Peer-reviewed articles from 1999 to 2024 were sourced from PubMed and Google Scholar. During the review process, the following search terms were employed: “Tumour suppressor genes OR variations OR alterations OR oncogenes OR diagnostics OR ethnicity OR biomarkers OR prostate cancer genomics OR prostate cancer structural variations OR tumour and molecular subtypes OR therapeutic implications OR immunotherapy OR immunogenetics.”

There were 13,030 total results for our search query: 5,903 publications from Google Scholar with the patent and citation unchecked filer options and 7,127 articles from PubMed with the abstract, free full text, and full-text options selected.

The filtering method also yielded irrelevant results due to the overly broad key phrases in the search string. The following criteria for inclusion were applied during the manual screening of the obtained articles: 1) Articles discussing the phenotypic or genetic disorders associated with PCa, 2) publications detailing genetic changes or variants linked to PCa, 3) articles outlining changes in tumour-suppressor genes and oncogenes related to PCa, 4) articles exploring how genes associated with PCa may influence prognosis and diagnosis, 5) articles on the clinical applications of tumour subtyping and PCa risk classification, and 6) tumour-suppressor genes and oncogenes in the context of PCa treatments. Unpublished works were excluded. Except for four articles published between 1998 and 1999, all other selected articles published in 2000 and later were included. However, papers containing irrelevant information or redundant or duplicate content were not considered for this review. Thus, 134 articles were ultimately retained for this review.

Structurally, PTEN is located at the 10q23 locus on chromosome 10, with nine exons and eight introns. It is roughly 200-kb long and codes for a 403-amino acid multifunctional protein that has lipid phosphatase activity (9, 10). PTEN dephosphorylates phosphoinositide substrates to create a dual-specific protein phosphatase that is essential for controlling the PI3K/AKT signalling pathway (9, 10). This regulation affects essential cellular functions such as apoptosis, cell cycle regulation, cell invasion inhibition, and general tumour suppression (9, 10). Approximately 50% of castration-resistant prostate tumours frequently exhibit PTEN mutations, deletions, and inactivation, which contribute to dysregulated PI3K/AKT signalling (7). As a result, the onset, spread, and poor clinical outcomes of PCa are all strongly associated with the loss of PTEN function (9, 10).

The androgen-regulated gene TMPRSS2 is found on chromosome band 21q22 and is mainly expressed in the prostate (3). The ERG gene, also mapped to 21q22, is located approximately 3 Mb downstream of TMPRSS2. The TMPRSS2:ERG gene fusion, the most prevalent structural variation in PCa, has been reported in nearly half of all PCa cases (28, 29). This fusion is common in both early and advanced stages of the disease underlining its importance in PCa pathogenesis (5, 30, 31). While it is not frequently reported in normal prostate tissue, TMPRSS2:ERG fusions facilitate tumour progression by promoting angiogenesis, inflammation, and epithelial–mesenchymal transition ultimately leading to metastasis, advanced tumour stages, and increased mortality (32–34). Other ETS family members, such as ETV1, ETV4, and ETV5, as well as androgen receptor (AR) targets, like SLC45A3 and NDRG, are also implicated in gene fusions in PCa.

The TMPRSS2:ERG fusion occurs when androgen and prostate-specific regulatory regions of TMPRSS2 are juxtaposed with the first exon(s) of ERG leading to androgen-driven overexpression of the fusion transcript. In nearly 50%–60% of fusion-positive tumours, this results from an intronic deletion on chromosome 21, which deletes the genomic region between TMPRSS2 and ERG. Alternatively, complicated genomic rearrangements involving chromosome 21q22 and other chromosomes may also give this fusion (35–37). The recurring nature of this fusion is associated with a common deletion spot connecting ERG and TMPRSS2 (38). The deletion site is characterised by two types of breakpoints, with the 3′ end of ERG consistently fused to the 5′ end of TMPRSS2. This fusion leads to the overexpression of ERG, facilitated by the androgen-responsive promoter of TMPRSS2, resulting in elevated PCa cell invasion, proliferation, angiogenesis, and tumour aggressiveness (39, 40). Moreover, the TMPRSS2:ERG fusion triggers downstream oncogenes, further amplifying its carcinogenic effects (41).

