The zinc-finger protein ZCCHC2 suppresses retinoblastoma tumorigenesis by inhibiting HectH9-mediated K63-linked polyubiquitination and activation of c-Myc.

Retinoblastoma (RB) is the most common intraocular malignancy. The tumor propagation of RB is maintained by several core transcriptional regulators, including c-Myc. Strictly regulated posttranslational modifications control the c-Myc protein. However, the posttranslational regulatory mechanisms for c-Myc in retinoblastoma remain largely unclear. Here, we identified the zinc-finger protein ZCCHC2 as a critical negative regulator of c-Myc-associated tumorigenesis. Knockout of ZCCHC2 promoted retinoblastoma cell proliferation, whereas ZCCHC2 overexpression had the opposite effect. Meanwhile, the level of ZCCHC2 was positively correlated with retinoblastoma tumorigenesis and animal survival in vivo. Mechanistically, ZCCHC2 was associated with c-Myc and negatively regulated the K63-linked polyubiquitination of c-Myc. We demonstrated that ZCCHC2 inhibits the interaction of the E3 ubiquitin ligase HectH9 with c-Myc and that ZCCHC2 inhibits HectH9-mediated K63-linked polyubiquitination and activation of c-Myc. Altogether, these data suggest that ZCCHC2 plays a role in the regulation of RB tumorigenesis through the inhibition activity of c-Myc.

Medical radiation exposure and risk of sporadic retinoblastoma.

BACKGROUND: While there is evidence that parental exposure to medical radiation is associated with increased risk of sporadic bilateral retinoblastoma in offspring, this association has not been confirmed. Additionally, the relationship between paternal and maternal exposures and sporadic unilateral retinoblastoma has not been fully investigated. PROCEDURE: Data were obtained from two large multicenter case-control studies of retinoblastoma. For the paternal analyses, 268 bilateral cases, 155 unilateral cases, and 358 controls were included. For the maternal analyses, 298 bilateral cases, 184 unilateral cases, and 404 controls were included. Logistical regression models were used to estimate odds ratios (OR) and 95% confidence intervals (CI) to evaluate the associations between parental exposures to medical radiation and sporadic retinoblastoma, while adjusting for potential confounders. RESULTS: Paternal exposure to medical radiation was not significantly associated with sporadic bilateral retinoblastoma in offspring. However, increasing paternal exposure to gonadal radiation was associated with increased risk of unilateral retinoblastoma (P-trend = .03). Maternal history of upper and lower gastrointestinal (GI) series was associated with bilateral retinoblastoma (OR = 1.9, 95% CI: 1.1-3.2 and OR = 6.9, 95% CI: 2.9-16.4, respectively). However, there was no association between maternal exposure to medical radiation and unilateral retinoblastoma in offspring. CONCLUSION: Our investigation adds to the evidence that medical radiation exposure in fathers as well as mothers prior to pregnancy may increase the risk of germline alterations leading to the development of retinoblastoma in their offspring. However, our findings could point to a more complex etiological framework for this important pediatric malignancy.

Changes in visual function and ocular morphology in women who have undergone ART treatment and children born as a result of ART treatment: a systematic review.

As all the structures of the human eye are characterized by sex hormone receptors, this study tested the hypothesis that assisted reproductive technology (ART) treatment influences visual function and ocular morphology in women who have undergone ART treatment and children born as a result of ART treatment. A systematic literature search of all original articles published up to August 2018 was performed using the PubMed database, including all original studies available in the literature. Review articles, studies in which participants underwent mixed interventions (i.e. other than ART treatment), studies reporting data on ocular malformations in ART offspring, and studies written in languages other than English were excluded. All selected articles were analysed to assess the level of evidence according to the Oxford Centre for Evidence-Based Medicine 2011 guidelines, and the quality of evidence according to the Grading of Recommendations Assessment, Development and Evaluation system. Although sparse data suggest that ART treatment can influence visual function and ocular morphology in women who have undergone ART treatment and children born as a result of ART treatment, the available evidence is inconclusive given its low level and quality. More high-quality research is needed to assess the potential interaction between ART treatment and the eye.

