Hereditary Retinoblastoma Patients Research Articles

Magnetic Resonance Imaging Screening for Trilateral Retinoblastoma: The Memorial Sloan Kettering Cancer Center Experience 2006–2016

Magnetic resonance imaging (MRI) has been used for baseline brain imaging and afterward as a screening tool for trilateral retinoblastoma (TRB), but there is no consensus on timing or frequency of screening worldwide. In this study, a cohort of hereditary retinoblastoma patients at increased risk for TRB was identified and the usefulness of aggressive neuroimaging was examined. Retrospective review of the medical records and MRI reports of patients with retinoblastoma treated at Memorial Sloan Kettering Cancer Center between January 1, 2006, and December 31, 2016. Three hundred forty-nine total patients with retinoblastoma, including 215 hereditary retinoblastoma patients in the screening group. We reviewed 804 MRI studies of the orbit or brain. Patient and disease characteristics, including laterality, family history, and gene mutation status were analyzed. The impression of every MRI was coded 1 to 5, each value representing a different abnormality. We calculated the incidence of TRB in patients with germline disease as well as the incidence of screening MRI scans showing TRB. Among our hereditary retinoblastoma screening cohort (n=215) 4 patients with TRB were identified on screening MRI. All 4 patients showed bilateral disease, pineal gland tumors, and a latency period of at least 1 year. Three of the 4 were deceased by the end of the study. The incidence of TRB diagnosis was 1.9% (95% confidence interval [CI], 0.7%-4.9%). Of the 804 screening MRI scans performed on the screening cohort, 691 (86%) were unremarkable and 4 reported a lesion suspicious for TRB. The overall incidence of detecting TRB on screening MRI in the at-risk cohort was 0.5% (95% CI, 0.2%-1.3%) with a number needed to treat of 202. All cases of TRB in our center during the study period developed before the patient was 3 years of age and after a total of only 4 lifetime MRIs. Overall survival from TRB was not improved as a result of screening, andmany false-positive results required additional, subsequent MRI scans with anesthesia.

Patterns of Cause-Specific Mortality Among 2053 Survivors of Retinoblastoma, 1914-2016.

Previous studies of hereditary retinoblastoma survivors have reported elevated mortality, particularly for sarcomas, compared with the general population. However, cause-specific mortality patterns for long-term hereditary and nonhereditary retinoblastoma survivors are poorly understood. Among 2053 retinoblastoma patients diagnosed during 1914-2006 at two major US treatment centers and followed to 2016, we estimated cumulative mortality, standardized mortality ratios (SMRs), and absolute excess risks (AERs) compared with the US general population. Most deaths occurred in 1129 hereditary retinoblastoma patients (n = 518 deaths, cumulative mortality 70 years after retinoblastoma = 75.8%, 95% CI = 69.0% to 82.6%; SMR = 8.5, 95% CI = 7.7 to 9.2). Of these, 267 were due to subsequent cancers (SMR = 27.4, 95% CI = 24.2 to 30.9; AER = 72.3 deaths/10 000 person-years), for which SMRs were highest 15-29 years after diagnosis (n = 69, SMR = 89.9, 95% CI = 70.0 to 113.8) but remained statistically significantly elevated at 60 and more years (n = 14, SMR = 6.7, 95% CI = 3.6 to 11.2), whereas AERs increased with time (AER<15years = 38.0; AER60+years = 327.5). Increased risk of death due to cancers of pancreas, large intestines, and kidney were noted for the first time. Overall risk of subsequent cancers was greater for those treated with radiotherapy and chemotherapy compared to radiotherapy alone, although patterns varied by organ site. For 924 patients with nonhereditary retinoblastoma, we noted a modestly increased risk of death for subsequent cancers (n = 27, SMR = 1.8, 95% CI = 1.2 to 2.6) possibly due to treatment or misclassification of hereditary status. Risks of noncancer causes of death were not elevated for hereditary or nonhereditary patients. Hereditary retinoblastoma survivors died mainly from an excess risk of subsequent cancers up to six decades later, highlighting the need to develop long-term clinical management guidelines for hereditary retinoblastoma survivors treated in the past.

