Platinum Priority – Collaborative Review – From Lab to ClinicEditorial by Mattias Höglund on pp. 738–739 of this issueIntratumour Heterogeneity in Urologic Cancers: From Molecular Evidence to Clinical Implications
Introduction
Intertumour heterogeneity of genetic driver aberrations has been identified in each of the most common urologic cancer types [1], [2], [3]. This is thought to be a major reason for the variability of outcomes even between patients with tumours of the same histologic type, stage, and grade. These and similar observations in other cancer types have led to the concept of personalised cancer therapy that aims to identify the optimal treatment for each individual patient based on molecular or pathologic biomarkers. Personalised therapy has successfully improved therapeutic outcomes and eliminated side effects from unnecessary treatment in some cancer types, for example in non–small cell lung cancer, where the effectiveness of epidermal growth factor receptor (EGFR) inhibitors is restricted to patients whose tumours harbour an activating EGFR mutation [4]. However, attempts to personalise therapy in urologic cancers through prognostic or predictive biomarkers have largely been unsuccessful to date.
The molecular characteristics of tumours can also vary within individual patients. Whereas intertumour heterogeneity provides a theoretical basis for treatment personalisation, intratumour heterogeneity (ITH) can complicate the precise molecular profiling and the identification of the optimal therapy for cancers harbouring several functionally distinct tumour subclones. This review summarises current insights into ITH and its potential implications for personalised cancer medicine approaches in the most common urologic cancers. It also outlines novel approaches to address ITH in the clinic.
Most cancers originate from a single cell that has been transformed through a small number of cancer driver mutations [5]. However, additional mutations can be acquired during the subsequent expansion of the cancer population, leading to genetic heterogeneity between the cells of a tumour. Although most new mutations are likely to be neutral (passenger mutations) or deleterious, advantageous mutations (driver mutations) occasionally occur and can lead to the expansion of intratumoural subclones with new functional characteristics. The heterogeneous nature of tumours was recognised by Nowell, who described cancer as an evolutionary process that can readily adapt to new environments such as those encountered during cancer drug therapy [6]. Genomic instability frequently occurs in malignant tumours [7] and can increase the genetic variability of cancer cell populations. Thus aggressive or drug-resistant tumour subclones may develop more rapidly in genomically unstable cancers.
This review focuses on genetic ITH in urologic cancers. However, ITH can also result from nongenetic molecular alterations [8]. Epigenetic DNA methylation can promote evolutionary adaptation similar to genetic alterations. Different functional states such as quiescent and proliferative states and cancer stem cell differentiation but also the heterogeneity of the tumour microenvironment add additional layers of complexity that may have an impact on therapeutic success.
Early studies into genetic ITH mainly relied on conventional Sanger DNA sequencing of spatially or temporally separated tumour samples. Many heterogeneous genetic alterations may have remained undetected with this low-throughput technology that restricts analysis to a small number of genes and lacks sensitivity for the detection of subclonal mutations present at low frequency. Today, next-generation sequencing (NGS) technologies permit nucleotide resolution analysis of all protein-coding DNA regions (exome sequencing) or of the entire genome. Through deeper NGS coverage, the subclonal mutations present in a small percentage of cells can be detected, and the subclonal structures present within a sample can be inferred [9]. Thus NGS technology has dramatically increased the ability to detect and characterise ITH (Fig. 1A and 1B). Emerging sequencing technologies will provide an even clearer picture of the heterogeneity at the single-cell level [10], [11].
Thus sequencing technology is no longer a limiting factor for the study of ITH. The new challenge is to develop sampling technologies to analyse somatic genetic alterations across different primary tumour regions and associated metastases and the dynamic changes of cancer genomes over time.
NGS applied to circulating tumour cells (CTCs) [12] or circulating cell-free DNA (cfDNA) from tumour [13] has shown that cancer-specific genomic alterations can be detected and tracked in the blood of cancer patients. These minimally invasive technologies may circumvent the limited availability of tumour samples, but further work will be necessary to reveal whether sufficient CTCs or cfDNA can be derived from most patients with a specific tumour type, whether these technologies are sufficiently sensitive for the analysis of early stage disease, and whether the clinically relevant subclones in heterogeneous cancers are represented.
