Investigation of the methylation changes in the promoter region of RB1 gene in retinoblastoma: Unraveling the epigenetic puzzle in retinoblastoma.

Retinoblastoma is an infrequent neoplasm that arises during childhood from retinal nerve cells and is attributed to the biallelic inactivation of the RB1 gene. In conjunction with anatomical anomalies, it is widely acknowledged that epigenetic modifications play a significant role in the pathogenesis of cancer. The association between methylation of the RB1 gene promoter and tumor formation has been established; however, there is currently no scholarly evidence to substantiate the claim that it is responsible for the inheritance of retinoblastoma. The initial hypothesis posited for this work was that familial retinoblastoma disease would be similarly observed in cases with RB1 promotor gene methylation, akin to RB1 mutations. The RB1 gene promoter region was subjected to methylation screening using real-time PCR in individuals diagnosed with familial retinoblastoma but lacking RB1 mutations. The study involved a comparison of the germline methylation status of the RB1 gene in the peripheral blood samples of 50 retinoblastoma patients and 52 healthy individuals. The healthy individuals were carefully selected to match the retinoblastoma patients in terms of age, sex, and ethnicity. The data obtained from both groups were subjected to statistical analysis. The study revealed that the methylation level in a cohort of 50 individuals diagnosed with retinoblastoma and 52 healthy control participants was determined to be 36.1% and 33.9%, respectively. As a result, there was no statistically significant disparity observed in RB1 promoter methylation between the patient and control groups (p = 0.126). The methylation of the promoter region of the RB1 gene in familial retinoblastoma does not exert any influence on the hereditary transmission of the disease.

Identification of candidate genes in a family with cancer overload by whole-exome sequencing.

BACKGROUND: Approximately 120 out of every 1 million children in the world develop cancer each year. In Turkey, 2500-3000 children are diagnosed with new cancer each year. The causes of childhood cancer have been studied for many years. It is known that many cancers in children, as in adults, cause uncontrolled cell growth, and develop as a result of mutations in genes that cause cancer. METHODS: The investigation of family history within this context in the study, a total of 13 individuals consisting of all children and adults in the family were examined using the whole-exome sequencing (WES) with the individuals who were diagnosed with cancer in the family, who were detected to have different cancer profiles, and defined as high risk and to determine the gene or genes through which the disease has developed. RESULTS: At the end of the study, a total of 30 variants with a pathogenic record in the family were identified. A total of 10 pathogenic variants belonging to 8 different genes from these variants have been associated with various cancer risks. CONCLUSIONS: A significant scientific contribution has been made to the mechanism of disease formation by studying a family with a high cancer burden and by finding the genes associated with the disease. In addition, by the results obtained, family members with cancer predisposition were selected after a risk analysis conducted in this family, and the necessary examinations and scans were recommended to provide an early diagnostic advantage.

Childhood Rhabdomyosarcoma of the Female Genital Tract: Association with Pathogenic DICER1 Variation, Clinicopathological Features, and Outcomes.

STUDY OBJECTIVE: Rhabdomyosarcomas (RMSs) of the female genital tract (FGT) have been recently shown to be associated with germline pathogenic variation in DICER1, which can underlie a tumor predisposition disorder. We sought to determine the incidence of a pathogenic variation in DICER1 in a cohort of RMSs of the FGT, as well as to evaluate the clinicopathological features and outcomes of the patients. DESIGN, SETTING, PARTICIPANTS, INTERVENTIONS, AND MAIN OUTCOME MEASURES: We retrospectively reviewed medical records of the patients diagnosed with RMS of the FGT between 1990 and 2019. Molecular genetic sequencing of the tumor to detect an RNase IIIb domain hot spot mutation in DICER1 samples was performed in 7 patients. Individuals with a missense mutation in the tumor were also screened for a loss of function germline mutation in DICER1. RESULTS: Of 210 cases of pediatric RMS, 11 arose from the FGT. Molecular genetic sequencing of the tumor samples revealed a somatic missense mutation in the RNase IIIb domain of DICER1 in a total of 3 patients, 2 patients with embryonal RMS of the cervix/uterus, and 1 patient with ovarian embryonal RMS. As a result of genetic testing for the loss of function germline mutation in DICER1, a heterozygous pathogenic variant was also found in 2 of these patients. CONCLUSION: Despite the limited number of patients, our findings suggest that it is important to be aware of the possible association between RMS of FGT and pathogenic germline DICER1 variants because the detection of this mutation in a patient or relatives can provide the opportunity for surveillance of related conditions that might improve long-term outcomes and survival.

Lymphoma Predisposing Gene in an Extended Family: CD70 Signaling Defect.

