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Spatial genomic heterogeneity within localized, multifocal prostate cancer

Abstract

Herein we provide a detailed molecular analysis of the spatial heterogeneity of clinically localized, multifocal prostate cancer to delineate new oncogenes or tumor suppressors. We initially determined the copy number aberration (CNA) profiles of 74 patients with index tumors of Gleason score 7. Of these, 5 patients were subjected to whole-genome sequencing using DNA quantities achievable in diagnostic biopsies, with detailed spatial sampling of 23 distinct tumor regions to assess intraprostatic heterogeneity in focal genomics. Multifocal tumors are highly heterogeneous for single-nucleotide variants (SNVs), CNAs and genomic rearrangements. We identified and validated a new recurrent amplification of MYCL, which is associated with TP53 deletion and unique profiles of DNA damage and transcriptional dysregulation. Moreover, we demonstrate divergent tumor evolution in multifocal cancer and, in some cases, tumors of independent clonal origin. These data represent the first systematic relation of intraprostatic genomic heterogeneity to predicted clinical outcome and inform the development of novel biomarkers that reflect individual prognosis.

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Figure 1: The landscape of Gleason score 7 prostate cancer.
Figure 2: Recurrent MYCL mutations.
Figure 3: Structural variations in Gleason score 7 prostate cancer.
Figure 4: SNVs in Gleason score 7 prostate cancer.
Figure 5: Clinical relevance of intratumoral heterogeneity.
Figure 6: Evidence of multiclonal prostate cancer.

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Acknowledgements

The authors thank all members of the Boutros and Bristow laboratories for helpful suggestions. This study was conducted with the support of Movember funds through Prostate Cancer Canada and with the additional support of the Ontario Institute for Cancer Research, funded by the government of Ontario. This study was conducted with the support of the Ontario Institute for Cancer Research to P.C.B. through funding provided by the government of Ontario. This work has been funded by a Doctoral Fellowship from the Canadian Institutes of Health Research (CIHR) to E.L. The authors gratefully thank the Princess Margaret Cancer Centre Foundation and the Radiation Medicine Program Academic Enrichment Fund for support (to R.G.B.). R.G.B. is a recipient of a Canadian Cancer Society Research Scientist Award. This work was supported by Prostate Cancer Canada and is proudly funded by the Movember Foundation, grant RS2014-01. P.C.B. was supported by a Terry Fox Research Institute New Investigator Award and a CIHR New Investigator Award. This project was supported by Genome Canada through a Large-Scale Applied Project contract to P.C.B., S.P.S. and R. Morin.

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Contributions

Sample preparation and molecular biology: M.F., A. Meng, T.C., M.S., C.L.H., J.J., L.T., N.B., A.W., J.D.W., T.T.S., G.Z., A.D.P., A. Berlin, S.D.P. and A. Brown. Pathology analyses: D.T., B.T. and T.v.d.K. Statistics and bioinformatics: P.C.B., N.J.H., R.d.B., E.L., P.H.H.-Y., A. McPherson, V.Y.S., A.Z., N.S.F., J.L., Y.-J.S., J.W., T.A.B., T.T.S., C.P., F.N., X.L., K.C.C., J.S., M.A.C.-S.-Y., F.Y., R.E.D., L.C.C., G.M.C., E.J., M.H.W.S., H.C., S.K.G., J.H., A.D., M.P., C.F., F.H. and D.W. Initiation of the project: P.C.B., M.F., C.C., T.J.H., J.D.M., T.v.d.K., R.E., D.N. and R.G.B. Supervision of research: P.C.B., M.F., T.A.B., P.L., L.B.M., B.T., C.C.C., L.D.S., N.F., S.P.S., C.S., T.J.H., L.B.M., T.v.d.K. and R.G.B. Writing of the first draft of the manuscript: P.C.B. Writing and editing the revised manuscript: M.F., P.C.B. and R.G.B. All authors approved the manuscript.

