Cancer in Costello syndrome: a systematic review and meta-analysis.

BACKGROUND: Costello syndrome (CS) is a cancer-predisposition disorder caused by germline pathogenic variants in HRAS. We conducted a systematic review using case reports and case series to characterise cancer risk in CS. METHODS: We conducted a systematic review to identify CS cases to create a retrospective cohort. We tested genotype-phenotype correlations and calculated cumulative incidence and hazard rates (HR) for cancer and cancer-free death, standardised incidence rates (SIR) and survival after cancer. RESULTS: This study includes 234 publications reporting 621 patients from 35 countries. Over nine percent had cancer, including rhabdomyosarcoma, bladder, and neuroblastoma. The rate of cancer and death associated with p.Gly12Ser were lower when compared to all other variants (P < 0.05). Higher mortality for p.Gly12Cys, p.Gly12Asp, p.Gly12Val and p.Gly60Val and higher malignancy rate for p.Gly12Ala were confirmed (P < 0.05). Cumulative incidence by age 20 was 13% (cancer) and 11% (cancer-free death). HR (death) was 3-4% until age 3. Statistically significant SIRs were found for rhabdomyosarcoma (SIR = 1240), bladder (SIR = 1971), and neuroblastoma (SIR = 60). Survival after cancer appeared reduced. CONCLUSIONS: This is the largest investigation of cancer in CS to date. The high incidence and SIR values found to highlight the need for rigorous surveillance and evidence-based guidelines for this high-risk population.

ATDC binds to KEAP1 to drive NRF2-mediated tumorigenesis and chemoresistance in pancreatic cancer.

Pancreatic ductal adenocarcinoma is a lethal disease characterized by late diagnosis, propensity for early metastasis and resistance to chemotherapy. Little is known about the mechanisms that drive innate therapeutic resistance in pancreatic cancer. The ataxia-telangiectasia group D-associated gene (ATDC) is overexpressed in pancreatic cancer and promotes tumor growth and metastasis. Our study reveals that increased ATDC levels protect cancer cells from reactive oxygen species (ROS) via stabilization of nuclear factor erythroid 2-related factor 2 (NRF2). Mechanistically, ATDC binds to Kelch-like ECH-associated protein 1 (KEAP1), the principal regulator of NRF2 degradation, and thereby prevents degradation of NRF2 resulting in activation of a NRF2-dependent transcriptional program, reduced intracellular ROS and enhanced chemoresistance. Our findings define a novel role of ATDC in regulating redox balance and chemotherapeutic resistance by modulating NRF2 activity.

Oncogenic N-Ras Mitigates Oxidative Stress-Induced Apoptosis of Hematopoietic Stem Cells.

Leukemic relapse is believed to be driven by transformed hematopoietic stem cells (HSC) that harbor oncogenic mutations or have lost tumor suppressor function. Recent comprehensive sequencing studies have shown that mutations predicted to activate Ras signaling are highly prevalent in hematologic malignancies and, notably, in refractory and relapsed cases. To better understand what drives this clinical phenomenon, we expressed oncogenic NrasG12D within the hematopoietic system in mice and interrogated its effects on HSC survival. N-RasG12D conferred a survival benefit to HSCs and progenitors following metabolic and genotoxic stress. This effect was limited to HSCs and early progenitors and was independent of autophagy and cell proliferation. N-RasG12D-mediated HSC survival was not affected by inhibition of canonical Ras effectors such as MEK and PI3K. However, inhibition of the noncanonical Ras effector pathway protein kinase C (PKC) ameliorated the protective effects of N-RasG12D. Mechanistically, N-RasG12D lowered levels of reactive oxygen species (ROS), which correlated with reduced mitochondrial membrane potential and ATP levels. Inhibition of PKC restored the levels of ROS to that of control HSCs and abrogated the protective effects granted by N-RasG12D. Thus, N-RasG12D activation within HSCs promotes cell survival through the mitigation of ROS, and targeting this mechanism may represent a viable strategy to induce apoptosis during malignant transformation of HSCs. SIGNIFICANCE: Targeting oncogenic N-Ras-mediated reduction of ROS in hematopoietic stem cells through inhibition of the noncanonical Ras effector PKC may serve as a novel strategy for treatment of leukemia and other Ras-mutated cancers.

