A high-risk retinoblastoma subtype with stemness features, dedifferentiated cone states and neuronal/ganglion cell gene expression

Abstract

Retinoblastoma is the most frequent intraocular malignancy in children, originating from a maturing cone precursor in the developing retina. Little is known on the molecular basis underlying the biological and clinical behavior of this cancer. Here, using multi-omics data, we demonstrate the existence of two retinoblastoma subtypes. Subtype 1, of earlier onset, includes most of the heritable forms. It harbors few genetic alterations other than the initiating RB1 inactivation and corresponds to differentiated tumors expressing mature cone markers. By contrast, subtype 2 tumors harbor frequent recurrent genetic alterations including MYCN-amplification. They express markers of less differentiated cone together with neuronal/ganglion cell markers with marked inter- and intra-tumor heterogeneity. The cone dedifferentiation in subtype 2 is associated with stemness features including low immune and interferon response, E2F and MYC/MYCN activation and a higher propensity for metastasis. The recognition of these two subtypes, one maintaining a cone-differentiated state, and the other, more aggressive, associated with cone dedifferentiation and expression of neuronal markers, opens up important biological and clinical perspectives for retinoblastomas.

TFF1 in Aqueous Humor—A Potential New Biomarker for Retinoblastoma

“…Correlation of the clinical and pathological characteristics of the investigated RB tumors with the TFF1 expression status in the AH of the patients' eye did not allow for any stratification. The lack of correlation is most likely attributable to the comparatively small sample size, because we and others have already shown that TFF1 expression in RB tumors indeed correlates with clinical parameters [4,9]. Our group demonstrated that TFF1 correlates with a higher clinical tumor-node-metastasis (TNM) stage and poorly differentiated tumor cells [8] and a recent study showed that TFF1 is linked to RBs which are associated with a higher risk of metastasis, referred to as subtype 2 [4].…”

“…The lack of correlation is most likely attributable to the comparatively small sample size, because we and others have already shown that TFF1 expression in RB tumors indeed correlates with clinical parameters [4,9]. Our group demonstrated that TFF1 correlates with a higher clinical tumor-node-metastasis (TNM) stage and poorly differentiated tumor cells [8] and a recent study showed that TFF1 is linked to RBs which are associated with a higher risk of metastasis, referred to as subtype 2 [4]. Summarizing, one can state that the identification of TFF1 in the AH of RB patients opens the field for new diagnostic approaches.…”

“…In addition, we could show that TFF1 functionally acts as tumor suppressor gene in RB cell lines [10] and is epigenetically regulated [11]. In a most recent study by Liu et al, the relevance of TFF1 as potential marker for RB was confirmed and connected to a subtype of RBs associated with a higher risk of metastasis [4]. TFF peptides are ectopically expressed in different human tumors (for review see: [12]) and three members-TFF1, TFF2, and TFF3-of this family of small secreted proteins have been characterized in mammals so far.…”

“…Although some patients develop metastases, survival rates are over 90% in high-income countries, whereas in low-income countries, tumors remain undiagnosed and grow to an advanced, globe-threatening stage [3]. Therefore, the main therapeutic focus lies on life-saving treatment regimens including ocular tumor treatment and prevention of metastatic spread [4]. A second critical goal of RB therapy is maximization of eye and visual preservation [4].…”

“…Therefore, the main therapeutic focus lies on life-saving treatment regimens including ocular tumor treatment and prevention of metastatic spread [4]. A second critical goal of RB therapy is maximization of eye and visual preservation [4]. For a long period, biopsies or the removal of eye fluid were contraindicative due to the risk of tumor dissemination [5].…”