Sporadic Bilateral Retinoblastoma Research Articles

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

Simple SummaryBreastfeeding has been shown to lower the risk of oncogenesis in many pediatric cancers, with longer periods of breastfeeding having the most protective effect. However, an association has not yet been determined for the consequence or benefit of breastfeeding in retinoblastoma (RB), the most common intraocular malignancy of childhood affecting 8000 children worldwide each year. Herein, we aimed to understand the role of breastfeeding in the severity of development of nonhereditary RB, specifically its relationship to age at diagnosis, ocular prognosis, and extraocular involvement. Our analysis of 344 patients indicated that neither breastfeeding nor formula feeding was associated with differences in age at diagnosis, ocular prognosis, or extraocular involvement. More research elucidating the factors affecting the development of RB is warranted both to understand the pathophysiology of tumor development and to develop clinical recommendations for preventive care.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.

Medical radiation exposure and risk of sporadic retinoblastoma.

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. 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. 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. 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.

Abstract 5039: Medical radiation exposure and risk of retinoblastoma: A report from the Children’s Oncology Group

Abstract Retinoblastoma, which results from mutations in the RB1 gene, is the most common intraocular malignancy in childhood. Approximately 10% of cases are familial, and the remaining cases (both bilateral and unilateral) are considered sporadic. Although little is known about the causes of sporadic cases, there is some evidence that parental exposure to medical radiation is associated with sporadic bilateral retinoblastoma in offspring. These findings, however, have not been confirmed. Further, the relation between medical radiation exposure and sporadic unilateral retinoblastoma has not been investigated. Therefore, we evaluated the role of medical radiation exposure on sporadic bilateral and unilateral retinoblastoma. Eligible patients were diagnosed with sporadic bilateral or unilateral retinoblastoma from 1998 to 2011 and treated at one of nine participating institutions. Controls were recruited from the friends and relatives of cases. Telephone interviews were conducted with parents to obtain information on demographic factors and exposures, including medical procedures prior to conception of the index child. Gonadal radiation doses were estimated utilizing PCXMC and ImPACT software. Logistic regression models were used to evaluate the associations between parental medical radiation exposure and retinoblastoma. In maternal analyses, there were 298 bilateral cases, 184 unilateral cases, and 404 controls. In paternal analyses, there were 268 bilateral cases, 155 unilateral cases, and 358 controls. We found that compared to mothers without medical radiation exposure, mothers who reported a lower gastrointestinal (GI) series were more likely to have a child who developed bilateral retinoblastoma (odds ratio [OR]=6.9, 95% confidence interval [CI]: 2.9-16.4). A similar association was observed for unilateral retinoblastoma though the confidence interval included the null (OR=2.8, 95% CI: 0.8-9.7). When evaluating gonadal dose, increasing maternal exposure was associated with bilateral retinoblastoma (P for trend=0.03). Further, compared to unexposed mothers, mothers in the highest dose category were more likely to have a child who developed sporadic bilateral retinoblastoma (OR=2.3, 95% CI: 1.4-4.1). Notably, the same trend was not observed for unilateral retinoblastoma. Transversely, increasing paternal gonadal dose was associated with unilateral retinoblastoma (P for trend=0.03) but not bilateral retinoblastoma. These results are in contrast to previously hypothesized patterns (i.e., that maternal exposure would be associated with unilateral retinoblastoma, whereas paternal exposure would be associated with bilateral retinoblastoma due to a de novo mutation in RB1 of paternal origin). Our findings could point to a more complex etiologic framework for this important pediatric malignancy. Citation Format: Omar Shakeel, Nelson Pace, Philip J. Lupo, Michael E. Scheurer, Arupa Ganguly, Greta R. Bunin. Medical radiation exposure and risk of retinoblastoma: A report from the Children’s Oncology Group [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5039.

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

BackgroundThe risk factors for sporadic (ie, non-familial) retinoblastoma remain largely unknown.ObjectivesWe examined the relationship between paternal occupational exposures from jobs held 10 years and 1 year prior to conception and...

Incidence of pineal gland cyst and pineoblastoma in children with retinoblastoma during the chemoreduction era

Pineoblastoma is an important cause of mortality in retinoblastoma patients during the first 5 years of life. In the pre-chemoreduction era, pineoblastoma was found in 8% of all bilateral familial retinoblastoma and 5% of all bilateral sporadic retinoblastoma.

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

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. 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. 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). 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.

