig. 2. For A24 and A34, hierarchical clustering of the VAF was performed separately for substitutions (a) and (i) and indels (b) and (j). Heatmaps are annotated as described in Extended Data Fig. 2. Indels that could not be assigned to any cluster (if any) are annotated with black. Additional samples for A24 and A34 are incorporated into the phylogenetic tree (c) and (k). The additional cluster in A24, supported by rearrangements only, is indicated by a light green branch in the tree. Numbers of substitutions in WGS data assigned to each subclone are plotted in (d) and (l). VAFs from WGS and validation data, plotted as scatter plots (e) and (m), are very highly correlated. Number of indels (f) and (n) and rearrangements (g) and (o) present in different subsets of samples are plotted as bar charts. Subclone Colour keys for A24 and A34 (h and p) respectively.

Extended Data Figure 5 Validation of the subclonal hierarchies in A10 and A29.

Validation strategy as described in Extended Data Fig. 2. For A10 and A29, hierarchical clustering of the VAF was performed separately for substitutions (a) and (h) and indels (b) and (i). Heat maps are annotated as described in Extended Data Fig. 2. Indels that could not be assigned to any cluster (if any) are annotated with black. Loci with depth <20X are coloured in light blue. The additional sample (D) for A29 is incorporated into the phylogenetic tree (j). Validation experiment for A10-E, the prostate sample, gave very low coverage (d). Subclones for A29-A and A29-C are annotated in the 2d-DP plot (k). Numbers of substitutions in WGS data assigned to each subclone are plotted in (c) and (l). VAFs from WGS and validation data, plotted as scatter plots (d) and (m), are very highly correlated. Number of indels (e) and (n) and rearrangements (f) and (o) present in different subsets of samples are plotted as bar charts. Subclone Colour keys for A10 and A29 (g and p) respectively.

Extended Data Figure 6 Validation of the subclonal hierarchies in A17 and A12.

Validation strategy as described in Extended Data Fig. 2. For A17 and A12, hierarchical clustering of the VAF was performed separately for substitutions (a) and (i) and indels (b) and (j). Heat maps are annotated as described in Extended Data Fig. 2. Mutations that could not be assigned to any cluster are annotated with black. For A12, the C-specific cluster that is not present in substitutions is shown in very light green. Subclones for A17 AD are annotated in the 2d-DP plot (c). Numbers of substitutions in WGS data assigned to each subclone are plotted in (d) and (l). VAFs from WGS and validation data, plotted as scatter plots (e) and (m), are very highly correlated. Number of indels (f) and (n) and rearrangements (g) and (o) present in different subsets of samples are plotted as bar charts. Additional samples for A12 are incorporated into the phylogenetic tree (k). Subclone Colour keys for A17 and A12 (h and p) respectively.

Extended Data Figure 7 Validation of the subclonal hierarchies in A21.

Validation strategy as described in Extended Data Fig. 2. Hierarchical clustering of the VAF was performed separately for substitutions (a) and indels (b). Heat maps are annotated as described in Extended Data Fig. 2. Loci with depth <20X is coloured in light blue. Additional samples L, N, and Q from FFPE material had low coverage. The only loci present in these samples were all truncal. These samples are incorporated into the phylogenetic tree (c). Numbers of substitutions in WGS data assigned to each subclone are plotted in (d). Number of indels (e) and rearrangements (f) present in different subsets of samples are plotted as bar charts. VAFs from WGS and validation data, plotted as scatter plots (g), are very highly correlated. Subclone Colour key (h).

Extended Data Figure 8 Convergent evolution at the AR locus.

Rearrangements and copy number segments in the vicinity of the AR locus are shown for A31, A21, A29 and A10. (a) In A31, there are three different AR amplification events. In orange is a tandem duplication whose existence is supported by tumour reads in ADEF but not C. However, PCR-gel validation confirms its existence in the prostate sample C—the faintness of the band suggesting that this rearrangement is present subclonally in A31-C—as well as the prostate sample I, which was not subject to WGS. One tandem duplication is common to both prostate samples (shown in green) while the other is specific to sample C (dark pink). (b) In A21, there are four different sets of complex rearrangements, one shared by ACDEGH and the remainder specific to F, I and J. (c) Rearrangements in the vicinity of the AR locus and inter-mutation distances for A29 plotted on a log10 scale for lesions specific to the metastasis (left) and specific to the prostate (middle). Each sample has a different set of complex rearrangements, which are associated with distinct kataegis events. (d) In A10, one tandem duplication is shared by CD while four others are each specific to a single sample.

Extended Data Table 1 Validation of mutation calling
Extended Data Table 2 Copy number genes

Supplementary information

Supplementary Information

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Supplementary Tables

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Supplementary Data

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Gundem, G., Van Loo, P., Kremeyer, B. et al. The evolutionary history of lethal metastatic prostate cancer. Nature 520, 353–357 (2015). https://doi.org/10.1038/nature14347

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