Pan-cancer molecular analysis of the RB tumor suppressor pathway

Abstract

The retinoblastoma tumor suppressor gene (RB1) plays a critical role in coordinating multiple pathways that impact cancer initiation, disease progression, and therapeutic responses. Here we probed molecular features associated with the RB-pathway across 31 tumor-types. While the RB-pathway has been purported to exhibit multiple mutually exclusive genetic events, only RB1 alteration is mutually exclusive with deregulation of CDK4/6 activity. An ER+ breast cancer model with targeted RB1 deletion was used to identify signatures of CDK4/6 activity and RB-dependency (CDK4/6-RB integrated signature). This signature was prognostic in tumor-types with gene expression features indicative of slower growth. Single copy loss on chromosome 13q encompassing the RB1 locus is prevalent in many cancers, yielding reduced expression of multiple genes in cis, and is inversely related to the CDK4/6-RB integrated signature supporting a cause-effect relationship. Genes that are positively and inversely correlated with the CDK4/6-RB integrated signature define new tumor-specific pathways associated with RB-pathway activity.

Non-Canonical Functions of the Gamma-Tubulin Meshwork in the Regulation of the Nuclear Architecture

“…Accordingly, in various tumors (retinoblastoma, bladder, breast, colorectal and small cell lung carcinoma (SCLC) tumors), γtubulin and RB1 moderate each other's expression, and in the absence of γtubulin and RB1, the uncontrolled transcriptional activity of E2Fs upregulates apoptotic genes, causing cell death [88,108]. The RB pathway is one of the most well-described tumor suppressor pathways, and it is found to be highly mutated in a large spectrum of cancers [144,145]. Using the cbioportal [143], we found that among 31 subtypes of cancer, 30% exhibit defects in the RB pathway, with 7% of the patients exhibiting a loss of RB1 [144].…”

“…The RB pathway is one of the most well-described tumor suppressor pathways, and it is found to be highly mutated in a large spectrum of cancers [144,145]. Using the cbioportal [143], we found that among 31 subtypes of cancer, 30% exhibit defects in the RB pathway, with 7% of the patients exhibiting a loss of RB1 [144]. In brain tumors, high expression of γtubulin is associated with high-grade astrocytomas and glioblastomas, as compared to low-grade astrocytomas, which exhibited weaker γtubulin staining [146].…”

The CRTC1-MAML2 fusion is the major oncogenic driver in mucoepidermoid carcinoma

“…Using MSigDB oncogenic signatures, we found that MEC transcriptomes were enriched with the oncogenic signatures (Supplemental Table 2), such as cAMP-induced signature (cAMP-up), oncogenic EGFR-induced signature (EGFR-up), and RB1/RBL1 loss-induced signature (RB.107_DN-up) (Figure 4F). Moreover, a CDK4/6-RB integrated signature, identified from a recent pan-cancer molecular analysis (41), was also found to be overrepresented in fusion-induced MEC (Figure 4G). These data were again in agreement with the CREB activation and enhanced EGFR signaling in human MEC, as we previously reported (32).…”

Non-Canonical Functions of the γTubulin Meshwork in the Regulation of the Nuclear Architecture

“…Accordingly, in various tumours (retinoblastoma, bladder, breast, colorectal and small cell lung carcinoma (SCLC) tumors), tubulin and RB1 moderate each other's expression, and in the absence of tubulin and RB1, the uncontrolled transcriptional activity of E2Fs upregulates apoptotic genes, causing cell death [98,103]. The RB pathway is one of the most well described tumour suppressor pathways, and it is found to be highly mutated in a large spectrum of cancers [143,144]. Using the cbioportal [142], we found that among 31 subtypes of cancer, 30% exhibit defects in the RB pathway, with 7% of the patients exhibiting a loss of RB1 [143].…”

“…The RB pathway is one of the most well described tumour suppressor pathways, and it is found to be highly mutated in a large spectrum of cancers [143,144]. Using the cbioportal [142], we found that among 31 subtypes of cancer, 30% exhibit defects in the RB pathway, with 7% of the patients exhibiting a loss of RB1 [143]. In brain tumours, high expression of tubulin is associated with high grade astrocytomas and glioblastomas, as compared to low grade astrocytomas, which exhibited weaker tubulin staining [145].…”