Correlation between RB1germline mutations and second primary malignancies in hereditary retinoblastoma patients treated with external beam radiotherapy

Retinoblastoma (Rb) results from biallelic inactivation of the RB1 gene. Hereditary Rb patients i. e germline carriers of a RB1 mutation also have a risk of developing subsequent malignant neoplasms (SMN) such as osteosarcomas. This SMN risk is maximized by external beam radiotherapy treatments (EBRT), which is why these treatments are now avoided. Nevertheless, EBRT is still a matter of great concern, as EBRT-treated patients are in their adulthood and SMNs remain the major cause of death for patients.To decipher the relationship between RB1 genotype and SMN development in EBRT treated patients, we conducted a retrospective study in a cohort of 160 irradiated hereditary Rbs with fully resolved RB1 mutational status. Median follow-up was 22 years [1-51] and median age of patients was 27 years old [7-53]. Among these 160 Rb patients, 120 did not develop any SMN (75%) and 40 developed SMNs (25%). The age at which EBRT is given (i.e. before or after the age of 12 months) was not correlated to SMN development (p = 0.6). We didn't find any difference in RB1 mutation type between patients with or without SMN, neither could we detect any linkage between mutation type and SMN location, SMN type and age at diagnosis. Interestingly, among 13 carriers of a RB1 low penetrance mutation, 3 of them developed sarcomas, a rare tumor that cannot be attributed to the general population.Our study cannot explain why a RB1 mutation leads or not to a SMN but demonstrated that EBRT patients with a low penetrance mutation remain at risk of SMN and should be cautiously monitored.

A polymorphism in mir-34b/c as a potential biomarker for early onset of hereditary retinoblastoma.

Retinoblastoma (RB) is a malignant pediatric tumor and, mainly because of late diagnosis, most patients undergo enucleation. The tumor almost always initiates by two inactivation events at the RB1 gene. Single nucleotide polymorphisms (SNPs) in p53 pathway have been found to represent genetic modifiers of RB. To investigate whether a SNP (rs4938723T > C) in mir-34b/c gene, a key effector of p53, could influence RB risk and patients' age of onset. mir-34b/c rs4938723T > C was sequenced in 130 RB patients and in 105 control individuals. Statistical analysis consisted of χ 2 tests or Fisher's exact, odds ratios (ORs) and Mann-Whitney test. The presence of the C allele did not change the risk for retinoblastoma. However, in hereditary RB patients, the mean age at diagnosis is much lower (1.4 ± 1.4 months) among CC carriers than when it is compared to TT genotype (13.8 ± 6.4, p = 0.001). Besides, hereditary RB patients with CC genotype are around 4 times more likely to present retinoblastoma under the age of 3 months (OR = 4.44; IC: 2.50-7.90; p = 0.002). The C allele together with a germ-line RB1 gene mutation may speed retinoblastoma onset which suggests that mir-34b/c rs4938723T > C may represent a candidate biomarker for hereditary RB.

Second cranio-facial malignancies in hereditary retinoblastoma survivors previously treated with radiation therapy: Clinic and radiologic characteristics and survival outcomes

