Cancers emerge from an on-going Darwinian evolutionary process, often leading to multiple competing subclones within a single primary tumour1-4. 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 supported6-8, recent studies using mouse models of cancer demonstrated the existence of polyclonal seeding from and inter-clonal cooperation between multiple subclones9,10. In this study, 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 characterised 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.
The pan-cancer analysis of whole genomes The expansion of whole-genome sequencing studies from individual ICGC and TCGA working groups presented the opportunity to undertake a meta-analysis of genomic features across tumour types. To achieve this, the PCAWG Consortium was established. A Technical Working Group implemented the informatics analyses by aggregating the raw sequencing data from different working groups that studied individual tumour types, aligning the sequences to the human genome and delivering a set of high-quality somatic mutation calls for downstream analysis (Extended Data Fig. 1). Given the recent meta-analysis
This WHO/ISUP system is an attempt to develop as broad a consensus as possible in the classification of urothelial neoplasms, building upon earlier works and classification systems. It is meant to serve as a springboard for future studies that will help refine this classification, thus enabling us to provide better correlation of these lesions with their biologic behavior using uniform terminology.
SUMMARY Background Optimal management of clinically localized prostate cancer presents unique challenges because of its highly variable and often indolent natural history. To predict disease aggressiveness, clinicians combine clinical parameters to create prognostic models, but the accuracy of current models is very limited. There is significant clinical need for biomarkers that improve our ability to predict disease outcome. Methods Using quantitative RT-PCR on RNA from formalin fixed paraffin-embedded tumour samples, we measured the expression level of 31 genes involved in cell cycle progression (CCP genes), created a predefined score and evaluated its ability to predict disease outcome. The signature was tested in a retrospective cohort of 366 patients from the U.S. who had undergone radical prostatectomy, and in a retrospective cohort of 337 men with clinically localized prostate cancer diagnosed by a transurethral resection (TURP) in the UK and managed conservatively. Findings The cell cycle progression signature was a highly significant predictor of outcome in both cohorts. After prostatectomy the CCP score predicted biochemical recurrence in univariate (Hazard ratio (HR) for a one unit change in CCP (doubling) = 1.89; 95% CI (1.54, 2.31) χ2 = 34·0, 1df, p = 5·6 × 10−9) and multivariate analysis (HR = 1.74; 95% CI (1.39, 2.17) χ2 = 21·65, 1df, p = 3·3 ×10−6). The CCP score and PSA were the dominant variables in the best predictive model and were much more significant than any other clinical measure. In the TURP cohort, the CCP score was the dominant variable for predicting death from prostate cancer in both univariate (HR= 2.92; 95% CI (2.38, 3.57) χ2 = 92·7, 1df, p = 6.1 × 10−22) and multivariate analyses (χ2 = 42·2, p = 8·2 × 10−11), where it was much stronger than all other prognostic factors. In no case 4 was there significant evidence for heterogeneity in the hazard ratio for the CCP score across any clinical parameter. Interpretation The CCP score provides a substantial amount of independent information about the risk of recurrence after radical prostatectomy and the risk of death in conservatively managed prostate cancer diagnosed by TURP. Taken together, these studies provide strong evidence that the CCP score is a highly robust prognostic marker which, after additional validation, could have a central role in determining appropriate treatment for prostate cancer patients. Funding Study funded by Cancer Research UK, the Orchid Appeal, US National Institutes of Health (SPORE CA92629), and the Koch Foundation. Molecular testing performed at Myriad Genetics.
Long interspersed nuclear element–1 (L1) retrotransposons are mobile repetitive elements that are abundant in the human genome. L1 elements propagate through RNA intermediates. In the germ line, neighboring, nonrepetitive sequences are occasionally mobilized by the L1 machinery, a process called 3′ transduction. Because 3′ transductions are potentially mutagenic, we explored the extent to which they occur somatically during tumorigenesis. Studying cancer genomes from 244 patients, we found that tumors from 53% of the patients had somatic retrotranspositions, of which 24% were 3′ transductions. Fingerprinting of donor L1s revealed that a handful of source L1 elements in a tumor can spawn from tens to hundreds of 3′ transductions, which can themselves seed further retrotranspositions. The activity of individual L1 elements fluctuated during tumor evolution and correlated with L1 promoter hypomethylation. The 3′ transductions disseminated genes, exons, and regulatory elements to new locations, most often to heterochromatic regions of the genome.