Similarly, androgen receptor activation provides a key role in this process by enhancing TMPRSS2 promoter function leading to the production of an ERG mRNA fusion transcript. This transcript is translated into the ERG transcription factor, which consequently activates downstream oncogenic signalling pathways (42, 43). This molecular cascade provides two key therapeutic targets. First, androgen receptor inhibitors (e.g., enzalutamide and abiraterone) suppress TMPRSS2 activation reducing fusion transcript production and ERG overexpression (44). Second, bromodomain inhibitors (e.g., JQ1) disrupt the transcriptional machinery required for ERG-mediated gene activation, thereby preventing its oncogenic effects (42, 45). These targeted approaches, which interrupt critical nodes in the TMPRSS2:ERG fusion pathway, provide potential opportunities for personalised therapy in PCa (46, 47). The mechanisms regulating ERG overexpression in PCa cells are illustrated in Figure 2 .

The interaction between ERG and the androgen receptor (AR) plays an essential role in the aetiology and progression of PCa. This interaction is predominantly significant in the context of the TMPRSS2:ERG gene fusion, a common genetic alteration found in PCa (5). Available data suggest that ERG and AR collaborate to drive PCa development, with ERG modulating the AR transcriptional program and facilitating the expression of AR target genes that enhance tumour growth and survival (5). Moreover, ERG may indirectly influence AR signalling pathway by altering chromatin structure and accessibility, thereby promoting AR binding to DNA and transcriptional activation. In the lack of androgens, AR remains inactive in the cytoplasm, bound to the chaperone protein HSP90. Androgen binding triggers a conformational change in AR initiating it to dissociate from HSP90 and translocate into the nucleus (78). Once in the nucleus, AR binds to androgen response elements (AREs) in the promoter or enhancer regions of target genes to regulate their transcription. In normal prostate cells, this process mechanism upregulates genes, which are essential for prostate function (79). However, in PCa cells with the TMPRSS2:ERG fusion, androgen-bound AR aberrantly triggers the ERG oncogene leading to tumourigenesis (80). This dual role of androgen signalling pathway controlling both normal cellular functions and oncogenic signalling pathways underlines potential therapeutic targets (5). For instance, androgen deprivation therapies (ADTs), which reduce androgen levels or prevent AR role, have been reported to reduce ERG expression in TMPRSS2:ERG fusion-positive tumours, thus reducing their oncogenic potential (81). The association between ERG and AR also has significant effects for combination therapies in PCa. Combining AR-targeted therapies with agents that selectively disrupt ERG function or its downstream pathways provides potential synergistic options for treating TMPRSS2:ERG fusion-positive PCa (81). However, directly targeting ERG raises challenges due to its nature as a transcription factor. Despite this, ongoing research remains to explore strategies to prevent ERG–DNA binding or interrupt ERG–AR interactions (81). The mechanisms underlying androgen regulation of gene expression in PCa cells are illustrated in Figure 3 .

Recent studies suggest that prostatic intraepithelial neoplasia (PIN) can advance to invasive cancer when ERG activation coincides with loss of PTEN function (82). While some studies have proposed a link between ERG expression and Gleason score, the current evidence remains inconclusive underscoring the need for further investigation. In contrast, there is stronger evidence associating reduced PTEN expression with higher Gleason scores and poor prognosis (74). Although the relationship between ERG overexpression and loss of PTEN function has not been extensively explored, studies investigating the therapeutic potential of targeting ERG and PTEN have yielded promising results (74). Furthermore, PTEN loss has been consistently associated with adverse clinical outcomes, including poor overall survival, unfavourable pathological tumour behaviour, and the development of castration-resistant and metastatic PCa (69, 83). These findings suggest that PTEN loss may represent a more clinically significant chromosomal alteration in PCa compared to TMPRSS2:ERG fusion emphasising its importance as a potential biomarker and therapeutic target.

