Loss of heterozygosity of essential genes represents a widespread class of potential cancer vulnerabilities.

Alterations in non-driver genes represent an emerging class of potential therapeutic targets in cancer. Hundreds to thousands of non-driver genes undergo loss of heterozygosity (LOH) events per tumor, generating discrete differences between tumor and normal cells. Here we interrogate LOH of polymorphisms in essential genes as a novel class of therapeutic targets. We hypothesized that monoallelic inactivation of the allele retained in tumors can selectively kill cancer cells but not somatic cells, which retain both alleles. We identified 5664 variants in 1278 essential genes that undergo LOH in cancer and evaluated the potential for each to be targeted using allele-specific gene-editing, RNAi, or small-molecule approaches. We further show that allele-specific inactivation of either of two essential genes (PRIM1 and EXOSC8) reduces growth of cells harboring that allele, while cells harboring the non-targeted allele remain intact. We conclude that LOH of essential genes represents a rich class of non-driver cancer vulnerabilities.

Alternative-splicing defects in cancer: Splicing regulators and their downstream targets, guiding the way to novel cancer therapeutics.

Defects in alternative splicing are frequently found in human tumors and result either from mutations in splicing-regulatory elements of specific cancer genes or from changes in the regulatory splicing machinery. RNA splicing regulators have emerged as a new class of oncoproteins and tumor suppressors, and contribute to disease progression by modulating RNA isoforms involved in the hallmark cancer pathways. Thus, dysregulation of alternative RNA splicing is fundamental to cancer and provides a potentially rich source of novel therapeutic targets. Here, we review the alterations in splicing regulatory factors detected in human tumors, as well as the resulting alternatively spliced isoforms that impact cancer hallmarks, and discuss how they contribute to disease pathogenesis. RNA splicing is a highly regulated process and, as such, the regulators are themselves tightly regulated. Differential transcriptional and posttranscriptional regulation of splicing factors modulates their levels and activities in tumor cells. Furthermore, the composition of the tumor microenvironment can also influence which isoforms are expressed in a given cell type and impact drug responses. Finally, we summarize current efforts in targeting alternative splicing, including global splicing inhibition using small molecules blocking the spliceosome or splicing-factor-modifying enzymes, as well as splice-switching RNA-based therapeutics to modulate cancer-specific splicing isoforms. This article is categorized under: RNA in Disease and Development > RNA in Disease RNA Processing > Splicing Regulation/Alternative Splicing.

Coordination of the third step of protein splicing in two cyanobacterial inteins.

The third step of protein splicing is cyclization of Asn coupled to peptide bond cleavage. In two related cyanobacterial inteins, this step is facilitated by Asn or Gln. For a Synechococcus sp. PCC7002 intein, the isolated third step of protein splicing is more efficient with its native Asn than with substitution to Gln. For a Trichodesmium erythraeum intein, its native Gln facilitates the third step as efficiently as with Asn. Despite these differences, the yield of splicing is not affected, suggesting that the third step is influenced by mechanism-linked conformational changes. A conserved catalytic His and the penultimate residue also play roles in promoting side-chain cyclization.

Copy-number and gene dependency analysis reveals partial copy loss of wild-type SF3B1 as a novel cancer vulnerability.

Genomic instability is a hallmark of human cancer, and results in widespread somatic copy number alterations. We used a genome-scale shRNA viability screen in human cancer cell lines to systematically identify genes that are essential in the context of particular copy-number alterations (copy-number associated gene dependencies). The most enriched class of copy-number associated gene dependencies was CYCLOPS (Copy-number alterations Yielding Cancer Liabilities Owing to Partial losS) genes, and spliceosome components were the most prevalent. One of these, the pre-mRNA splicing factor SF3B1, is also frequently mutated in cancer. We validated SF3B1 as a CYCLOPS gene and found that human cancer cells harboring partial SF3B1 copy-loss lack a reservoir of SF3b complex that protects cells with normal SF3B1 copy number from cell death upon partial SF3B1 suppression. These data provide a catalog of copy-number associated gene dependencies and identify partial copy-loss of wild-type SF3B1 as a novel, non-driver cancer gene dependency.

Multicentric Low-Grade Gliomas.

BACKGROUND: Multicentric low-grade gliomas are rare entities that occur in disparate regions of the brain. They can present with distinct pathologic and imaging findings and may harbor a worse prognosis. We present a case of multicentric low-grade gliomas and highlight their pathogenesis, imaging characteristics, and molecular signatures, with implications for clinical management. CASE: A 49-year-old man presented with left-sided headaches for 3 months. Magnetic resonance imaging revealed concurrent non-enhancing lesions in the left medial temporal lobe and superior cerebellum. Increased size and the development of contrast enhancement in the temporal lesion promoted a left temporal craniotomy. Pathology revealing a grade II ganglioglioma. Three months later, the cerebellar lesion also acquired new contrast enhancement and was found to be a grade II astrocytoma following a supracerebellar infratentorial approach for resection. At 2 years follow-up, the patient remains clinically stable, receiving adjuvant chemotherapy for new non-enhancing, unresectable pontine lesion. CONCLUSION: Tumor growth rate, detailed pathologic findings, imaging characteristics, and molecular signatures influence the clinical course of multicentric low-grade gliomas. PDGFRA amplifications and IDH1 wild-type status may act in a concerted fashion to produce an accelerated course of radiologic changes and tumor recurrence, as noted in our case. Additional research is needed to stratify the risk of transformation in patients with multicentric low-grade glioma and to guide management strategies.