Retinoblastoma in Patients with 13q deletion syndrome - case series.

Deletion of the long arm of chromosome 13 (13q deletion syndrome) is very rare chromosomal aberration which causes mental retardation and multiple congenital malformations. Furthermore, it is associated with the increased risk of retinoblastoma. The aim of the paper was to present two cases of retinoblastomna in children with 13q deletion syndrome, discussing the diagnostic and therapeutic management, clinical manifestation and the importance of genetic testing which helps to determine the type of retinoblastoma and may also contribute to the diagnosis of other congenital abnormalities associated with intraocular tumors.

Maternal diet during pregnancy and unilateral retinoblastoma.

PURPOSE: Previous studies have suggested a role for parental diet in childhood cancer prevention, but there are few studies of retinoblastoma. The aim of this study was to examine the relation between maternal diet and unilateral retinoblastoma. METHODS: A case-control study of 163 unilateral RB cases and 136 controls ascertained information on maternal diet during pregnancy using a standardized food frequency questionnaire. Logistic regression was used to assess the relation between retinoblastoma and food groups and dietary patterns. RESULTS: We observed a negative association between retinoblastoma and intake of fruit [odds ratio (OR) 0.38, 95 % confidence interval (CI) 0.14-1.02]. Positive associations were seen with intake of cured meats (OR 5.07, 95 % CI 1.63-15.70) and fried foods (OR 4.89, 95 % CI 1.72-13.89). A food pattern of high fruits and vegetables and low fried food and sweets was negatively associated with disease (OR 0.75, 95 % CI 0.61-0.92). CONCLUSION: Our study provides preliminary evidence that mothers who consume diets higher in fruit and lower in fried foods and cured meats during pregnancy may reduce the risk of unilateral retinoblastoma in their offspring.

Optical coherence tomography enables imaging of tumor initiation in the TAg-RB mouse model of retinoblastoma.

PURPOSE: Retinoblastoma is the most common primary intraocular malignancy in children. Although significant advances in treatment have decreased mortality in recent years, morbidity continues to be associated with these therapies, and therefore, there is a pressing need for new therapeutic options. Transgenic mouse models are popular for testing new therapeutics as well as studying the pathophysiology of retinoblastoma. The T-antigen retinoblastoma (TAg-RB) model has close molecular and histological resemblance to human retinoblastoma tumors; these mice inactivate pRB by retinal-specific expression of the Simian Virus 40 T-antigens. Here, we evaluated whether optical coherence tomography (OCT) imaging could be used to document tumor growth in the TAg-RB model from the earliest stages of tumor development. METHODS: The Micron III rodent imaging system was used to obtain fundus photographs and OCT images of both eyes of TAg-RB mice weekly from 2 to 12 weeks of age and at 16 and 20 weeks of age to document tumor development. Tumor morphology was confirmed with histological analysis. RESULTS: Before being visible on funduscopy, hyperreflective masses arising in the inner nuclear layer were evident at 2 weeks of age with OCT imaging. After most of these hyperreflective cell clusters disappeared around 4 weeks of age, the first tumors became visible on OCT and funduscopy by 6 weeks. The masses grew into discrete, discoid tumors, preferentially in the periphery, that developed more irregular morphology over time, eventually merging and displacing the inner retinal layers into the vitreous. CONCLUSIONS: OCT is a non-invasive imaging modality for tracking early TAg-RB tumor growth in vivo. Using OCT, we characterized TAg-positive cells as early as 2 weeks, corresponding to the earliest stages at which tumors are histologically evident, and well before they are evident with funduscopy. Tracking tumor growth from its earliest stages will allow better analysis of the efficacy of novel therapeutics and genetic factors tested in this powerful mouse model.

miRNA signature identification of retinoblastoma and the correlations between differentially expressed miRNAs during retinoblastoma progression.

