Identification of novel somatic fusions of ERG‐VEGFA, TMPRSS2‐ERG, and VEGFA‐TMPRSS2 in prostate cancer treated with anlotinib and androgen deprivation therapy: A case report

Abstract

The TMPRSS2‐ERG fusion gene has frequently been found in prostate cancer and is associated with malignancy. Identifying novel fusions will help to stratify patients and establish patient‐tailored therapies. A 78‐year‐old man presented to our hospital with severe symptoms of urinary urgency and frequency for 2 years, as well as severe bone pain for 1 year. He was diagnosed with metastatic prostate cancer with a Gleason score of 5 + 5. Three gene fusions, ERG_VEGFA, TMPRSS2_ERG, and VEGFA_TMPRSS2, were identified in the patient's prostate cancer tissue. Notably, administration of the tyrosine kinase inhibitor, anlotinib, in combination with a gonadotropin‐releasing hormone agonist (GnRHa) and abiraterone, reduced the patient's bone pain and also stabilized his prostate cancer for more than 2 years. This is the first report of somatic fusions among the VEGFA, ERG, and TMPRSS2 genes in cancer tissues from a patient with prostate cancer who responded well to antiangiogenic treatment combined with a GnRHa and abiraterone.

Three gene fusions ERG (PMT. . PMT)_VEGFA (vascular endothelial growth factor A, EX8E. . END), TMPRSS2 (PMT. . IVS1)_ERG (IVS1. . END), and VEGFA (PMT. . IVS7)_TMPRSS2 (IVS1. . END) were identified in a patient's prostate cancer tissue. The administration of anlotinib, a tyrosine kinase inhibitor, in the combination of GnRHa (gonadotropin‐releasing hormone agonist, Goserelin) and abiraterone not only reduced bone pain dramatically but also stabilized the disease for more than 2 years in the patient with these fusions.

Abbreviations

AR

androgen receptor

CRPC

castration‐resistant prostate cancer

ERG

erythroblast transformation‐specific transcription factor‐related gene

GnRHa

gonadotropin‐releasing hormone agonist

PARP

poly ADP‐ribose polymerase

PSA

prostate‐specific antigen

TMPRSS2

transmembrane serine protease 2

VEGFA

vascular endothelial growth factor A

1. INTRODUCTION

Prostate cancer is the most common cancer and the second most prevalent cause of cancer‐related death worldwide in men [1]. Although the localized disease can be treated effectively with surgery and radiation [2], the prognosis of castration‐resistant advanced prostate cancer is still disappointing. Androgen deprivation therapy is the cornerstone of first‐line treatments for patients with metastatic prostate cancer [3]; however, most metastatic hormone‐sensitive prostate cancers become castration‐resistant prostate cancer (CRPC) within 18 to 24 months. Despite the efficacies of the second‐generation anti‐androgen drugs abiraterone and enzalutamide for CRPC [3, 4], significant challenges persist. The development of genetic molecular detection and targeted drug research and development has led to molecularly targeted therapy becoming an indispensable treatment for different types of tumors. Given that angiogenesis plays a major role in the development and spread of prostate cancer, targeting angiogenesis might offer a promising strategy for subtypes of prostate cancer [5]. However, multiple tyrosine kinase inhibitors targeting the vascular endothelial growth factor (VEGF) receptor (VEGFR) and antiangiogenic drugs have demonstrated minimal clinical activity, complicated with severe adverse reactions, in patients with prostate cancer [6]. Further studies are therefore needed to clarify the effects of these drugs in patients with prostate cancer.

A fusion between the genes encoding transmembrane serine protease 2 (TMPRSS2) and erythroblast transformation‐specific transcription factor‐related gene (ERG) was reported in prostate cancer in 2005 [7], since then the roles of TMPRSS2‐ERG fusion in prostate cancer development have attracted wide attention. ERG is a member of the E‐26 transformation‐specific family with important physiological and pathological roles. ERG binds to DNA at specific sequences to regulate the expression of multiple target genes and is involved in both angiogenesis and vascular homeostasis. TMPRSS2 is an androgen‐regulated gene that is frequently fused to the coding sequence of ERG. Under the control of the androgen receptor (AR), high levels of the TMPRSS2‐ERG fusion transcript can be translated into wild‐type or N‐terminally truncated ERG with functional domains [8]. Accumulating evidence suggests that approximately 50% of prostate cancers are positive for the TMPRSS2‐ERG fusion gene [9], and more than 90% of prostate cancers with overexpressed ERG result from the TMPRSS2‐ERG fusion [10]. In addition, prostate cancers with the TMPRSS2‐ERG fusion gene are more aggressive and lethal [11]. Here we report the case of a patient with prostate cancer with three gene fusions: ERG (PMT. . PMT)_VEGFA (EX8E. . END), TMPRSS2 (PMT. . IVS1)_ERG (IVS1. . END), and VEGFA (PMT. . IVS7)_TMPRSS2 (IVS1. . END). Notably, administration of the tyrosine kinase inhibitor anlotinib, in combination with the gonadotropin‐releasing hormone agonist (GnRHa) goserelin, and abiraterone not only reduced the patient's bone pain but also stabilized his disease for more than 2 years.