Paternal Occupational Exposures and the Risk of Childhood Sporadic Bilateral Retinoblastoma

Paternal Occupational Exposures and the Risk of Childhood Sporadic Bilateral Retinoblastoma

Parental diet and risk of retinoblastoma resulting from new germline RB1 mutation

We conducted a case-control study of sporadic bilateral retinoblastoma, which results from a new germline RB1 mutation, to investigate the role of parents' diet before their child's conception. Parents of 206 cases from nine North American institutions and 269 controls participated; of these, fathers of 184 cases and 223 controls and mothers of 204 cases and 260 controls answered a food frequency questionnaire administered by phone about their diet in the year before the child's conception. Cases provided DNA for RB1 mutation testing. We assessed parents' diet by examining 19 food groups. Father's intake of dairy products and fruit was associated with decreased risk and cured meats and sweets with increased risk. Mother's intake was not associated with disease for any food group. Considering analyses adjusted for the other food groups significantly associated with disease, energy intake, and demographic characteristics as well as more fully adjusted models, the associations with father's dairy products and cured meat intake were the most robust. In the fully adjusted, matched analysis, the odds ratios per daily serving were 0.70 (95% confidence interval (CI) 0.49-1.00, P = 0.047) for dairy products and 5.05 (CI 1.46-17.51, P = 0.01) for cured meat. The pattern of associations with paternal but not maternal diet is consistent with the fact that 85% of new germline RB1 mutations occur on the father's allele. As few human data exist on the role of diet in any condition resulting from new germ-cell mutation, additional studies will be needed to replicate or refute our findings.

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.

Unilateral retinoblastoma, lack of familial history and older age does not exclude germline RB1 gene mutation

Conclusive identification of RB1 mutations in retinoblastoma is predicted to improve the clinical management of affected children and relatives. However, despite clear clinical benefits, RB1 screening remains difficult, most of the alterations being unique and randomly distributed throughout the entire coding sequence. In this report, we present the results of a constitutional RB1 analysis undertaken in our institution over the last four years. The detection of RB1 gene deletion or mutation was performed by Southern blot and sequence analyses in 73 patients (including three families with 2, 3 and 3 probands, respectively). Complementary constitutional chromosome and fluorescent in situ hybridization (FISH) analyses of RB1 gene were applied in cases where hereditary retinoblastoma was suspected despite negative detection. Altogether, germline abnormalities were found in 11% (4/36 patients) of sporadic unilateral retinoblastoma (median age, 21.5 months) and 86% (32/37 patients) of sporadic bilateral or positive familial history retinoblastoma (median age, 5 months). The spectrum of germline alterations found in 31 distinct families included 12 nonsense mutations (39%); 10 point insertions or deletions with frameshift (32%); 4 mutations and 1 deletion affecting splice sites (16%); 2 missense mutations (6%); and 2 large deletions (6%). A total of 15 mutations have not been previously reported. In this small series, splicing mutations were associated with bilateral disease whilst most of the frameshift mutations were identified in patients with an early age at diagnosis, bilateral disease or hereditary forms of the disease. This study confirms that screening for constitutional RB1 mutation should become an integral part of current management of any patient affected by retinoblastoma irrespective of the tumour laterality and familial background.

A novel constitutional mutation affecting splicing of retinoblastoma tumor suppressor gene intron 23 causes partial loss of pRB activity

Hereditary predisposition to retinoblastoma is caused by germ line mutations in the RB1 gene. Genetic counseling of affected individuals and accurate risk prediction for their families requires identification of the disease causing mutation. Furthermore, the nature of a mutation can determine genetic penetrance, disease presentation and prognosis. We describe, and functionally characterize here, a novel mutant allele of RB1 present in the germ line of a patient with sporadic bilateral retinoblastoma. The mutation generates an operational splice acceptor site resulting in a predicted protein product with loss of 81 amino acids from its carboxy terminus. We demonstrate that the aberrantly spliced transcript is present in substantial amounts in peripheral blood of the patient and present evidence that the predicted protein product displays partial loss of activity reflecting in degree and presentation that of the partially penetrant RB1 missense mutant R661W. This infers that disease with reduced expressivity and incomplete penetrance may arise in individuals that carry the mutation and predicts such presentation for similar mutations with found in sporadic cases in the past.