IntroductionHereditary retinoblastoma survivors have an increased risk for cranio-facial second primary tumours (SPT), especially after treatment with external beam radiotherapy (EBRT). This multicentre study evaluates the clinical and imaging characteristics and outcomes of cranio-facial SPTs in irradiated retinoblastoma survivors. Patients and MethodsClinical and radiological data of 42 hereditary retinoblastoma patients with 44 second and third malignancies were reviewed. Radiological data included anatomic location and computed tomography (CT) and magnetic resonance (MR) characteristics. Cox regression and likelihood ratio chi-square test were used to evaluate differences in patients’ survival rates. ResultsCranio-facial SPTs were diagnosed at a median age of 13years. Histological types included osteosarcomas (43%), rhabdomyosarcomas (20%) (57% embryonal, 43% alveolar) and a variety of other types of SPT (37%). Predilection sites were: temporal fossa (39%), ethmoid sinus (23%), orbit (18%), maxillary sinus (16%) and intracranial dura mater (4%). Most of the osteosarcomas (78%) and rhabdomyosarcomas (80%) occurred in patients treated with EBRT in the first year-of-life. Treatment of SPTs with a microscopically complete surgical resection led to a significantly better 5-year overall survival (OS) (P=0.017) and event-free survival (EFS) (P=0.012) compared to patients treated without surgery or incomplete resection (OS: 83% versus 52%; EFS: 80% versus 47%). ConclusionsOsteosarcomas and rhabdomyosarcomas are the most common cranio-facial SPTs in irradiated hereditary retinoblastoma survivors, which develop in specific locations and occur predominantly in patients irradiated in their first year-of-life. Microscopically complete surgical resection of SPTs is a major prognostic factor, suggesting the potential benefit of early detection by imaging.

Increased risk of secondary uterine leiomyosarcoma in hereditary retinoblastoma

ObjectiveIn the US, second non-ocular malignancies are the primary cause of death in retinoblastoma survivors with the germline RB1 mutation. Soft tissue sarcomas are one of the most likely malignancies to pose a risk to these patients, with leiomyosarcoma (LMS) being the most common subtype. As our cohort is followed for a longer period, we discover new second malignancy risks for these patients. MethodsWe estimated the risk for uterine leiomyosarcoma (ULMS) in a cohort of 1854 patients with retinoblastoma who were diagnosed at two US institutions from 1914 through 1996. The standardized incidence ratio and excess absolute risk were calculated by comparison with population data from the Connecticut Tumor Registry or from National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) database. The cumulative risk at 50years of age was also calculated. ResultsSeven of 525 female hereditary retinoblastoma patients developed ULMS. Five of these patients were used in the risk analysis, resulting in an excess risk of 3.87 per 10,000 women. Among hereditary patients who developed ULMS the excess risk increases dramatically with age: to 20/10,000 for female hereditary retinoblastoma patients aged between 30 and 39years, and to 27/10,000 for patients aged 40+ years. ConclusionThere is a substantial excess risk of ULMS in female hereditary retinoblastoma patients. As more patients survive into their thirties, this number is likely to increase. These findings raise the question of early childbearing, screening and prophylactic measures in hereditary retinoblastoma patients: all issues that would benefit from confirmation from other retinoblastoma cohorts, to allow for better guided counsel of these patients.

P53 Arg72Pro and MDM2 309 SNPs in hereditary retinoblastoma

The tumor suppressor p53 and its negative regulator MDM2 have crucial roles in a variety of cellular functions such as the control of the cell cycle, senescence, genome stability and apoptosis, and are frequently deregulated in carcinogenesis. Previous studies have highlighted the contribution of the common functional polymorphisms p53 p.Arg72Pro and MDM2 309SNP to the risk of both common cancers and Li-Fraumeni syndrome. Their possible role in retinoblastoma has recently been addressed by Castéra et al, who however only studied the MDM2 309SNP. Here, for the first time, we analyzed both single nucleotide polymorphisms (SNPs) in a case-control study of 111 Italian hereditary retinoblastoma patients. We found a significant association of the p53 Pro/Pro genotype with the disease (odds ratio=3.58, P=0.002). The MDM2 309SNP showed a weak negative association of allele G that deserves further investigation. These findings further support the hypothesis that genetic variability of the p53 pathway contributes to the individual susceptibility to retinoblastoma, as shown for Li-Fraumeni syndrome and a variety of non-hereditary cancers.