PURPOSE: Retinoblastoma (RB) is a common pediatric cancer. The study aimed to uncover the mechanisms of RB progression and identify novel therapeutic biomarkers. METHODS: The miRNA expression profile GSE7072, which includes three RB samples and three healthy retina samples, was used. After data normalization using the preprocessCore package, differentially expressed miRNAs (DE-miRs) were selected by the limma package. The targets of the DE-miRs were predicted based on two databases, followed by construction of the miRNA-target network. Pathway enrichment analysis was conducted for the targets of the DE-miRNAs using DAVID. The CTD database was used to predict RB-related genes, followed by clustering analysis using the pvclust package. The correlation network of DE-miRs was established. MiRNA expression was validated in another data set, GSE41321. RESULTS: In total, 24 DE-miRs were identified whose targets were correlated with the cell cycle pathway. Among them, hsa-miR-373, hsa-miR-125b, and hsa-miR-181a were highlighted in the miRNA-target regulatory network; 14 DE-miRs, including hsa-miR-373, hsa-miR-125b, hsa-miR-18a, hsa-miR-25, hsa-miR-20a, and hsa-let-7 (a, b, c), were shown to distinguish RB from healthy tissue. In addition, hsa-miR-25, hsa-miR-18a, and hsa-miR-20a shared the common target BCL2L11; hsa-let-7b and hsa-miR-125b targeted the genes CDC25A, CDK6, and LIN28A. Expression of three miRNAs in GSE41321 was consistent with that in GSE7072. CONCLUSIONS: Several critical miRNAs were identified in RB progression. Hsa-miR-373 might regulate RB invasion and metastasis, hsa-miR-181a might involve in the CDKN1B-mediated cell cycle pathway, and hsa-miR-125b and hsa-let-7b might serve as tumor suppressors by coregulating CDK6, CDC25A, and LIN28A. The miRNAs hsa-miR-25, hsa-miR-18a, and hsa-miR-20a might exert their function by coregulating BCL2L1.

A case-control study of sporadic retinoblastoma in relation to maternal health conditions and reproductive factors: a report from the Children's Oncology group.

BACKGROUND: The early age at retinoblastoma occurrence, the most common eye malignancy in childhood, suggests that perinatal factors may contribute to its etiology. METHODS: In a large multicenter study of non-familial retinoblastoma, we conducted structured interviews with the parents of 280 cases and 146 controls to elicit information on health during the perinatal period. We used unconditional logistic regression to assess associations between retinoblastoma and parental fertility treatment, birth control use in the year prior to pregnancy, maternal health conditions and the use of prescription medications during pregnancy, and whether mothers breastfed the index child. RESULTS: Bilateral retinoblastoma was related to maternal underweight (body mass index <18.5) prior to pregnancy [Odds Ratio (OR) = 4.5, 95 % confidence interval (CI) 1.0, 20]. With regards to unilateral retinoblastoma, we observed a negative association with the use of condoms in the year prior to pregnancy (OR = 0.4, CI 0.2, 0.9), and a trend towards a positive association with maternal diabetes (OR = 2.2, CI 0.8, 6.6). CONCLUSIONS: Results from our study suggest a role for several maternal health and reproductive factors. Given that there are few epidemiologic studies of retinoblastoma, our results require replication in studies which utilize medical record review.

Prenatal exposure to traffic-related air pollution and risk of early childhood cancers.

Exposure to air pollution during pregnancy has been linked to the risk of childhood cancer, but the evidence remains inconclusive. In the present study, we used land use regression modeling to estimate prenatal exposures to traffic exhaust and evaluate the associations with cancer risk in very young children. Participants in the Air Pollution and Childhood Cancers Study who were 5 years of age or younger and diagnosed with cancer between 1988 and 2008 were had their records linked to California birth certificates, and controls were selected from birth certificates. Land use regression-based estimates of exposures to nitric oxide, nitrogen dioxide, and nitrogen oxides were assigned based on birthplace residence and temporally adjusted using routine monitoring station data to evaluate air pollution exposures during specific pregnancy periods. Logistic regression models were adjusted for maternal age, race/ethnicity, educational level, parity, insurance type, and Census-based socioeconomic status, as well as child's sex and birth year. The odds of acute lymphoblastic leukemia increased by 9%, 23%, and 8% for each 25-ppb increase in average nitric oxide, nitrogen dioxide, and nitrogen oxide levels, respectively, over the entire pregnancy. Second- and third-trimester exposures increased the odds of bilateral retinoblastoma. No associations were found for annual average exposures without temporal components or for any other cancer type. These results lend support to a link between prenatal exposure to traffic exhaust and the risk of acute lymphoblastic leukemia and bilateral retinoblastoma.