Interleukin-6 (IL-6) cytokine signalling, PTEN loss, and activation of the PI3K–AKT pathway are among key contributors to the pathophysiology of PCa. Their complex relationship promotes tumour growth, boosts cell survival, and facilitates therapeutic resistance, underlining the significance of integrating molecular approaches in developing targeted therapies and improving prognostic assessment (84, 85). Chronic inflammation is closely linked to the genetic alterations and mechanisms facilitating PCa progression (86, 87). Among the key cytokine’s mediators of inflammation, IL-6 plays a key role in PCa pathogenesis by facilitating angiogenesis, tumour development, and disease progression. Pro-inflammatory cytokine, IL-6, is the most frequently associated inflammatory mediator in PCa (88). Beyond its inflammatory role, elevated IL-6 expression is strongly associated with poor clinical outcomes, treatment resistance, and advanced disease stages. The oncogenic effects of IL-6 are facilitated through IL-6 receptor (IL-6R) signalling, which promotes the PI3K–AKT pathway, thus stimulating PCa cell growth and survival rates (84, 85). This process introduces a positive feedback loop, where PTEN loss and consequent hyperactivation of the PI3K–AKT signalling pathway further upregulate IL-6 expression amplifying its oncogenic effects.

The therapeutic potential of targeting IL-6-mediated pathways is significant. Anti-IL-6 treatments, like monoclonal antibodies against IL-6 or IL-6R, may interfere with IL-6 signalling and slow the growth of PCa (84, 85). Additionally, the potential of combination therapy is highlighted by the dynamic interaction between PI3K–AKT signalling, PTEN loss, and IL-6. Strategies that target PTEN loss block the PI3K–AKT pathway and reduce IL-6 signalling together have the potential to improve PCa treatment outcomes. These combined approaches present an achievable means to improve patient outcomes and overcome treatment resistance (84, 85).

Prostate cancer (PCa) can be classified into four distinct molecular subtypes based on IHC staining analysis of ERG and PTEN expression. These molecular subtypes include the following: (1) normal ERG with loss of PTEN expression (ERG−/PTEN−), (2) rearranged ERG with normal PTEN expression (ERG+/PTEN+), (3) normal ERG with normal PTEN expression (ERG−/PTEN+), and (4) rearranged ERG with loss of PTEN expression (ERG+/PTEN−) (58, 89, 90). These tumour molecular subtypes have surfaced as valuable tools for patient stratification allowing personalised approaches to treatment based on individual molecular subtypes. The prevalence of these molecular subtypes varies across different populations, as summarised in Table 2 . Additionally, these molecular subtypes present distinct therapeutic potentials, particularly in the setting of immunotherapy and personalised treatment, providing opportunities for more precise and efficient treatment strategies (92, 93).

Prostate cancer characterised by PTEN loss and absence of ERG expression (ERG−/PTEN−) signifies a distinct molecular subtype with profound biological and therapeutic implications (74). This subtype exhibits reduced dependence on androgen receptor (AR) signalling compared to ERG-positive tumours, contributing to resistance to AR-targeted therapies such as androgen deprivation therapy (ADT) (94). ERG−/PTEN− tumours are often more aggressive, driven by their reliance on PI3K/AKT signalling and heightened genomic instability, and are associated with poor prognosis (69, 95, 96). Notably, this subtype appears to be more prevalent in certain populations, such as African American men, who exhibit higher rates of PTEN loss and lower frequencies of TMPRSS2:ERG fusion highlighting potential ethnic and genetic variations in PCa subtypes (97). While ERG−/PTEN− tumours pose therapeutic challenges due to their reduced sensitivity to conventional AR-targeted therapies, they also present opportunities for novel treatment strategies (98). To address cross-pathway interactions, inhibitors that target the PI3K/AKT/mTOR pathway have shown potential, especially when combined with AR inhibitors (99). Additionally, immunotherapy, including immune checkpoint inhibitors, is a promising therapeutic approach for this subtype, as PTEN loss has been connected to immune evasion. The findings highlight how crucial it is to use both pathway-specific and immune-modulating treatment methods to treat ERG−/PTEN− tumours to enhance patient outcomes.

