Genomic and phenotypic heterogeneity in prostate cancer

Abstract

From a clinical, morphological and molecular perspective, prostate cancer is a heterogeneous disease. Primary prostate cancers are often multifocal, having topographically and morphologically distinct tumour foci. Sequencing studies have revealed that individual tumour foci can arise as clonally distinct lesions with no shared driver gene alterations. This finding demonstrates that multiple genomically and phenotypically distinct primary prostate cancers can be present in an individual patient. Lethal metastatic prostate cancer seems to arise from a single clone in the primary tumour but can exhibit subclonal heterogeneity at the genomic, epigenetic and phenotypic levels. Collectively, this complex heterogeneous constellation of molecular alterations poses obstacles for the diagnosis and treatment of prostate cancer. However, advances in our understanding of intra-tumoural heterogeneity and the development of novel technologies will allow us to navigate these challenges, refine approaches for translational research and ultimately improve patient care.

Fig. 1 |. Model of clonal progression of prostate cancer.

In the context of benign epithelial cells, which can harbour unique genomic alterations, precursor lesions can arise and progress into clonally and spatially distinct foci of invasive carcinoma. Within a given tumour focus, individual cells can acquire additional genomic driver changes, resulting in subclonal tumour cell populations. Subclones can further evolve, replace other tumour cell populations (clonal sweep) and disseminate to distant sites. Disseminated tumour cells can clonally expand, but systemic therapies can induce a major re-sculpting of the subclonal composition selecting for cells with intrinsic or adapted resistance mechanisms. Resistant subclones that pass through therapy-induced clonal bottlenecks contribute to disease recurrence and therapy failure.

Fig. 2 |. Visualizing clonal and subclonal heterogeneity in tumour tissues.

Genetically validated antibodies for ERG and PTEN can be used to highlight clonal and subclonal cancer ceLL populations in tissue sections. a | An ERG⁺ (brown nuclear stain) tumour that infiltrates between benign glands (highlighted by an intact basal ceLL Layer, red stain). Arrows show a benign gland. b | The tumour shows subclonal loss of PTEN (loss of cytoplasmic staining) in a subset of cancer glands (separated by the red dotted line). Intact basal cells are shown in red. Arrows show a benign gland.

Fig. 3 |. Multifocal prostate cancer.

Reconstruction and whole-mount cross-section of a radical prostatectomy specimen with two distinct tumour foci. Note that the larger tumour focus located in the left posterior prostate shows high-grade morphology and extraprostatic extension (Gleason score 5 + 4 = 9), whereas a smaller anterior tumour appears well differentiated (Gleason score 3 + 3 = 6).

Fig. 4 |. Morphological heterogeneity in mCRPC.

a | Adenocarcinoma with cribriform architecture. b | Adenocarcinoma with squamous differentiation. c | Carcinoid-like differentiation in a neuroendocrine-marker-positive carcinoma. d | Poorly differentiated carcinoma with pleomorphic giant cells. e | Small-cell carcinoma. f | High-grade carcinoma with discohesive cells. g | Hybrid lesion composed of prostatic adenocarcinoma (PAC) with cribriform morphology (left) and small-cell neuroendocrine prostate cancer (NEPC) (right). mCRPC, metastatic castration-resistant prostate cancer.

Fig. 5 |. Schematic of scenarios of clonal evolution of metastatic prostate cancer.

Initial presentation: primary prostate cancers often harbour more than one tumour clone. Distinct clones can have different metastatic potential. Although clone 1 and clone 3 can seed distant micro-metastases, clone 2 is restricted and cannot progress beyond the formation of nodal metastases. Biochemical recurrence: after surgical resection of the prostate, the expansion of micro-metastatic tumour deposits results in increased PSA levels. Note that at this stage, it is possible that more than one clone from the primary tumour can contribute to the pool of the distant micro-metastases. Although some clones expand and seed additional metastases (clone 1), other clones stay dormant or show minimal expansion (clone 3). Overt metastases: as the size of individual metastases increases, the subclonal compositions of the tumours broaden and additional metastases are seeded. Resistance to therapy: systemic therapy results in a re-sculpting of the clonal composition of distant metastases. Clone 3 and several subclonal lesions of clone 1 are effectively eliminated or greatly reduced in their size. A new subclone that arose from clone 1 is therapy resistant, expands and further disseminates. Individual subclones that arise in distinct metastases seed to other sites (inter-metastasis seeding), thereby contributing further to the inter-tumour and intra-tumour heterogeneity.