The RB1 Story: Characterization and Cloning of the First Tumor Suppressor Gene.

The RB1 gene is the first described human tumor suppressor gene and plays an integral role in the development of retinoblastoma, a pediatric malignancy of the eye. Since its discovery, the stepwise characterization and cloning of RB1 have laid the foundation for numerous advances in the understanding of tumor suppressor genes, retinoblastoma tumorigenesis, and inheritance. Knowledge of RB1 led to a paradigm shift in the field of cancer genetics, including widespread acceptance of the concept of tumor suppressor genes, and has provided crucial diagnostic and prognostic information through genetic testing for patients affected by retinoblastoma. This article reviews the long history of RB1 gene research, characterization, and cloning, and also discusses recent advances in retinoblastoma genetics that have grown out of this foundational work

Every-Other-Day Clutch-Initiation Synchrony as an Adaptive Response to Egg Cannibalism in Glaucous-Winged Gulls (Larus glaucescens)

Sea surface temperatures (SST) in the Pacific Northwest of North America rose 1 °C during the last half of the twentieth century. Cannibalism, a behavior observed in diverse taxa, is often associated with low food supplies, which for marine animals can be precipitated by high SSTs. In an 8 year study, we found that in years of higher sea surface temperatures, Glaucous-winged Gulls (Larus glaucescens) breeding in a colony in Washington State, Salish Sea, USA, tended to exhibit higher rates of egg cannibalism by males, higher levels of every-other-day clutch-initiation synchrony by females, and longer egg-laying seasons than in years of lower SST. Clutch-initiation synchrony increased the odds that an egg survived cannibalism and may serve as an adaptive response to egg cannibalism. Short-term climate and resource fluctuations associated with El Niño Southern Oscillation (ENSO) events may select for behavioral plasticity in marine organisms, allowing long-lived individuals such as marine birds to switch between alternative life history tactics. The implications for long-term SST warming, however, remain unknown

Egg cannibalism as a foraging tactic by less fit Glaucous-winged Gulls (Larus glaucescens)

Cannibalism, the killing and eating of conspecifics of any life stage, leads to a variety of behavioral and ecological consequences and is influenced by a range of environmental circumstances among numerous taxa. In birds, cannibalism is particularly well known among gulls. Although multiple studies have linked cannibalism to egg and chick failure in gull populations, gull cannibal behavior is poorly understood. During the 2014 and 2015 breeding seasons, we observed the behavior of Glaucous-winged Gulls (Larus glaucescens) that used conspecific egg predation, a form of cannibalism, as a feeding tactic on Protection Island, Washington, USA. Most egg stealing by egg cannibals occurred during colony disturbances, especially by Bald Eagles (Haliaeetus leucocephalus), but egg stealing often occurred without concurrent disturbances. Among other findings, our data showed that egg cannibals were always males, the number of eggs stolen each day correlated with the daily number of eggs laid, egg cannibals ate fewer fish than non-cannibals, and the reproductive success of egg cannibals was lower than that of non-cannibals. This study provides the most comprehensive evaluation to date of how larid cannibals find, capture, and eat conspecific eggs, and it includes the first assessment of reproductive success of egg cannibals in comparison with non-cannibals

Establishing the Clinical Utility of ctDNA Analysis for Diagnosis, Prognosis, and Treatment Monitoring of Retinoblastoma: The Aqueous Humor Liquid Biopsy

Because direct tumor biopsy is prohibited for retinoblastoma (RB), eye-specific molecular biomarkers are not used in clinical practice for RB. Recently, we demonstrated that the aqueous humor (AH) is a rich liquid biopsy source of cell-free tumor DNA. Herein, we detail clinically-relevant molecular biomarkers from the first year of prospective validation data. Seven eyes from 6 RB patients who had AH sampled at diagnosis and throughout therapy with ≥12 months of follow-up were included. Cell-free DNA (cfDNA) from each sample was isolated and sequenced to assess genome-wide somatic copy number alterations (SCNAs), followed by targeted resequencing for pathogenic variants using a RB1 and MYCN custom hybridization panel. Tumoral genomic information was detected in 100% of diagnostic AH samples. Of the seven diagnostic AH samples, 5/7 were positive for RB SCNAs. Mutational analysis identified RB1 variants in 5/7 AH samples, including the 2 samples in which no SCNAs were detected. Two eyes failed therapy and required enucleation; both had poor prognostic biomarkers (chromosome 6p gain or MYCN amplification) present in the AH at the time of diagnosis. In the context of previously established pre-analytical, analytical, and clinical validity, this provides evidence for larger, prospective studies to further establish the clinical utility of the AH liquid biopsy and its applications to precision oncology for RB