The Emerging Role of Ras Pathway Signaling in Pediatric Cancer.

As genomic sequencing has become more widely available, the high prevalence of Ras pathway mutations in pediatric diseases has begun to emerge. Germline Ras-activating mutations have been known to contribute to cancer predisposition in a group of disorders known as the RASopathies, and now large pediatric sequencing studies have identified frequent somatic Ras pathway alterations across a diverse group of pediatric malignancies. These include glial brain tumors, relapsed high-risk neuroblastoma, embryonal rhabdomyosarcoma, acute myeloid leukemia, and relapsed acute lymphoblastic leukemia, and their prognostic impact is becoming increasingly better understood. Clinically, there has been success in targeting the Ras pathway in pediatric diseases, including the use of MEK inhibitors in plexiform neurofibromas associated with neurofibromatosis type 1 and the use of Ras pathway inhibitors in low-grade gliomas. Given the importance of this pathway in pediatric cancer, it is imperative that future studies strive to better understand the functional significance of these mutations, including their role in tumor growth and treatment resistance and how they can be better targeted to improve outcomes.

Mutations predictive of hyperactive Ras signaling correlate with inferior survival across high-risk pediatric acute leukemia.

BACKGROUND: Cancer remains the number one cause of disease-related mortality in children, and despite advances in the molecular understanding of leukemia and targeted therapies, refractory leukemia remains a leading cause of death. It therefore is essential to further define features, e.g., FLT3 alterations and KMT2A rearrangements, associated with inferior survival early to augment or alter therapeutic strategies to improve outcomes. METHODS: To gain insights into the genetic drivers predictive of aggressive clinical behavior among pediatric leukemia patients, we performed comprehensive integrative clinical sequencing (ICS), including paired tumor/normal DNA sequencing and RNA-seq, for pediatric patients who presented at our institution over a period of five years with acute lymphoblastic or myelogenous leukemia (ALL and AML; n=43) and high-risk clinical features (high white blood cell count, extramedullary disease, or refractory and/or relapsed disease). RESULTS: We found that RAS- and Ras-pathway aberrations, including N-RAS, NF1 and PTPN11, are frequent somatic mutations and, importantly, associated with decreased event free and overall survival (OS) (P=0.04, median event free survival 22.8 vs. 5.6 months; P=0.04, median OS 124 vs. 22.5 months). CONCLUSIONS: We thus propose that hyperactive Ras signaling confers inferior survival in high-risk pediatric acute leukemia and that Ras pathways should be molecularly characterized to inform clinical decision making and to identify patients for experimental clinical trials and RAS-targeted therapy.

ATDC/TRIM29 Drives Invasive Bladder Cancer Formation through miRNA-Mediated and Epigenetic Mechanisms.

Bladder cancer is a common and deadly malignancy but its treatment has advanced little due to poor understanding of the factors and pathways that promote disease. ATDC/TRIM29 is a highly expressed gene in several lethal tumor types, including bladder tumors, but its role as a pathogenic driver has not been established. Here we show that overexpression of ATDC in vivo is sufficient to drive both noninvasive and invasive bladder carcinoma development in transgenic mice. ATDC-driven bladder tumors were indistinguishable from human bladder cancers, which displayed similar gene expression signatures. Clinically, ATDC was highly expressed in bladder tumors in a manner associated with invasive growth behaviors. Mechanistically, ATDC exerted its oncogenic effects by suppressing miR-29 and subsequent upregulation of DNMT3A, leading to DNA methylation and silencing of the tumor suppressor PTEN. Taken together, our findings established a role for ATDC as a robust pathogenic driver of bladder cancer development, identified downstream effector pathways, and implicated ATDC as a candidate biomarker and therapeutic target.

