Germline pathogenic variants in neuroblastoma patients are enriched in BARD1 and predict worse survival.

BACKGROUND: Neuroblastoma is an embryonal cancer of the developing sympathetic nervous system. The genetic contribution of rare pathogenic or likely pathogenic germline variants in patients without a family history remains unclear. METHODS: Germline DNA sequencing was performed on 786 neuroblastoma patients. The frequency of rare cancer predisposition gene pathogenic or likely pathogenic variants in patients was compared with 2 cancer-free control cohorts. Matched tumor DNA sequencing was evaluated for second hits, and germline DNA array data from 5585 neuroblastoma patients and 23 505 cancer-free control children were analyzed to identify rare germline copy number variants. Patients with germline pathogenic or likely pathogenic variants were compared with those without to test for association with clinical characteristics, tumor features, and survival. RESULTS: We observed 116 pathogenic or likely pathogenic variants involving 13.9% (109 of 786) of neuroblastoma patients, representing a statistically significant excess burden compared with cancer-free participants (odds ratio [OR] = 1.60, 95% confidence interval [CI] = 1.27 to 2.00). BARD1 harbored the most statistically significant enrichment of pathogenic or likely pathogenic variants (OR = 32.30, 95% CI = 6.44 to 310.35). Rare germline copy number variants disrupting BARD1 were identified in patients but absent in cancer-free participants (OR = 29.47, 95% CI = 1.52 to 570.70). Patients harboring a germline pathogenic or likely pathogenic variant had a worse overall survival compared with those without (P = 8.6 x 10-3). CONCLUSIONS: BARD1 is an important neuroblastoma predisposition gene harboring both common and rare germline pathogenic or likely pathogenic variations. The presence of any germline pathogenic or likely pathogenic variant in a cancer predisposition gene was independently predictive of worse overall survival. As centers move toward paired tumor-normal sequencing at diagnosis, efforts should be made to centralize data and provide an infrastructure to support cooperative longitudinal prospective studies of germline pathogenic variation

Epigenomic profiling of neuroblastoma cell lines.

Understanding the aberrant transcriptional landscape of neuroblastoma is necessary to provide insight to the underlying influences of the initiation, progression and persistence of this developmental cancer. Here, we present chromatin immunoprecipitation sequencing (ChIP-Seq) data for the oncogenic transcription factors, MYCN and MYC, as well as regulatory histone marks H3K4me1, H3K4me3, H3K27Ac, and H3K27me3 in ten commonly used human neuroblastoma-derived cell line models. In addition, for all of the profiled cell lines we provide ATAC-Seq as a measure of open chromatin. We validate specificity of global MYCN occupancy in MYCN amplified cell lines and functional redundancy of MYC occupancy in MYCN non-amplified cell lines. Finally, we show with H3K27Ac ChIP-Seq that these cell lines retain expression of key neuroblastoma super-enhancers (SE). We anticipate this dataset, coupled with available transcriptomic profiling on the same cell lines, will enable the discovery of novel gene regulatory mechanisms in neuroblastoma

RB1 in cancer: Different mechanisms of RB1 inactivation and alterations of pRb pathway in tumorigenesis.

Loss of RB1 gene is considered either a causal or an accelerating event in retinoblastoma. A variety of mechanisms inactivates RB1 gene, including intragenic mutations, loss of expression by methylation and chromosomal deletions, with effects which are species-and cell type-specific. RB1 deletion can even lead to aneuploidy thus greatly increasing cancer risk. The RB1gene is part of a larger gene family that includes RBL1 and RBL2, each of the three encoding structurally related proteins indicated as pRb, p107, and p130, respectively. The great interest in these genes and proteins springs from their ability to slow down neoplastic growth. pRb can associate with various proteins by which it can regulate a great number of cellular activities. In particular, its association with the E2F transcription factor family allows the control of the main pRb functions, while the loss of these interactions greatly enhances cancer development. As RB1 gene, also pRb can be functionally inactivated through disparate mechanisms which are often tissue specific and dependent on the scenario of the involved tumor suppressors and oncogenes. The critical role of the context is complicated by the different functions played by the RB proteins and the E2F family members. In this review, we want to emphasize the importance of the mechanisms of RB1/pRb inactivation in inducing cancer cell development. The review is divided in three chapters describing in succession the mechanisms of RB1 inactivation in cancer cells, the alterations of pRb pathway in tumorigenesis and the RB protein and E2F family in cance

The miR-17/92 cluster: a comprehensive update on its genomics, genetics, functions and increasingly important and numerous roles in health and disease.