Subsequent tumors in retinoblastoma survivors: The role of the head and neck surgeon

Hereditary retinoblastoma patients are at an increased risk for subsequent primary tumors after successful treatment for their initial cancer. Two mechanisms may be responsible for this increased incidence of second malignancies: genetic susceptibility (RB1 gene alterations) and induction by radiation that is frequently used as treatment for retinoblastoma. Because of the high cure rates obtained in the treatment of retinoblastoma, the risk of subsequent primary tumors is substantial, especially in the radiation field. We present four retinoblastoma survivors who developed multiple subsequent primary tumors. Two retinoblastoma survivors developed one and the other two patients two subsequent primary tumors. Despite extensive treatments two patients died of their second primary tumor in the head and neck region. The head and neck surgeon has an increasingly important role in the diagnosis and management of subsequent primary tumors in retinoblastoma survivors.

Incidence of New Tumor Formation in Patients with Hereditary Retinoblastoma Treated with Primary Systemic Chemotherapy: Is There a Preventive Effect?

To report the incidence of new tumor formation in hereditary retinoblastoma patients treated with primary systemic chemotherapy. Noncomparative retrospective case series. Fifty-eight consecutive patients with hereditary retinoblastoma treated with primary systemic chemotherapy. The charts of 58 consecutive patients with hereditary retinoblastoma treated between January 1996 and August 2005 were reviewed. Data extracted included gender, age at diagnosis, family history of retinoblastoma, laterality of disease, tumors per eye, Reese-Ellsworth grouping of affected eyes, starting and ending dates for chemotherapy, number of cycles of chemotherapy, chemotherapy regimen, need for external beam radiotherapy and/or enucleation, and development and location (macula, midzone, and periphery) of new tumors after the start of systemic chemotherapy. New tumor formation after treatment with primary systemic chemotherapy. Of the 58 patients, 48 had bilateral involvement at diagnosis. Median age at diagnosis was 6.6 months. Thirteen patients had a positive family history. Of the eyes with tumor (n = 106) at diagnosis, 52 (49%) were in Reese-Ellsworth groups I to III, whereas 54 (51%) were in group IV or V. Seven patients (12%) with a median age of 1.6 months at diagnosis formed 36 new tumors in 11 eyes after the start of chemotherapy. Median time from initiation of chemotherapy to detection of the first new tumor was 3 months (range, 1-15). Cumulative incidence of new tumor formation at 2 years was 10+/-3%. An age of <6 months at diagnosis, family history of retinoblastoma, and Reese-Ellsworth grouping of I to III were found to correlate significantly with an increased incidence of new tumor formation (P<0.001, P<0.001, and P = 0.021, respectively). Median follow-up for all patients was 5 years (range, 1-10.1). New tumors continue to form in patients with hereditary retinoblastoma despite treatment with primary systemic chemotherapy. Younger patients and those with a positive family history are more likely to have new tumors formed. However, chemotherapy may impact small previously undetected lesions by slowing their growth and facilitating later focal consolidation.

Identification of 26 new constitutionalRB1gene mutations in Spanish, Colombian, and Cuban retinoblastoma patients

Constitutional mutations in the RB1 gene predispose to retinoblastoma development. Hence genetic screening of retinoblastoma patients and relatives is important for genetic counseling purposes. In addition, RB1 gene mutation studies may help decipher the molecular mechanisms leading to tumors with different degrees of penetrance or expressivity. In the course of genetically screening of 107 hereditary and non-hereditary retinoblastoma patients (11 familiar bilateral, 4 familiar unilateral, 49 sporadic bilateral and 43 sporadic unilateral) and kindred from Spain, Colombia and Cuba, using direct PCR sequencing, we observed 45 distinct mutations and four RB1 deletions in 53 patients (9 familiar bilateral, 2 familiar unilateral, 31 sporadic bilateral and 11 sporadic unilateral). Most of these mutations (26/45, 57%) have not been reported before. In 32 patients, the predisposing mutations correspond to nonsense (mainly CpG transitions) and small insertions or deletions whose expected outcome is a truncated Rb protein that lacks the functional pockets and tail. Five single aminoacid replacements and seventeen mutations affecting splicing sites were also observed in retinoblastoma patients. Two of these sixteen mutations are of unclear pathogenic nature.

