A Literature Review and Pooled Case Analysis of Cardiofaciocutaneous Syndrome to Estimate Cancer Risk.

Background: Cardiofaciocutaneous syndrome (CFC) is a rare disorder with multiple congenital anomalies including macrocephaly, failure to thrive, and neurocognitive delay. CFC is part "RASopathy" syndromes caused by pathogenic germline variants in and To estimate cancer risk in CFC we conducted a systematic review using case reports and series.

Methods: We reviewed articles and abstracted CFC cases to form a retrospective cohort based on PRISMA guidelines.

Cancer incidence and surveillance strategies in individuals with RASopathies.

RASopathies are a set of clinical syndromes that have molecular and clinical overlap. Genetically, these syndromes are defined by germline pathogenic variants in RAS/MAPK pathway genes resulting in activation of this pathway. Clinically, their common molecular signature leads to comparable phenotypes, including cardiac anomalies, neurologic disorders and notably, elevated cancer risk.

Epigenetic downregulation of Socs2 contributes to mutant N-Ras-mediated hematopoietic dysregulation.

RAS mutations occur in a broad spectrum of human hematopoietic malignancies. Activating Ras mutations in blood cells leads to hematopoietic malignancies in mice. In murine hematopoietic stem cells (HSCs), mutant N-RasG12D activates Stat5 to dysregulate stem cell function.

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.

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 within the hematopoietic system in mice and interrogated its effects on HSC survival.

ER-associated degradation preserves hematopoietic stem cell quiescence and self-renewal by restricting mTOR activity.

Hematopoietic stem cells (HSC) self-renew to sustain stem cell pools and differentiate to generate all types of blood cells. HSCs remain in quiescence to sustain their long-term self-renewal potential. It remains unclear whether protein quality control is required for stem cells in quiescence when RNA content, protein synthesis, and metabolic activities are profoundly reduced.

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.

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.

Adaptive endoplasmic reticulum stress signalling via IRE1α-XBP1 preserves self-renewal of haematopoietic and pre-leukaemic stem cells.

Over their lifetime, long-term haematopoietic stem cells (HSC) are exposed to a variety of stress conditions that they must endure. Many stresses, such as infection/inflammation, reactive oxygen species, nutritional deprivation and hypoxia, activate unfolded protein response signalling, which induces either adaptive changes to resolve the stress or apoptosis to clear the damaged cell. Whether unfolded-protein-response signalling plays any role in HSC regulation remains to be established.

Oncogenic N-Ras and Tet2 haploinsufficiency collaborate to dysregulate hematopoietic stem and progenitor cells.

Concurrent genetic lesions exist in a majority of patients with hematologic malignancies. Among these, somatic mutations that activate oncogenes and inactivate the epigenetic modifier ten-eleven translocation 2 () frequently co-occur in human chronic myelomonocytic leukemias (CMMLs) and acute myeloid leukemias, suggesting a cooperativity in malignant transformation. To test this, we applied a conditional murine model that endogenously expressed oncogenic and monoallelic loss of and explored the collaborative role specifically within hematopoietic stem and progenitor cells (HSPCs) at disease initiation.

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 (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.

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.

ATDC/TRIM29 phosphorylation by ATM/MAPKAP kinase 2 mediates radioresistance in pancreatic cancer cells.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by therapeutic resistance for which the basis is poorly understood. Here, we report that the DNA and p53-binding protein ATDC/TRIM29, which is highly expressed in PDAC, plays a critical role in DNA damage signaling and radioresistance in pancreatic cancer cells. Ataxia-telangiectasia group D-associated gene (ATDC) mediated resistance to ionizing radiation in vitro and in vivo in mouse xenograft assays.

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.