Recent sequencing studies have extensively explored the somatic alterations present in the nuclear genomes of cancers. Although mitochondria control energy metabolism and apoptosis, the origins and impact of cancer-associated mutations in mtDNA are unclear. In this study, we analyzed somatic alterations in mtDNA from 1675 tumors. We identified 1907 somatic substitutions, which exhibited dramatic replicative strand bias, predominantly C > T and A > G on the mitochondrial heavy strand. This strand-asymmetric signature differs from those found in nuclear cancer genomes but matches the inferred germline process shaping primate mtDNA sequence content. A number of mtDNA mutations showed considerable heterogeneity across tumor types. Missense mutations were selectively neutral and often gradually drifted towards homoplasmy over time. In contrast, mutations resulting in protein truncation undergo negative selection and were almost exclusively heteroplasmic. Our findings indicate that the endogenous mutational mechanism has far greater impact than any other external mutagens in mitochondria and is fundamentally linked to mtDNA replication.DOI: http://dx.doi.org/10.7554/eLife.02935.001
New predictive markers for managing prostate cancer are urgently required because of the highly variable natural history of this disease. At the time of diagnosis, Gleason score provides the gold standard for assessing the aggressiveness of prostate cancer. However, the recent discovery of TMPRSS2 fusions to the ERG gene in prostate cancer raises the possibility of using alterations at the ERG locus as additional mechanism-based prognostic indicators. Fluorescence in situ hybridization (FISH) assays were used to assess ERG gene status in a cohort of 445 prostate cancers from patients who had been conservatively managed. The FISH assays detected separation of 5 0 (labelled green) and 3 0 (labelled red) ERG sequences, which is a consequence of the TMPRSS2-ERG fusion, and additionally identify interstitial deletion of genomic sequences between the tandemly located TMPRSS2 and ERG gene sequences on chromosome 21. Cancers lacking ERG alterations exhibited favourable cause-specific survival (90% survival at 8 years). We identify a novel category of prostate cancers, characterized by duplication of the fusion of TMPRSS2 to ERG sequences together with interstitial deletion of sequences 5 0 to ERG (called '2 þ Edel'), which by comparison exhibited extremely poor cause-specific survival (hazard ratio ¼ 6.10, 95% confidence ratio ¼ 3.33-11.15, Po0.001, 25% survival at 8 years). In multivariate analysis, '2 þ Edel' provided significant prognostic information (P ¼ 0.003) in addition to that provided by Gleason score and prostate-specific antigen level at diagnosis. Other individual categories of ERG alteration were associated with intermediate or good prognosis. We conclude that determination of ERG gene status, including duplication of the fusion of TMPRSS2 to ERG sequences in 2 þ Edel, allows stratification of prostate cancer into distinct survival categories.
Whole genome DNA sequencing was used to decrypt the phylogeny of multiple samples from distinct areas of cancer and morphologically normal tissue taken from the prostates of three men. Mutations were present at high levels in morphologically normal tissue distant from the cancer reflecting clonal expansions, and the underlying mutational processes at work in morphologically normal tissue were also at work in cancer. Our observations demonstrate the existence of on-going abnormal mutational processes, consistent with field-effects, underlying carcinogenesis. This mechanism gives rise to extensive branching evolution and cancer clone mixing as exemplified by the coexistence of multiple cancer lineages harboring distinct ERG fusions within a single cancer nodule. Subsets of mutations were shared either by morphologically normal and malignant tissue or between different ERG-lineages, indicating earlier or separate clonal cell expansions. Our observations inform on the origin of multifocal disease and have implications for prostate cancer therapy in individual cases.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
334 Leonard St
Brooklyn, NY 11211
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.