Parental nutrient intake and risk of retinoblastoma resulting from new germline RB1 mutation.

PURPOSE: We conducted a case-control study to examine the role of parents' nutrient intake before their child's conception in the child's risk of sporadic bilateral retinoblastoma, which results from a new germline RB1 mutation. METHODS: Parents of 206 cases from 9 North American institutions and 269 friend and relative controls participated; fathers of 182 cases and 223 controls and mothers of 202 cases and 260 controls provided useable information in telephone interviews on their diet in the year before the child's conception. We also asked parents about supplements, a significant source of nutrients in users. RESULTS: Father's intake of dairy-associated nutrients and his use of calcium supplements were associated with decreased risk, while his intake of copper, manganese, and vitamin E was associated with increased risk. Mother's use of multivitamins close to conception was associated with lower risk as was her intake of several micronutrients found in these supplements. In analyses to elucidate the primary factor from multiple correlated factors, the most robust findings were for father's calcium intake (adjusted OR = 0.46-0.63 for 700 mg increase) and calcium supplement use (OR = 0.35-0.41) and mother's multivitamin use (ORs 0.28-0.48). CONCLUSIONS: There are few directly relevant studies but some data indirectly support the biologic plausibility of the inverse associations with father's calcium intake and mother's use of multivitamins; however, we cannot rule out contributions of bias, confounding, or chance. Our findings provide a starting point for further investigation of diet in the etiology of retinoblastoma and new germline mutation generally.

Retinoblastoma.

PURPOSE OF REVIEW: Retinoblastoma is the most common malignant intraocular tumor of childhood. Treatment and diagnostic modalities associated to this condition are changing rapidly as our understanding of this condition crystallizes. The purpose of this review is to provide an update of the current understanding of retinoblastoma. RECENT FINDINGS: Knowledge on tumorigenesis and genomic expression has expanded tremendously with the development of a mouse model for retinoblastoma. Tumor hypoxia has been identified as a significant step in the tumor progression and a novel target for future treatments. Current globe-sparing therapies, including periocular carboplatin, selective ophthalmic artery chemoreduction, intravitreal melphalan, and focal consolidation are being used and investigated actively. Diagnosis and the management of retinoblastoma is also undergoing major advances including wide-field photography, autofluorescence, and high-resolution optical coherence tomography. SUMMARY: Progressive advances in the understanding of retinoblastoma pathogenesis continue to lead treatment strategies. Improvements in the diagnosis and management of retinoblastoma are improving morbidity and mortality associated to this condition in the developed nations. However, it is of outmost importance to flatten the international boundaries to offer prompt care to retinoblastoma children in underdeveloped communities.

A case-control study of paternal occupational exposures and the risk of childhood sporadic bilateral retinoblastoma.