An infant with Down syndrome and retinoblastoma. A possible non-fortuitous association

Satge et al.' reported in Ophthalmic Genetics an infant with Down syndrome and retinoblastoma and presented also a review of the literature. They are to be commended with a very interesting study. As the authors stated in their article, it is unlikely that all cases with both Down syndrome and retinoblastoma are reported in the literature and included in their study. In fact, they missed at least one study' published in your journal regarding the prevalence of mental retardation in patients with hereditary retinoblastoma. We did an epidemiological study and found in the Dutch retinoblastoma Register 8.7% cumulative incidence of mental retardation in 241 patients Nith hereditary retinoblastoma born in a 5o year period between 1 9451 994 . Two patients (females) of the 241 hereditary retinoblastoma patients had both Down syndrome (trisomy 21) and sporadic bilateral retinoblastoma (no 13q deletion found)! Tliat is much higher than the Down syndrome in 690 life births reported by the WHO. In summary, our epidemiological study supports the idea of Statge et al.' that hereditary retinoblastoma patients may have an increased risk for Down syndrome.

Clinicopathologic features of retinoblastoma after primary chemoreduction.

Primary chemotherapy is a new treatment approach in retinoblastoma, aiming to avoid radiogenic adverse effects, such as second tumor-associated mortality, as observed following external beam irradiation. To describe the clinical and histopathologic regression pattern after primary chemotherapy in retinoblastoma. Five patients with sporadic bilateral retinoblastoma underwent planned enucleation of their functionally blind eye after 2, 3 (in 2 patients), 4, and 6 courses of primary chemotherapy with carboplatin, etoposide, cyclophosphamide, and vincristine. The eyes were examined histopathologically, using light microscopy and immunohistochemical analysis with proliferation markers. One patient had a type 1 (cottage cheese) regression and 4 patients had either a type 2 (fish flesh) or a type 3 (combined) regression pattern. Histopathologic examination revealed a complete tumor necrosis in 1 patient with type 1 regression after 3 courses of chemotherapy and in 1 patient with type 3 regression after 4 courses of chemotherapy. The remaining 3 patients with type 2 or type 3 regression had histologically still active proliferative tumor cells after 2, 3, and 6 courses of chemotherapy. This article correlates histopathologically the clinically described efficacy of primary chemotherapy in the treatment of retinoblastoma, underlining, however, the necessity of careful observation and the use of ancillary treatment whenever there is no complete tumor regression.

Genetics of retinoblastoma: A study

We have analyzed 43 families with either familial retinoblastoma (RB) (four kindreds), bilateral sporadic RB (10 individuals), or unilateral sporadic RB (29 individuals). Genetic studies focused on karyotype analysis, loss of heterozygosity of intragenic polymorphisms, and search for point mutations. We have been able to identify the genetic defect underlying the disease in eight cases. Deletions have been found in three patients with sporadic RB, two bilateral in one of which karyotyping had previously detected an interstitial deletion of chromosome 13 affecting (q13–q31) and one unilateral. Five different point mutations were responsible for three cases of bilateral sporadic RB, one case of unilateral sporadic RB, and one case of bilateral familial RB. The low frequency of constitutional mutations found in our study has led us to review and evaluate the possibilities and limitations of the present genetic analyses on RB and to access the different factors influencing the detection of mutations causing the disease, because genetic counseling is mainly based on mutation identification.

Orbital rhabdomyosarcoma fifty-seven years after radiotherapy for retinoblastoma

A 58-year-old man developed a left orbital mass 57 years after bilateral enucleation and external beam radiotherapy for bilateral sporadic retinoblastoma. Eighteen years earlier, the patient had a basal cell carcinoma successfully excised from the same area. Orbital computed tomography revealed an infiltrative soft tissue mass measuring 50 ± 40 ± 15 mm involving the left medial orbit, left ethmoid sinus and the cribriform plate. An incisional biopsy was performed, and the lesion proved to be a poorly differentiated rhabdomyosarcoma of alveolar cell type. Despite aggressive chemotherapy, intracranial extension progressed and the patient expired.Late second malignancy following irradiated and non-irradiated retinoblastoma has been documented to occur even up to 54 years after retinoblastoma diagnosis. The 57-year interval between retinoblastoma and second cancer highlights this phenomenon and emphasizes the need for long term medical care of these patients.

Germline mutations in the RB1 gene in patients with hereditary retinoblastoma.