ATDC (Ataxia Telangiectasia Group D Complementing) Promotes Radioresistance through an Interaction with the RNF8 Ubiquitin Ligase.

Induction of DNA damage by ionizing radiation (IR) and/or cytotoxic chemotherapy is an essential component of cancer therapy. The ataxia telangiectasia group D complementing gene (ATDC, also called TRIM29) is highly expressed in many malignancies. It participates in the DNA damage response downstream of ataxia telangiectasia-mutated (ATM) and p38/MK2 and promotes cell survival after IR. To elucidate the downstream mechanisms of ATDC-induced IR protection, we performed a mass spectrometry screen to identify ATDC binding partners. We identified a direct physical interaction between ATDC and the E3 ubiquitin ligase and DNA damage response protein, RNF8, which is required for ATDC-induced radioresistance. This interaction was refined to the C-terminal portion (amino acids 348-588) of ATDC and the RING domain of RNF8 and was disrupted by mutation of ATDC Ser-550 to alanine. Mutations disrupting this interaction abrogated ATDC-induced radioresistance. The interaction between RNF8 and ATDC, which was increased by IR, also promoted downstream DNA damage responses such as IR-induced γ-H2AX ubiquitination, 53BP1 phosphorylation, and subsequent resolution of the DNA damage foci. These studies define a novel function for ATDC in the RNF8-mediated DNA damage response and implicate RNF8 binding as a key determinant of the radioprotective function of ATDC.

ATDC induces an invasive switch in KRAS-induced pancreatic tumorigenesis.

The initiation of pancreatic ductal adenocarcinoma (PDA) is linked to activating mutations in KRAS. However, in PDA mouse models, expression of oncogenic mutant KRAS during development gives rise to tumors only after a prolonged latency or following induction of pancreatitis. Here we describe a novel mouse model expressing ataxia telangiectasia group D complementing gene (ATDC, also known as TRIM29 [tripartite motif 29]) that, in the presence of oncogenic KRAS, accelerates pancreatic intraepithelial neoplasia (PanIN) formation and the development of invasive and metastatic cancers. We found that ATDC up-regulates CD44 in mouse and human PanIN lesions via activation of ß-catenin signaling, leading to the induction of an epithelial-to-mesenchymal transition (EMT) phenotype characterized by expression of Zeb1 and Snail1. We show that ATDC is up-regulated by oncogenic Kras in a subset of PanIN cells that are capable of invading the surrounding stroma. These results delineate a novel molecular pathway for EMT in pancreatic tumorigenesis, showing that ATDC is a proximal regulator of EMT.

The immunomodulatory benzodiazepine Bz-423 inhibits B-cell proliferation by targeting c-myc protein for rapid and specific degradation.

Myc proteins regulate cell growth and are oncogenic in many cancers. Although these proteins are validated molecular anticancer targets, new therapies aimed at modulating myc have yet to emerge. A benzodiazepine (Bz-423) that was discovered in efforts to find new drugs for lupus was found recently to have antiproliferative effects on Burkitt's lymphoma cells. We now show that the basis for the antiproliferative effects of Bz-423 is the rapid and specific depletion of c-myc protein, which is coupled to growth-suppressing effects on key regulators of proliferation and cell cycle progression. c-Myc is depleted as a result of signals coupled to Bz-423 binding its molecular target, the oligomycin sensitivity-conferring protein subunit of the mitochondrial F(1)F(o)-ATPase. Bz-423 inhibits F(1)F(o)-ATPase activity, blocking respiratory chain function and generating superoxide, which at growth-inhibiting concentrations triggers proteasomal degradation of c-myc. Bz-423-induced c-myc degradation is independent of glycogen synthase kinase but is substantially blocked by mutation of the phosphosensitive residue threonine 58, which when phosphorylated targets c-myc for ubiquitination and subsequent proteasomal degradation. Collectively, this work describes a new lead compound, with drug-like properties, which regulates c-myc by a novel molecular mechanism that may be therapeutically useful.