BACKGROUND: The risk factors for sporadic (ie, non-familial) retinoblastoma remain largely unknown. OBJECTIVES: We examined the relationship between paternal occupational exposures from jobs held 10 years and 1 year prior to conception and the risk of sporadic bilateral retinoblastoma in children. METHODS: Paternal occupational data were obtained for 198 incident cases diagnosed with sporadic bilateral retinoblastoma from January 1998 to May 2006 and 245 referral-based controls from the case child's relatives and friends who were matched to 135 of the cases on birth year. Industrial hygienists independently assigned exposure scores for nine agents. Adjusted ORs and 95% CIs were computed using logistic regression models, using the full sample of cases and controls as well as subset of cases with matched controls only. RESULTS: There was some indication of an elevated risk associated with paternal pesticide exposure in the 10 years prior to conception (OR=1.64; 95% CI 1.08 to 2.50) as well as in the year before conception (OR=2.12; 95% CI 1.25 to 3.61). However, results for pesticide exposure were inconsistent and varied by analysis approach. An increased risk was also observed for non-welding metal exposure during the 10 years prior to conception in the full (OR=1.35; 95% CI 0.86 to 2.12) and matched (OR=1.40; 95% CI 0.82 to 2.37) samples, but not in the year before conception. Exposure-response trends were observed for pesticides and non-welding metal exposures. CONCLUSIONS: Our findings suggest a potential role of paternal occupational exposures to non-welding metals and perhaps pesticides in the aetiology of childhood retinoblastoma.

The association between maternal nutrient intake during pregnancy and the risk of sporadic unilateral retinoblastoma among offspring.

Previous studies have associated maternal diet during pregnancy with the development of sporadic unilateral retinoblastoma (RB), but few studies have focused on the role of individual nutrients. The aim of this study is to investigate the association between maternal nutrient intake during pregnancy and the development of sporadic unilateral RB in the offspring. A modified food frequency questionnaire, with additional questions on supplement use, was completed via a phone interview. Cases were recruited from hospitals and controls were comprised of friends and relatives of the patient without a history of cancer. Overall, 168 sporadic unilateral RB cases and 145 controls were included in case-control study. We performed logistic regression to estimate odds ratios (ORs) and 95 % confidence intervals (CI), adjusting for child's age, child's sex, parental race/ethnicity, maternal education, total calorie intake during pregnancy, maternal age at birth, maternal smoking during pregnancy, pre-pregnancy body mass index, maternal weight gain during pregnancy, paternal age at birth, and maternal multivitamin use in the year before pregnancy. In the adjusted model, the interquartile (IQR) increase in vitamin A intake, which was measured in retinol activity equivalent (RAE; OR: 0.64, 95 % CI: 0.46-0.90), and vitamin D intake (OR: 0.62, 95 % CI: 0.42-0.91) significantly reduced the risk of sporadic unilateral RB. These findings suggest that a higher intake of vitamins A and D can be a protective factor for sporadic unilateral RB. Further analyses in consideration of multi-exposures such as parental occupational exposures are warranted to discover the complex etiology of sporadic unilateral RB. In addition, the role of nutritional epigenetics for how maternal nutrient intake influences the risk of sporadic unilateral RB in the offspring still needs to be explored.

Are children with birth defects at higher risk of childhood cancers?

Birth defects may influence the risk of childhood cancer development through a variety of mechanisms. The rarity of both birth defects and childhood cancers makes it challenging to study these associations, particularly for the very rare instances of each. To address this limitation, the authors conducted a record linkage-based cohort study among Texas children born between 1996 and 2005. Birth defects in the cohort were identified through the Texas Birth Defects Registry, and children who developed cancer were identified by using record linkage with Texas Cancer Registry data. Over 3 million birth records were included; 115,686 subjects had birth defects, and there were 2,351 cancer cases. Overall, children with a birth defect had a 3-fold increased risk of developing cancer (incidence rate ratio (IRR) = 3.05, 95% confidence interval (CI): 2.65, 3.50), with germ cell tumors (IRR = 5.19, 95% CI: 2.67, 9.41), retinoblastomas (IRR = 2.34, 95% CI: 1.21, 4.16), soft-tissue sarcomas (IRR = 2.12, 95% CI: 1.09, 3.79), and leukemias (IRR = 1.39, 95% CI: 1.09, 1.75) having statistically significant elevated point estimates. All birth defect groups except for musculoskeletal had increased cancer incidence. Untangling the strong relation between birth defects and childhood cancers could lead to a better understanding of the genetic and environmental factors that affect both conditions.

Risk of retinoblastoma is associated with a maternal polymorphism in dihydrofolatereductase (DHFR) and prenatal folic acid intake.