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.

Second primary tumors in hereditary retinoblastoma: a register-based study, 1945-1997: is there an age effect on radiation-related risk?

The aim of this study is to evaluate the influence of age at external beam irradiation (EBRT) on the occurrence of second primary tumors (SPTs) inside and outside the irradiation field in hereditary retinoblastoma patients. Cross-sectional study. The study included 263 hereditary retinoblastoma patients born in The Netherlands between 1945 and 1997. A national register-based follow-up cohort study was performed on hereditary retinoblastoma patients. Information on therapy, age at irradiation, and location of SPT was obtained from the register. The Kaplan-Meier method calculated cumulative incidences of SPT in three subgroups: irradiation before (early EBRT) and after 12 months of age (late EBRT), and no irradiation. The Mantel-Cox method determined the statistical significance of differences between the cumulative incidence curves. Development of SPT inside and outside a precisely defined irradiation field in relation to age at irradiation. Our definition excluded pineoblastoma as SPT, because they constitute part of a trilateral retinoblastoma; in addition, they lie outside the field of irradiation. The cumulative incidence of SPT at the age of 25 years was 22% (95% confidence intervals 13%-34%) in the early EBRT group, 3% (0%-14%) in the late EBRT group, and 5% (1%-16%) in the nonirradiated group (Mantel-Cox overall: P = 0.001; between early and late EBRT, P = 0.04). However, in early irradiated patients, the incidence of SPTs inside and outside the irradiation field was similar (11%), and the difference between early and late EBRT in incidence of SPT inside the field of irradiation was less prominent than overall (11% vs. 3%: P = 0.37). Sensitivity analysis showed the results depended on the way SPT, irradiation field, and, especially, pineoblastomas are defined. Hereditary retinoblastoma confers an increased risk for the development of SPT, especially in patients treated with EBRT before the age of 12 months. However, the presence of similar numbers of SPTs inside and outside the irradiation field suggests that irradiation is not the cause. In other words, this study does not show an age effect on radiation-related risk. Rather, early EBRT is probably a marker for other risk factors of SPT.

At what age could screening for familial retinoblastoma be stopped? A register based study 1945–98

AIMTo evaluate until what age children in families with retinoblastoma should be screened.METHODSA register based cohort (n= 685) study of Dutch retinoblastoma patients (1945–1998). The records of all familial hereditary...

Rb1 gene mutations in osteosarcoma

Genetic alternations, such as mutations caused inactivities of tumor suppressor gene, have been identified in a wide variety of tumors, including osteosarcoma. Osteosarcoma is the most frequent primary malignant bone tumor that occurs in the extremities of young adolescents in most cases. Because of the high frequent occurrence of this type of tumor in hereditary retinoblastoma patients, involvement of the Rbl gene mutations was suspected in the development of osteosarcoma, and a few reports have shown alternations of the Rbl gene in osteosarcoma. We studied Rbl gene mutations in 9 osteosarcoma samples and one cell line (OS 732) to explore the types and mechanism of Rbl gene mutations in osteosarcoma.

Distribution of tumors in the retina in hereditary retinoblastoma patients

We have compared the location of the ocular tumors in hereditary retinoblastoma in relation to the age of the patients at time of diagnosis. Eighty fundus drawings were analyzed from 59 hereditary patients containing 159 tumors. At the time of diagnosis, indirect ophthalmoscopy was performed under general anaesthesia in all patients and standard drawings of the retina were made depicting the number and relative location of all tumors. The distance between the center of the tumor and the center of the macula was measured and plotted against the age of the patients at time of diagnosis. The results show that the distance between the center of the tumor and the center of the macula at time of diagnosis increases with age during the first seven months after birth.

Incidence and survival of retinoblastoma in the Netherlands: a register based study 1862–1995

AIMThe aim of this study was to determine the (time trends in) incidence and survival of hereditary (familial and sporadic) and non-hereditary retinoblastoma for male and female patients born in...