The ERG+/PTEN+ tumour molecular subtype of PCa is characterised by ERG rearrangements, most commonly the TMPRSS2:ERG fusion, and intact PTEN function (58). However, the occurrence of this molecular subtype varies due to the heterogeneousness of PTEN alterations, with PTEN loss reported in 20%–50% of cases. ERG rearrangements are found in nearly 40%–70% of prostate tumours (59, 60). Biologically, ERG rearrangements facilitate oncogenesis by promoting androgen receptor (AR)-regulated transcriptional pathways, which enhance tumour invasion and progression (100). The intact PTEN function in this molecular subtype helps regulate the PI3K/AKT signalling pathway differentiating it from the more aggressive ERG+/PTEN− molecular subtype (101, 102).

Clinically, ERG+/PTEN+ tumours are known to be sensitive to AR-targeted therapies, such as androgen deprivation therapy (ADT), abiraterone, and enzalutamide, which form the keystone of treatment for this tumour molecular subtype (103). Emerging therapeutic strategies, such as precision medicine approaches that target vulnerabilities in ERG driven pathways and DNA repair mechanisms, such as PARP inhibitors, may benefit a subset of these tumours, particularly those with additional mutations in DNA damage repair genes (104). Immune checkpoint inhibitors also represent a potential therapeutic avenue for ERG+/PTEN+ tumours, as this subtype may maintain a more immunologically active tumour microenvironment compared to PTEN-deficient subtypes, though the efficacy of these treatments remains under research (105, 106). Additionally, novel therapies targeting ERG-associated signalling pathways are being explored offering promising avenues for future treatment development (107). Despite these developments, several issues still need to be addressed, including the biology and clinical variation of this subtype in other populations and the need for biomarkers to direct tailored treatment. An improved understanding of the particular vulnerabilities of ERG+/PTEN+ tumours is necessary to improve treatment approaches and patient outcomes for patients with this genetic subtype of PCa (59, 60, 107).

The ERG−/PTEN+ tumour molecular subtype of PCa is described by the absence of ERG rearrangements, such as TMPRSS2:ERG fusions, and the retention of PTEN function, which is important for controlling the PI3K/AKT signalling pathway (58). This molecular subtype falls within the wide category of ERG-negative prostate tumours accounting for 30%–60% of PCa cases (58, 71). The occurrence of the ERG−/PTEN+ subtype varies throughout populations, with studies suggesting population-specific differences in disease biology. For instance, African American men demonstrate a higher frequency of PTEN-positive tumours and a reduced occurrence of ERG expression, stressing potential ethnic and genetic variations in PCa (97, 108).

The retention of PTEN function in ERG−/PTEN+ tumours distinguish them from more aggressive PTEN-deficient subtypes, as PTEN supports the regulation of cellular proliferation and survival (58, 61). Therapeutically, these molecular tumours continue to depend on androgen receptor (AR) signalling making them responsive to androgen deprivation therapy (ADT) and AR-targeted agents such as enzalutamide and abiraterone. Furthermore, the absence of PTEN loss may contribute to a more immunologically active tumour microenvironment fostering the possibility of exploring immunotherapies, including immune checkpoint inhibitors, potentially in combination with AR-targeted therapies (62, 103).

The lack of ERG expression in this molecular subtype indicates a dependency on alternative oncogenic signalling pathways emphasising the need for further research into precision medicine approaches and innovative therapeutic targets. Understanding the distinctive molecular and immunological characteristics of ERG−/PTEN+ tumour molecular subtypes is important for developing tailored treatment strategies and improving outcomes for patients with this subtype.