BACKGROUND: The incidence of unilateral retinoblastoma varies globally, suggesting possible environmental contributors to disease incidence. Maternal intake of naturally occurring folate from vegetables during pregnancy is associated inversely with the risk of retinoblastoma in offspring. METHODS: The authors used a case-control study design to examine the association between retinoblastoma risk and maternal variations in the folate-metabolizing genes methylenetetrahydrofolate reductase (MTHFR) (a cytosine-to-thymine substitution at nucleotide 677 [MTHFR677C→T]; reference single nucleotide polymorphism rs1801133) and dihydrofolate reductase (DHFR) (a 19-base-pair deletion of intron 1a [DHFR19bpdel]; rs70991108). In central Mexico, 103 mothers of children with newly diagnosed unilateral retinoblastoma were enrolled in an institutional review board-approved study along with a control group of 97 mothers who had healthy children. Mothers were interviewed regarding perinatal characteristics, including use of prenatal vitamin supplements, and gave peripheral blood samples, which were used for polymerase chain reaction-based genotyping of rs1801133 and rs70991108. RESULTS: The risk of having a child with unilateral retinoblastoma was associated with maternal homozygosity for DHFR19bpdel (odds ratio, 3.78; 95% confidence interval, 1.89-7.55; P = .0002), even after controlling for the child's DHFR19bpdel genotype (odds ratio, 2.81; 95% confidence interval, 1.32-5.99; P = .0073). In a subgroup of 167 mothers with data on prenatal intake of supplements containing folic acid (a synthetic form of folate), DHFR19bpdel-associated risk was elevated significantly only among those who reported taking folic acid supplements. Maternal MTHFR genotype was unrelated to the risk of having a child with retinoblastoma. CONCLUSIONS: Maternal homozygosity for a polymorphism in the DHFR gene necessary for converting synthetic folic acid into biologic folate was associated with an increased risk for retinoblastoma. Prenatal ingestion of synthetic folic acid supplements may be associated with increased risk for early childhood carcinogenesis in a genetically susceptible subset of the population.

Perinatal characteristics and retinoblastoma.

PURPOSE: The etiology of retinoblastoma remains poorly understood. In the present study, we examined associations between perinatal factors and retinoblastoma risk in California children. METHODS: We identified 609 retinoblastoma cases (420 unilateral, 187 bilateral, and 2 with laterality unknown) from California Cancer Registry records of diagnoses 1988-2007 among children < 6 years of age. We randomly selected 209,051 controls from California birth rolls. The source of most study data was birth certificates. Multivariable logistic regression was used to examine associations between retinoblastoma and perinatal characteristics. RESULTS: Bilateral retinoblastoma was associated with greater paternal age [for fathers over 35, crude odds ratio (OR) = 1.73, 95 % confidence interval (CI) 1.20, 2.47] and with twin births (OR = 1.93, 95 % CI 0.99, 3.79). Among unilateral cases, we observed an increased risk among children of US-born Hispanic mothers (OR = 1.34, 95 % CI 1.01, 1.77) while a decreased risk was observed for infants born to mothers with less than 9 years of education (OR = 0.70, 95 % CI 0.49, 1.00), a group that consisted primarily of mothers born in Mexico. We observed that maternal infection in pregnancy with any STD (OR = 3.59, 95 % CI 1.58, 8.15) was associated with bilateral retinoblastoma. CONCLUSIONS: This study supports the findings of previous investigations reporting associations between parental age, HPV infection, and retinoblastoma.

Are children born after infertility treatment at increased risk of retinoblastoma?