The miR-17/92 cluster is among the best-studied microRNA clusters. Interest in the cluster and its members has been increasing steadily and the number of publications has grown exponentially since its discovery with more than 1000 articles published in 2012 alone. Originally found to be involved in tumorigenesis, research work in recent years has uncovered unexpected roles for its members in a wide variety of settings that include normal development, immune diseases, cardiovascular diseases, neurodegenerative diseases and aging. In light of its ever-increasing importance and ever-widening regulatory roles, we review here the latest body of knowledge on the cluster\u27s involvement in health and disease as well as provide a novel perspective on the full spectrum of protein-coding and non-coding transcripts that are likely regulated by its members

Cooperation between Rb and Arf in suppressing mouse retinoblastoma

Retinoblastoma is a pediatric cancer that has served as a paradigm for tumor suppressor gene function. Retinoblastoma is initiated by RB gene mutations, but the subsequent cooperating mutational events leading to tumorigenesis are poorly characterized. We investigated what these additional genomic alterations might be using human retinoblastoma samples and mouse models. Array-based comparative genomic hybridization studies revealed deletions in the CDKN2A locus that include ARF and P16INK4A, both of which encode tumor suppressor proteins, in both human and mouse retinoblastoma. Through mouse genetic analyses, we found that Arf was the critical tumor suppressor gene in the deleted region. In mice, inactivation of one allele of Arf cooperated with Rb and p107 loss to rapidly accelerate retinoblastoma, with frequent loss of heterozygosity (LOH) at the Arf locus. Arf has been reported to exhibit p53-independent tumor suppressor roles in other systems; however, our results showed no additive effect of p53 and Arf coinactivation in promoting retinoblastoma. Moreover, p53 inactivation completely eliminated any selection for Arf LOH. Thus, our data reveal important insights into the p53 pathway in retinoblastoma and show that Arf is a key collaborator with Rb in retinoblastoma suppression

PTEN Is a Potent Suppressor of Small Cell Lung Cancer

UnlabelledSmall cell lung carcinoma (SCLC) is a highly metastatic tumor type with neuroendocrine features and a dismal prognosis. PTEN mutations and PIK3CA activating mutations have been reported in SCLC but the functional relevance of this pathway is unknown. The PTEN/PIK3CA pathway was interrogated using an AdenoCre-driven mouse model of SCLC harboring inactivated Rb and p53. Inactivation of one allele of PTEN in Rb/p53-deleted mice led to accelerated SCLC with frequent metastasis to the liver. In contrast with the high mutation burden reported in human SCLC, exome analyses revealed a low number of protein-altering mutations in mouse SCLC. Inactivation of both alleles of PTEN in the Rb/p53-deleted system led to nonmetastatic adenocarcinoma with neuroendocrine differentiation. This study reveals a critical role for the PTEN/PI3K pathway in both SCLC and lung adenocarcinoma and provides an ideal system to test the phosphoinositide 3-kinase (PI3K) pathway inhibitors as targeted therapy for subsets of patients with SCLC.ImplicationsThe ability of PTEN inactivation to accelerate SCLC in a genetic mouse model suggests that targeting the PTEN pathway is a therapeutic option for a subset of human patients with SCLC. VISUAL OVERVIEW: http://mcr.aacrjournals.org/content/early/2014/04/28/1541-7786.MCR-13-0554/F1.large.jpg

miR-17∼92 cooperates with RB pathway mutations to promote retinoblastoma

miR-17∼92 does not act via the miR-19–PTEN–apoptosis axis that is widely thought to underlie miR-17∼92 function in cancer cells. Instead, RB family member deletion led to compensation involving up-regulation of p21Cip1 and other CDK inhibitors (CDKIs) in retinoblastoma. Thus, the oncogenic determinants of miR-17∼92 are context-specific

PTEN Is a Potent Suppressor of Small Cell Lung Cancer

Small cell lung carcinoma (SCLC) is a highly metastatic tumor type with neuroendocrine features and a dismal prognosis. PTEN mutations and PIK3CA activating mutations have been reported in SCLC but the functional relevance of this pathway is unknown. The PTEN/PIK3CA pathway was interrogated using an AdenoCre-driven mouse model of SCLC harboring inactivated Rb and p53. Inactivation of one allele of PTEN in Rb/p53-deleted mice led to accelerated SCLC with frequent metastasis to the liver. In contrast to the high mutation burden reported in human SCLC, exome analyses revealed a low number of protein-altering mutations in mouse SCLC. Inactivation of both alleles of PTEN in the Rb/p53-deleted system led to non-metastatic adenocarcinoma with neuroendocrine differentiation. This study reveals a critical role for the PTEN/PI3-kinase pathway in both SCLC and lung adenocarcinoma and provides an ideal system to test PI3-kinase pathway inhibitors as targeted therapy for subsets of SCLC patients