The presence of ERG rearrangements, most frequently TMPRSS2:ERG fusions, and the loss of PTEN function are characteristics of the ERG+/PTEN− molecular subtype of PCa (58, 109). With more invasive tumours, higher Gleason scores, and an increased likelihood to develop castration-resistant PCa, this subtype is associated with aggressive disease (109, 110). ERG alterations increase transcriptional activity mediated by the androgen receptor (AR), whereas PTEN loss interferes with the PI3K/AKT signalling pathway leading to uncontrolled cell proliferation and resistance to apoptosis (111). ERG rearrangements characterised by ERG expression, are more common in Caucasian men compared to African American and Asian men, and the occurrence of ERG+/PTEN− tumours varies by ethnic group. However, all ethnic groups exhibit PTEN loss, especially in advanced stages of the disease (60, 65). Therapeutically, AR-targeted treatments, such as abiraterone, enzalutamide, and androgen deprivation therapy (ADT), are efficient against ERG-driven tumours. However, PTEN loss often confers resistance by triggering alternative signalling pathways (62, 103). To address this, inhibitors targeting the PI3K/AKT/mTOR pathway are being researched, with promising results when used in combination with AR-targeted therapies (103, 112, 113). Additionally, ERG+/PTEN− tumours commonly exhibit immunosuppressive characteristics, such as reduced CD8+ T-cell infiltration and enhanced recruitment of myeloid-derived suppressor cells (18, 95). These characteristics reduce the efficacy of immune checkpoint inhibitors (ICIs), such as anti-PD-1/PD-L1 or anti-CTLA-4 antibodies (18), though combination therapies that simultaneously target the PI3K/AKT pathway and boost immune responses may improve outcomes in certain subtypes (18, 95).

Significant research gaps still exist despite these developments, especially in the areas of clarifying resistance mechanisms, discovering predictive biomarkers, and understanding population-specific variances. To create more individualised and successful treatment plans for patients with ERG+/PTEN− PCa, several issues must be resolved.

Due to the TMPRSS2:ERG fusion, the ERG gene is more expressed in PCa in both its early and late stages (5, 114, 115). It has been suggested that this fusion event is a diagnostic biomarker for PCa and is a useful tool for distinguishing tumour molecular subtypes (116). Research indicates that over 50% of PCa cases have the TMPRSS2:ERG fusion and consequent ERG overexpression (115, 117). The identification of ERG protein overexpression through immunostaining in PCa samples or the presence of TMPRSS2:ERG in prostate tissue can both be used as reliable diagnostic markers. However, the absence of ERG expression is not sufficient evidence that PCa is not present. TMPRSS2:ERG fusion may also be a potential urine-based biomarker for PCa detection, according to recent data (118, 119). The prognostic significance of the TMPRSS2:ERG fusion remains controversial, with studies reporting contradictory findings (28). While some research challenges its predictive utility, others suggest that it can function as a prognostic biomarker, with increased TMPRSS2:ERG frequency connected to worse clinical outcomes (6, 8, 120). These discrepancies may stem from variations in patient demographics, methodologies used to detect gene fusions, and the therapeutic effects on the tumour samples analysed. As a result, cautiousness is necessary when interpreting studies that emphasise the prognostic utility of the TMPRSS2:ERG fusion. Despite these challenges, the TMPRSS2:ERG fusion remains a potential therapeutic target due to its specificity to PCa and its overexpression throughout various stages of tumour progression (121). As the most common genetic alteration in PCa, targeting TMPRSS2:ERG at the molecular level has gained significant interest as a potential treatment strategy. Additionally, ongoing research continues to explore the TMPRSS2:ERG fusion gene for its potential as a different biomarker, therapeutic target, and diagnostic and prognostic indicator in PCa (121).

Evaluating the prognosis for individuals with PCa remains a key issue in disease management. Various potential molecular indicators and biomarkers are being introduced, with different institutions developing their standards for PCa risk assessment (122). Generally, blood PSA levels and Gleason scores are utilised to determine whether patients require active monitoring and treatment decisions (122). However, these markers are associated with several limitations when classifying PCa patients for adequate disease management. The Gleason grade is regarded as the most reliable predictive biopsy metric having been enhanced through modifications to the Gleason grading system (123, 124), though the amount of data obtainable through this approach is also limited, necessitating the development of cost-effective and straightforward predictive biomarkers to identify potentially aggressive prostate tumours and assist in categorising PCa patients into various predictive groups for treatment options (125, 126). According to previously published research, PTEN depletion has been linked to PCa progression through various methods such as IHC and FISH (125). PTEN loss or deficiency plays a significant role in PCa development, as evidenced by numerous studies. Several publications have also shown a direct correlation between PTEN loss and an increased risk of biochemical recurrence following prostatectomy proving useful for categorising patients with PCa into different prognosis groups for targeted treatments (68, 69, 125, 127).