Corresponding authors

Correspondence to Paul C Boutros or Robert G Bristow.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–24. (PDF 3665 kb)

Supplementary Table 1

GeneWise CNA profiles for all patients. For each sample that received OncoScan SNP array interrogation of copy number aberrations (n = 75), this table gives for each gene whether it is amplified (1), deleted (–1) or unchanged (0). Additionally, each gene is annotated with the Ensembl gene and transcript IDs, the chromosome, the starting and ending base pairs, and the gene symbols from both HUGO and HGNC. (XLS 26652 kb)

Supplementary Table 2

Regions of recurrent CNAs. GISTIC analysis of copy number array data identified regions of recurrent copy number alteration (rows). The columns give the name for each region, its chromosomal location (both arm and precise coordinates and probes involved) and statistical support (q values and amplitude estimates). For each patient, a coding of 0 (no event) versus 1/2 (event) is given. (XLS 80 kb)

Supplementary Table 3

GISTIC genes. Genes identified in recurrent GISTIC peaks are listed, along with their individual locations, Cytobands, q values and gene symbols are given. (XLS 709 kb)

Supplementary Table 4

Validation of MYCL1 and MYC amplification. We performed quantitative PCR using probes directed to the putatively amplified regions of either MYCL1 or MYC, using a probe directed against RPPH1 (RNase P, component H) as a control gene. Overall validation rates are shown. (XLS 24 kb)

Supplementary Table 5

Summary of flanking qPCR. We performed qPCR analysis using the indicated probes, which flank the MYCL1 locus (which encompasses the probe shown in yellow) over a region of ~2 Mb. NCI-H510A non–small cell lung cancer cells were used as a positive control for MYCL1 amplification, as these cells contain a ~2.9-Mb amplification of chromosome 1p, including the entire region covered by these probes. PC3 prostate cancer cells were used as a negative control. (XLS 22 kb)

Supplementary Table 6

Genomic instability associated with MYC family gain. For each MYC family member, we assessed the mean, median and standard deviation of PGA and the total number of CNAs detected. (XLS 19 kb)

Supplementary Table 7

Differential CNAs associated with MYCL1 amplification. For each gene, we compared its frequency of CNA in MYCL1-amplified tumors and in MYC-amplified tumors. This table shows gene ID (both Ensembl gene and transcript) along with gene symbols and genomic location. It lists the frequency of occurrence in MYCL1-amplified tumors, the frequency of occurrence in MYC-amplified tumors, the P value from a proportion test and the multiple testing–adjusted q value. (XLS 1686 kb)

Supplementary Table 8

MYCL1-associated transcriptome dysregulation. Comparison of tumors harboring MYCL1 amplifications (n = 8) and those without (n = 16) identified 294 genes showing differential abundance (q < 0.05, Bayesian-moderated t test; Online Methods). A list of gene symbols for these genes is given. (XLS 37 kb)

Supplementary Table 9

Patient annotation. Key clinical information about each patient, including age at time of treatment, diagnostic Gleason score, clinical T category, biochemical recurrence status and ERG fusion status. (XLS 37 kb)

Supplementary Table 10

Tumor cellularity analysis. For each tumor sample subjected to whole-genome sequencing, tumor cellularity was assessed both by a urological pathologist (CellularityPath) and the Qpure algorithm executed on SNP microarray data (CellularityQpure). (XLS 26 kb)

Supplementary Table 11

Sequencing statistics. Overview of whole-genome sequencing. For each tumor and region, the collapsed coverage values for blood (replicated for each region) and tumor are given, along with the input material type for the tumor sequencing and the numbers of SNVs (of various functional categories), CNAs and genomic rearrangements. The number of somatic events in FFPE samples is elevated, likely owing to artifacts of the FFPE procedure. (XLS 25 kb)

Supplementary Table 12

All genomic rearrangements. All detected genomic rearrangements, along with their chromosomal positions and a categorization of the rearrangement type, genes involved and the score output from the deStruct algorithm. (XLS 275 kb)

Supplementary Table 13

Functional SNVs. All detected functional somatic SNVs, along with their genomic locations, base change and status in each sequenced tumor region. (XLS 398 kb)

Supplementary Table 14

WGA effects. Comparison of samples with and without WGA amplification based on the identity of SNPs detected by the OncoScan microarray platform. (XLS 17 kb)

Supplementary Table 15

Pathway analysis of MYCL1-associated mRNA differences. The GOEAST tool was used to assess functional enrichment among genes showing different mRNA abundance in MYCL1-amplified and MYCL1-neutral tumors. (XLS 80 kb)

Supplementary Table 16

Effects of WGA on SNP array performance. Comparison of concordance of SNP calls between matched WGA and non-WGA specimens on the OncoScan array platform. (XLS 30 kb)

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Boutros, P., Fraser, M., Harding, N. et al. Spatial genomic heterogeneity within localized, multifocal prostate cancer. Nat Genet 47, 736–745 (2015). https://doi.org/10.1038/ng.3315

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