BACKGROUND: Retinoblastoma (RB) is the most frequent eye tumour in children, with an incidence of 1 in 15-20,000 births. It accounts for 11% of all cancers in the first year of life. Except for the hereditary forms, its causes are not well-known. Studies have recently suggested an increased risk of RB among children born after IVF, but the relevant literature is sparse. We assessed the association between infertility treatment, subfertility and RB. METHODS: We included all children living in France diagnosed with RB between 1 January 2000 and 31 December 2006 at the Institut Curie, the national reference centre for RB diagnosis and treatment. We used multiple logistic regression to compare them with a national sample of births in France in 1998 and 2003 (n = 28 170). RESULTS: The study included 244 non-familial RB cases. The risk of RB increased with maternal age [adjusted odds ratio (adj OR) = 2.07, 95% confidence interval (CI) 1.33-3.22 at 35-39 years compared with younger than 25 years and adj OR = 2.42, 95% CI 1.22-4.81 at 40 years or older], but the associations with IVF (adj OR = 1.37, 95% CI 0.64-2.95) and ovarian stimulation or intrauterine insemination (adj OR = 1.35, 95% CI 0.77-2.38) were not statistically significant after adjustment for maternal age and tobacco use. Among women who had no infertility treatment, the risk of RB was significantly increased when time to pregnancy exceeded 24 months (adj OR = 2.02, 95% CI 1.17-3.48) compared with time to pregnancy ≤ 24 months. CONCLUSIONS: Our study did not observe a significantly increased risk of RB associated with infertility treatment, in particular with IVF. But we did find an increased risk for women for whom time to pregnancy exceeded 24 months.

Medical radiation exposure and risk of retinoblastoma resulting from new germline RB1 mutation.

Although ionizing radiation induces germline mutations in animals, human studies of radiation-exposed populations have not detected an effect. We conducted a case-control study of sporadic bilateral retinoblastoma, which results from a new germline RB1 mutation, to investigate gonadal radiation exposure of parents from medical sources before their child's conception. Parents of 206 cases from nine North American institutions and 269 controls participated; fathers of 184 cases and 223 friend and relative controls and mothers of 204 cases and 260 controls provided information in telephone interviews on their medical radiation exposure. Cases provided DNA for RB1 mutation testing. Of common procedures, lower gastrointestinal (GI) series conferred the highest estimated dose to testes and ovaries. Paternal history of lower GI series was associated with increased risk of retinoblastoma in the child [matched odds ratio (OR) = 3.6, 95% confidence interval (CI) = 1.2-11.2, two-sided p = 0.02], as was estimated total testicular dose from all procedures combined (OR for highest dose=3.9, 95% CI = 1.2-14.4, p = 0.02). Maternal history of lower GI series was also associated with increased risk (OR = 7.6, 95% CI = 2.8-20.7, p < 0.001) as was the estimated total dose (OR for highest dose = 3.0, 95% CI = 1.4-7.0, p = 0.005). The RB1 mutation spectrum in cases of exposed parents did not differ from that of other cases. Some animal and human data support our findings of an association of gonadal radiation exposure in men and women with new germline RB1 mutation detectable in their children, although bias, confounding, and/or chance may also explain the results.

Trilateral retinoblastoma.

Trilateral retinoblastoma is the association of hereditary bilateral or unilateral retinoblastoma with a pineal neuroblastic tumour. We describe two cases of trilateral retinoblastoma from a total of 141 cases of retinoblastoma seen over an 8.5 year period. Both had a fatal outcome, with survival times of only 4 and 8 months respectively.

Parental Occupation and Risk of Childhood Retinoblastoma in Denmark.

OBJECTIVE: Retinoblastoma is the most common primary intraocular tumor affecting children. We examine the role of parental occupational exposures and risk of retinoblastoma among offspring. METHODS: Our population-based case-control study linked data from four nationwide Danish registries and included all cases of retinoblastoma diagnosed in Danish children (<5 y, n = 144) between 1975 and 2014. We focused on two biologically relevant time periods: 90 days preconception to conception for fathers; conception to birth for mothers. Parents were grouped into major industry headings created from Danish industry codes. RESULTS: We observed increased risk of all retinoblastoma for children of fathers in the food and drink industry and iron and metal industry. Bilateral disease was associated with paternal work in manufacturing and land transportation. CONCLUSION: Our results suggest that some occupational exposures may increase the risk of childhood sporadic retinoblastoma.