We have analyzed the 27 exons and the promoter region of the RB1 gene in familial or sporadic bilateral retinoblastoma by using single-strand conformation polymorphism analysis. For improvement over previous studies, a new set of primers has been designed, which allow for amplification of the coding and splicing sequences only. The positioning of the polymerase chain reaction (PCR) primers was such that the resulting PCR products were of different sizes, which enabled us to analyze two different exons simultaneously and still distinguish between the banding profiles for both (biplex analysis). By using this approach, we were able to identify mutation in 22 new patients, but the overall efficiency of the procedure when we used a single-pass regimen was only 48%. The mutations were small insertions and deletions and point mutations in roughly equal proportions.

Identification of RB1 germline mutations in Argentinian families with sporadic bilateral retinoblastoma.

Hereditary predisposition to retinoblastoma is caused by germline mutations in the RB1 gene. Most of these mutations occur de novo and differ from one patient to another. DNA samples from 10 families with a child presenting sporadic bilateral retinoblastoma have been analysed for the causative mutation. Using intragenic DNA polymorphisms we detected large deletions in two patients. Heteroduplex and DNA sequence analysis of PCR products from each exon and the promoter region showed small mutations in four patients: a C to T transition in exon 18; 1 bp and 2 bp deletion in exons 20 and 19 respectively; and a 4 bp insertion in exon 7. All these mutations are likely to result in premature termination of transcription. In one of these families, an unaffected carrier was detected. This emphasises the importance of detection of the causative mutation for predictive diagnosis in families with sporadic bilateral retinoblastoma.

Transmission-ratio distortion of X chromosomes among male offspring of females with skewed X-inactivation.

We have begun a search for heritable variation in X-chromosome inactivation pattern in normal females to determine whether there is a genetic effect on the imprinting of X-chromosome inactivation in humans. We have performed a quantitative analysis of X-chromosome inactivation in lymphocytes from mothers in normal, three-generation families. Eight mothers and 12 grandmothers exhibited evidence of highly skewed patterns of X-chromosome inactivation. We observed that the male offspring of females with skewed X-inactivation patterns were three times more likely to inherit alleles at loci that were located on the inactive X chromosome (Xi) than the active X chromosome (Xa). The region of the X chromosome for which this phenomenon was observed extends from Xp11 to -Xq22. We have also examined X-chromosome inactivation patterns in 21 unaffected mothers of male bilateral sporadic retinoblastoma patients. Six of these mothers had skewed patterns of X-chromosome inactivation. In contrast to the tendency for male offspring of skewed mothers from nondisease families to inherit alleles from the inactive X chromosome, five of the six affected males inherited the androgen receptor alleles from the active X chromosome of their mother.

Thirty years of retinoblastoma (1960–89): changing patterns of incidence

This study of a 30-year population-based dataset investigates further an earlier observation that the incidence of sporadic bilateral retinoblastoma appeared to be increasing in recent years in the West Midlands Health Authority Region (WMHAR). Stringent measures were applied to ensure complete ascertainment of all cases of retinoblastoma in children in the region, resulting in a total of 117 cases diagnosed during the period 1960-89 in the WMHAR. Hospital case notes were abstracted and follow-up data obtained. Incidence rates were calculated. The overall incidence remained constant over the 30-year period, but that of sporadic bilateral tumours increased, with a corresponding decline in familial cases. There was a statistically significant excess seen in Asian children.

Clinical variations of trilateral retinoblastoma: a report of 13 cases.

Of 440 consecutive children with retinoblastoma whom we treated between April 1972 and April 1992, 13 (3%) developed a midline intracranial neoplasm. Four of these 13 patients had bilateral familial retinoblastoma, 7 had bilateral sporadic retinoblastoma, and 1 patient had unilateral familial retinoblastoma. The twin brother of the latter patient developed pinealoblastoma without retinoblastoma. In this series, the incidence of trilateral retinoblastoma was 8% of all bilateral familial retinoblastoma and 5% of all bilateral sporadic retinoblastoma. The retinoblastoma was diagnosed at a mean age of 4.5 months and the midline intracranial tumor was diagnosed at a mean age of 23 months. The mean time interval between the diagnosis of retinoblastoma and the intracranial tumor was 22 months (range, 0 to 48 months). Seven patients (55%) were asymptomatic and their intracranial neoplasm was found on routine brain-imaging studies. The primary intracranial neoplasm had a pineal location in 10 cases and parasellar location in three cases. Despite aggressive combined treatment, 12 patients (92%) have died at a mean interval of 11 months after the diagnosis of intracranial malignancy. The mean survival of patients with midline intracranial neoplasm who were asymptomatic was significantly longer than that of symptomatic patients (P = .05).(ABSTRACT TRUNCATED AT 250 WORDS)