2. CASE PRESENTATION

A 78‐year‐old man presented to our hospital with severe symptoms of urinary urgency and frequency for 2 years, as well as severe bone pain for 1 year. Laboratory examinations found elevated total prostate‐specific antigen (PSA) of 127.01 ng/ml (normal range <4 ng/ml). Positron emission tomography‐computed tomography scan revealed a mass in the periphery of the prostate and magnetic resonance imaging showed several masses in his scapulae, humerus, clavicles, and ribs. The bone scan showed multiple lesions. Prostate cancer with multiple metastases was suspected and a 12‐needle prostate tissue biopsy confirmed the diagnosis of prostate cancer, Gleason score 5 + 5, in 40%–80% of the biopsies (Figure 1a). Next‐generation sequencing using blood and three prostate tissue biopsy samples (Geneplus‐Beijing Institute) revealed somatic fusions among the ERG, TMPRSS2, and VEGFA genes in all three biopsy samples, generating ERG (PMT. . PMT)_VEGFA (EX8E. . END) fusion, TMPRSS2 (PMT. . IVS1)_ERG (IVS1. . END) fusion, and VEGFA (PMT. . IVS7)_TMPRSS2 (IVS1. . END) fusion (Figure 2). We also noted a few additional mutations (Table 1). Considering the effects of the aberrant expression of VEGFA and ERG on tumor angiogenesis, the patient was prescribed the antiangiogenic drug anlotinib in combination with goserelin and abiraterone. His bone pain reduced dramatically and his PSA levels remained low (<2 ng/ml) (Figure 1b) for about 2 years. However, the patient finally died in December 2020 as a result of cardiovascular dysfunction.

Figure 1.

(a) Hematoxylin‐eosin staining to confirm prostate cancer in the patient samples. (b) Serum levels of total prostate‐specific antigen (TPSA) during treatment.

Figure 2.

Identification of novel somatic fusions among the ERG, TMPRSS2, and VEGFA genes by next‐generation sequencing. (a–c) Schematic structure of the genomic DNA sequence with fusion points of the ERG‐VEGFA (a), TMPRSS2‐ERG (b), and VEGFA‐TMPRSS2 genes (c). (d–f) DNA sequences flanking the fusion regions using Integrative Genomics Viewer.

Table 1.

Somatic mutations and fusions in three individual prostate biopsy samples

	Sample 1	Sample 2	Sample 3
ERG‐VEGFA	Promoter: EX8E fusion	Promoter: EX8E fusion	Promoter: EX8E fusion
TMPRSS2‐ERG	EX1: EX2	EX1: EX2	EX1: EX2
VEGFA‐TMPRSS2	EX7: EX2	EX7: EX2
TBX3	c.547dupA, p.R183Kfs*44	c.547dupA, p.R183Kfs*44	c.547dupA, p.R183Kfs*44
JAK1	c.1625G>A, p.R542H
CDK12		c.3377_3378delAAinsCC, p. Q1126P
TPR			c.5093 G>A, p.R1698H

3. DISCUSSION AND CONCLUSION

To the best of our knowledge, this is the first report of somatic fusions among the VEGFA, ERG, and TMPRSS2 genes in cancer tissues from a patient with prostate cancer who responded well to antiangiogenic treatment combined with a GnRHa and abiraterone. Although his disease stabilization could not be attributed solely to anlotinib, this rare multiple fusion with a positive response to this specific therapeutic regimen suggests that clinicians should be aware of the existence of these gene fusions in patients with prostate cancer. Further studies of these fusions in prostate cancer will help to stratify patients and to establish patient‐tailored therapies.

TMPRSS2‐ERG fusions play important roles in multiple stages of prostate cancer development, including premalignant prostatic intraepithelial neoplasia lesions, primary and advanced prostate cancer [8]. Here we present a patient with metastatic prostate cancer with fusions among three genes, ERG, TMPRSS2, and VEGFA, indicating that these fusions might be associated with more advanced prostate cancer. However, the function of ERG‐VEGFA needs to be further substantiated. The formation of the TMPRSS2‐ERG fusion seems to depend on AR signaling. It is possible that activation of AR signaling could induce three‐dimensional proximity of the two genomic loci, providing the essential foundation for the fusion following the induction of DNA double‐strand breaks and aberrant repair [12]. Further studies are therefore needed to investigate the three‐dimensional proximity of the ERG, TMPRSS2, and VEGFA loci under certain conditions.