High parental age is associated with sporadic hereditary retinoblastoma: the Dutch retinoblastoma register 1862-1994.

We wished to determine the influence of parental age at the birth of a retinoblastoma patient on the risk of sporadic hereditary retinoblastoma. The parental age at birth of 941 patients of the Dutch retinoblastoma register (1862-1994) was identified and compared between sporadic hereditary and nonhereditary patients. In a subcohort (1936-1994), a comparison was made with parental age at birth in the general population, as obtained from the Central Bureau of Statistics. Missing birth dates of the parents of retinoblastoma patients were traced with the help of the municipal registries and the Central Bureau of Genealogy. The mean paternal age was 10.7 months higher and the mean maternal age was 11.0 months higher in the sporadic hereditary retinoblastoma patients than in parents of nonhereditary patients. In the subcohort, the mean paternal and maternal ages of sporadic hereditary patients were also higher (12.4 and 11.5 months, respectively) than those of the general population. All differences were statistically significant. This study shows that a high parental age is associated with an enhanced risk of sporadic hereditary retinoblastoma.

Cytogenetic responses to G 2 phase X-irradiation of cells from retinoblastoma patients

Fibroblast cell lines from 20 retinoblastoma (RB) patients with the hereditary bilateral form of disease compared with 16 lines from normal donors had a significantly higher chromatid aberration frequency (CAF), and more displaced and nondisplaced breaks per 100 metaphase cells after x-irradiation during the G 2 phase of the cell cycle. The mean CAF was 39 ± 1.0, range 30–46, for cells from normal subjects, compared to a mean of 245.6, range 101–506, for cells from hereditary RB patients (p < 10 −6). Of fibroblast lines from eight patients with unilateral RB, four had a CAF comparable to that of lines from normal donors (< 60) and four had a high CAF (> 130), resembling that of hereditary forms; two of the latter four lines were from patients with familial or deletion 13 forms of RB. Furthermore, in two families, PHA-stimulated blood lymphocytes from RB patients, one bilateral and one unilateral, and from certain unaffected first-degree relatives after G 2 phase X-irradiation had a high CAF (⩾ 110) compared to a CAF (⩾ 53) of cells from three normal donors sampled at the same time. These results were shown not to be related to differences in cell cycle progression or initial extent of chromatid damage. The results suggest that the high frequency of chromatid aberrations in the cells from hereditary RB patients results from a genetic deficiency in DNA repair.

Second nonocular tumors in cured unilateral retinoblastoma patients

According to recent data the incidence of second tumors in cured hereditary unilateral retinoblastoma patients is 20% within 10 years, 50% after 20 years and rises to 90% after 30 years. Nonhereditary unilateral retinoblastoma patients have not been regarded as susceptible for second nonocular tumors so far. A case is reported of such a patient having developed a second presacral retroperitoneal tumor after successful treatment of a nonhereditary unilateral retinoblastoma group V without intracranial extension or pulmonary metastases. Consequently all (hereditary and non-hereditary) retinoblastoma patients should receive at least quarterly intensive follow-up examinations after primary ophthalmologic treatment.

An important step in radiation carcinogenesis may be inactivation of cellular genes

The loss of genetic material may result in a predisposition to malignant disease. The best studied example is retinoblastoma where deletion or transcriptional inactivation of a specific gene is associated with the development of the tumor. When hereditary retinoblastoma patients are treated with radiation, the incidence of osteosarcoma within the treatment field is extremely high compared to other cancer patients treated with radiotherapy. These data, together with cytogenetic and molecular data on the development of acute non-lymphocytic leukemia secondary to radiotherapy and chemotherapy treatment suggest that radiation-induced deletions of critical DNA sequences may be an important event in radiation carcinogenesis. Therefore, we propose that radiation-induced tumors may result from deletion of tissue specific regulatory genes. Base alterations caused by radiation in dominantly transforming oncogenes may also contribute to radiation carcinogenesis.