Section snippets
Evidence acquisition
We identified publications in the English language assessing ITH in clear cell renal cell carcinoma (ccRCC), adenocarcinoma of the prostate (PCa), and urothelial cell carcinoma (UCC) of the bladder through literature searches in PubMed and Google Scholar. Key studies, with a particular emphasis on those applying genomewide analyses, were included in this expert review.
Spatial separation of subclones and driver mutation heterogeneity
The most common histologic subtype of kidney cancer is ccRCC. These tumours can display extensive morphologic heterogeneity, with low- and high-grade components frequently coexisting in the same tumour. ITH was studied in ccRCCs through exome sequencing of multiple regions from each of 10 stage T2–T4 primary tumours and of associated metastases in a subset of cases [14]. Each tumour was of monoclonal origin based on the ubiquitous detection of several somatic mutations and DNA copy number
Conclusions
ITH with spatially and temporally separated cancer subclones has been identified in all three major urologic tumour types. Heterogeneity of driver aberrations and prognostic and predictive markers strongly suggests the presence of functional differences between individual tumour subclones. Multiple metastases in one PCa and one ccRCC case derived from a single subclone within their respective primary tumours demonstrated that individual subclones may dominate the disease outcome. In both cases,
References (54)
- et al.
The life history of 21 breast cancers
Cell
(2012) On the origin of syn- and metachronous urothelial carcinomas
Eur Urol
(2007)- et al.
Molecular evolution and intratumor heterogeneity by topographic compartments in muscle-invasive transitional cell carcinoma of the urinary bladder
Lab Invest
(2000) - et al.
International variation in prostate cancer incidence and mortality rates
Eur Urol
(2012) - et al.
Punctuated evolution of prostate cancer genomes
Cell
(2013) - et al.
Exome sequencing of prostate cancer supports the hypothesis of independent tumour origins
Eur Urol
(2013) - et al.
TMPRSS2-ERG fusion heterogeneity in multifocal prostate cancer: clinical and biologic implications
Urology
(2007) - et al.
PTEN losses exhibit heterogeneity in multifocal prostatic adenocarcinoma and are associated with higher Gleason grade
Mod Pathol
(2013) - et al.
Phenotypic heterogeneity of end-stage prostate carcinoma metastatic to bone
Hum Pathol
(2003) - et al.
The lethal clone in prostate cancer: redefining the index
Eur Urol
(2014)
The genomic complexity of primary human prostate cancer
Nature
Comprehensive molecular characterization of clear cell renal cell carcinoma
Nature
Recurrent inactivation of STAG2 in bladder cancer is not associated with aneuploidy
Nat Genet
Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma
N Engl J Med
Clonal origin of human tumors
Ann Rev Med
The clonal evolution of tumor cell populations
Science
The causes and consequences of genetic heterogeneity in cancer evolution
Nature
Intra-tumour heterogeneity: a looking glass for cancer?
Nat Rev Cancer
Single-cell paired-end genome sequencing reveals structural variation per cell cycle
Nucleic Acids Res
Genome-wide detection of single-nucleotide and copy-number variations of a single human cell
Science
Complex tumor genomes inferred from single circulating tumor cells by array-CGH and next-generation sequencing
Cancer Res
Non-invasive analysis of acquired resistance to cancer therapy by sequencing of plasma DNA
Nature
Genomic architecture and evolution of clear cell renal cell carcinomas defined by multiregion sequencing
Nat Genet
Parallel evolution of tumour subclones mimics diversity between tumours
J Pathol
Prognostic relevance of the mTOR pathway in renal cell carcinoma: implications for molecular patient selection for targeted therapy
Cancer
Molecular stratification of clear cell renal cell carcinoma by consensus clustering reveals distinct subtypes and survival patterns
Genes Cancer
Intratumor heterogeneity and branched evolution revealed by multiregion sequencing
N Engl J Med
Cited by (96)
SOX2 function in cancers: Association with growth, invasion, stemness and therapy response
2022, Biomedicine and PharmacotherapyCoordinated AR and microRNA regulation in prostate cancer
2020, Asian Journal of UrologyCardiovascular mortality by cancer risk stratification in patients with localized prostate cancer: a SEER-based study
2023, Frontiers in Cardiovascular Medicine