Response criteria for intraocular retinoblastoma: RB-RECIST

Standardized guidelines for assessing tumor response to therapy are essential for designing and conducting clinical trials. The Response Evaluation Criteria In Solid Tumors (RECIST) provide radiological standards for assessment of solid tumors. However, no such guidelines exist for the evaluation of intraocular cancer, and ocular oncology clinical trials have largely relied on indirect measures of therapeutic response—such as progression-free survival—to evaluate the efficacy of treatment agents. Herein, we propose specific criteria for evaluating treatment response of retinoblastoma, the most common pediatric intraocular cancer, and emphasize a multimodal imaging approach for comprehensive assessment of retinoblastoma tumors in clinical trials.Fil: Berry, Jesse L.. University of Southern California; Estados UnidosFil: Munier, Francis L.. Universite de Lausanne; SuizaFil: Gallie, Brenda L.. University of Toronto; Canadá. University Of Toronto. Hospital For Sick Children; CanadáFil: Polski, Ashley. University of Southern California; Estados UnidosFil: Shah, Sona. University of Southern California; Estados UnidosFil: Shields, Carol L.. Wills Eye Hospital; Estados UnidosFil: Gombos, Dan S.. University of Texas; Estados UnidosFil: Ruchalski, Kathleen. University of California at Los Angeles. School of Medicine; Estados UnidosFil: Stathopoulos, Christina. Universite de Lausanne; SuizaFil: Shah, Rachana. Cancer and Blood Disease Institute at Children’s Hospital Los Angeles; Estados UnidosFil: Jubran, Rima. Cancer and Blood Disease Institute at Children’s Hospital Los Angeles; Estados UnidosFil: Kim, Jonathan W.. Cancer and Blood Disease Institute at Children’s Hospital Los Angeles; Estados UnidosFil: Mruthyunjaya, Prithvi. University of Stanford; Estados UnidosFil: Marr, Brian P.. Columbia University Medical Center; Estados UnidosFil: Wilson, Matthew W.. University of Tennessee Health Science Center,; Estados UnidosFil: Brennan, Rachel C.. No especifíca;Fil: Chantada, Guillermo Luis. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina. Universidad Austral. Facultad de Ciencias Biomédicas. Instituto de Investigaciones en Medicina Traslacional. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones en Medicina Traslacional; ArgentinaFil: Chintagumpala, Murali M.. Texas Children’s Cancer Center; Estados UnidosFil: Murphree, A. Linn. The Vision Center at Children’s Hospital Los Angeles; Estados Unido

The Effects of Breastfeeding on Retinoblastoma Development: Results from an International Multicenter Retinoblastoma Survey

The protective effects of breastfeeding on various childhood malignancies have been established but an association has not yet been determined for retinoblastoma (RB). We aimed to further investigate the role of breastfeeding in the severity of nonhereditary RB development, assessing relationship to (1) age at diagnosis, (2) ocular prognosis, measured by International Intraocular RB Classification (IIRC) or Intraocular Classification of RB (ICRB) group and success of eye salvage, and (3) extraocular involvement. Analyses were performed on a global dataset subgroup of 344 RB patients whose legal guardian(s) consented to answer a neonatal questionnaire. Patients with undetermined or mixed feeding history, family history of RB, or sporadic bilateral RB were excluded. There was no statistically significant difference between breastfed and formula-fed groups in (1) age at diagnosis (p = 0.20), (2) ocular prognosis measures of IIRC/ICRB group (p = 0.62) and success of eye salvage (p = 0.16), or (3) extraocular involvement shown by International Retinoblastoma Staging System (IRSS) at presentation (p = 0.74), lymph node involvement (p = 0.20), and distant metastases (p = 0.37). This study suggests that breastfeeding neither impacts the sporadic development nor is associated with a decrease in the severity of nonhereditary RB as measured by age at diagnosis, stage of disease, ocular prognosis, and extraocular spread. A further exploration into the impact of diet on children who develop RB is warranted