TMPRSS2 is a target of the AR, suggesting that TMPRSS2‐ERG fusions in AR‐positive prostate cancer would result in ERG overexpression, thus increasing the capacity of the tumor cells to migrate and invade and controlling the expression of genes involved in extracellular matrix remodeling, inflammation, migration, and angiogenesis [13, 14]. Multiple strategies targeting ERG have thus been investigated in patients with ERG‐fusion prostate cancer [8]. Considering the functional interaction between ERG and the poly ADP‐ribose polymerase (PARP) DNA damage‐repair protein, Brenner et al. revealed that treatment of ERG‐overexpressing cells with the PARP inhibitor olaparib not only decreased ERG‐mediated cell invasion and intravasation but also inhibited tumor growth in mouse xenograft models [15]. Several studies also demonstrated that histone deacetylase inhibitors and the small molecules YK‐4‐279, DB1255, and WP1130 inhibited the proliferation of ERG‐overexpressing cells [8]. The current patient with three fusions among the ERG, TMPRSS2, and VEGFA genes benefited from treatment with the antiangiogenic drug anlotinib combined with androgen deprivation therapy. However, further studies are needed to investigate the mechanism underlying the specific therapeutic strategy for patients with TMPRSS2‐ERG fusions.

VEGF plays important roles in physiological and pathological vasculogenesis and angiogenesis [16]. VEGFA, the prototype member of the VEGF family, is a key regulator of blood vessel growth. The human VEGFA gene consists of eight exons separated by seven introns and encodes several isoforms through alternative splicing [17]. The last exon (exon 8) is important for the alternative splicing of VEGF pre‐mRNA, which is a key element in the balance between proangiogenic and antiangiogenic VEGF isoforms [18]. VEGFA exon 8 has been shown to play important roles in the pathogenesis of multiple disease types, including cancer, macular degeneration, nephropathy, pre‐eclampsia, and ischemic limb disease [19]. Considering the classical regulation of VEGFA exon 8 splicing, the VEGFA exon 8 splicing‐sensitive fluorescent reporter mouse has been investigated as a novel tool to assess splicing regulation [19]. In this study, we discovered novel fusions among the VEGFA, TMPRSS2, and ERG genes. Although the ERG (PMT. . PMT)_VEGFA (EX8E. . END) fusion only encodes exon 8 of VEGFA, the effect of this peptide on VEGFA needs to be investigated further.

AUTHOR CONTRIBUTIONS

Qiuli Liu: data curation (lead); formal analysis (lead); investigation (lead); methodology (lead); project administration (lead); writing – original draft (lead); writing – review and editing (supporting). Shuo Wang: data curation (supporting); formal analysis (supporting); investigation (supporting); methodology (equal); resources (equal); writing – original draft (supporting). Ze Wang: data curation (supporting); formal analysis (supporting); investigation (equal); methodology (equal); resources (supporting); writing – review and editing (supporting). Peng Tang: formal analysis (supporting); investigation (equal); methodology (equal); resources (equal); software (equal); visualization (equal). Dianzheng Zhang: conceptualization (equal); formal analysis (equal); investigation (equal); supervision (equal); validation (equal); writing – original draft (equal); writing – review and editing (lead). Weihua Lan: conceptualization (supporting); data curation (equal); formal analysis (equal); investigation (equal); methodology (supporting); resources (equal). Jun Jiang: conceptualization (lead); data curation (lead); funding acquisition (lead); supervision (lead); validation (lead); writing – review and editing (lead).

CONFLICT OF INTEREST

The authors declare no conflict of interest.

ETHICS STATEMENT

The study was approved by the institutional ethic review boards of Daping Hospital (2018‐28) and was carried out in accordance with The Code of Ethics of the World Medical Association (Declaration of Helsinki) for experiments involving humans. [Correction added on 16 June 2022, after first online publication: In “Ethics Statement” the approval ID “(2018‐28)” was missed and included in this version.]

INFORMED CONSENT

Written informed consent was obtained from the patient's next of kin for publication of this case report and any accompanying images.

Liu Q, Wang S, Wang Z, Tang P, Zhang D, Lan W, et al. Identification of novel somatic fusions of ERG‐VEGFA, TMPRSS2‐ERG, and VEGFA‐TMPRSS2 in prostate cancer treated with anlotinib and androgen deprivation therapy: a case report. Cancer Innovation. 2022;1:114–118. 10.1002/cai2.11

DATA AVAILABILITY STATEMENT

All the data are included in the article. Further inquiries can be directed to the corresponding author.