Genome-wide sequencing studies in pediatric cancer cohorts indicate that about 10% of patients have germline mutations within cancer predisposition genes. Within this group, primary immune deficiencies take the priority regarding the vulnerability of the patients to infectious agents and the difficulties of cancer management. On the other hand, early recognition of these diseases may offer specific targeted therapies and hematopoietic stem cell transplantation as an option. Besides therapeutic benefits, early diagnosis will provide genetic counseling for the family members. Within this context, an extended family with multiple consanguineous marriages and affected individuals, who presented with combined immune deficiency (CID) and/or Hodgkin lymphoma phenotype, were examined by exome sequencing. A pathogenic homozygous missense CD70 variation was detected (NM_001252.5:c332C>T) in concordance with CD70 phenotype and familial segregation was confirmed. CD70 variations in patients with CID and malignancy have very rarely been reported. This paper reports extended family with multiple affected members with CID and malignancy carrying a missense CD70 variation, and reviews the rare cases reported in the literature. Primary immune deficiencies appear to be a potential cause for pediatric cancers. Better focusing on these inborn disorders to prevent or make an early diagnosis of malignant transformation and reduce mortalities is important.

Children with malignant melanoma: a single center experience from Turkey.

AIM: Malignant melanoma is the most frequent skin cancer in children and adolescents. It comprises 1-3% of all malignancies. In this study, we aimed to evaluate the clinical aspects, histopathologic features, and treatment outcomes of our patients with malignant melanoma. MATERIAL AND METHODS: Patients aged <15 years who were treated between 2003 and 2018 for malignant melanoma were retrospectively analyzed. RESULTS: Seventeen patients (10 females, 7 males), with a median age of 7 years (range, 7 months-13 years) were evaluated. Five patients had congenital melanocytic nevi. All had cutaneous melanoma except one with mucosal (conjunctival) melanoma. The most frequent primary tumor site was the lower extremities (35%). Sentinel lymphoscintigraphy, sentinel node biopsy, and PET/CT were performed as the staging procedures at initial diagnosis. Localized disease was present in eight patients; nine had regional lymph node metastasis. The only treatment was surgery in localized disease; surgery and adjuvant interferon treatment was given in patients with regional lymph node metastasis. Three developed distant metastasis (bone, lung, brain) at a median of 9 months. A three-year-old patient received a BRAF inhibitor (vemurafenib), and a 13-year-old patient received a check point inhibitor (ipilimumab); both died of progressive disease. The median follow-up for all patients was 25 months. The 5-year overall survival was 76.6%. CONCLUSION: Although malignant melanoma is rare in children, prognosis is good if diagnosed early. Physicians should be aware of skin lesions and full-layer biopsy should be obtained in suspicious skin lesions. Patients with congenital melanocytic nevi should also be followed up cautiously.

Nimotuzumab-containing regimen for pediatric diffuse intrinsic pontine gliomas: a retrospective multicenter study and review of the literature.

PURPOSE: Nimotuzumab is an IgG1 antibody that targets epidermal growth factor receptor (EGFR). Overexpression of EGFR is detected in some pediatric brain tumors including diffuse intrinsic pontine gliomas (DIPG)s. METHODS: Since May 2010, nimotuzumab, combined with carboplatin or vinorelbine or Temozolomide (TMZ), was administered during progressive disease (PD) after the use of the institutional protocol consisting of radiotherapy (RT) + TMZ and adjuvant TMZ. After May 2012, children with newly diagnosed disease received TMZ during RT, and nimotuzumab and TMZ after RT. Nimotuzumab was given as 150 mg/m2/dose once a week for 12 weeks, and then every other week with TMZ until PD. PD patients were switched to nimotuzumab + vinorelbine combination until death. RESULTS: Nimotuzumab was used in 24 children with DIPG (seven in the PD group, 17 in the newly diagnosed patient group). In the PD group, median survival time was 12 months (7-42 months); 1-year and 2-year overall survival (OS) rates were 42.9 ± 18% and 14.3 ± 13%, respectively. The median survival in this group, after the initiation of nimotuzumab was 6 months (3-8 months). In the newly diagnosed patient group, median survival time was 11 months (3-35 months) and median progression free survival was 4 months (1-21 months). The 1-year OS in this group was 35.3 ± 11% and 2 year OS was 11.8 ± 7%. Nimotuzumab ± chemotherapy was well tolerated with no major adverse effect. CONCLUSION: Nimotuzumab-containing regimens are feasible and tolerable; it might be that some patients either with newly diagnosed DIPG or with progressive disease may benefit modestly from nimotuzumab-containing combinations.

Osteosarcoma of the rib: A rare presentation.

In children and adolescents with chest pain and dyspnea, pneumonia, pleural effusion, and empyema are the frequent causes in the differential diagnosis. Malignant tumors of the chest wall are rare and most originate from the ribs. In children, the most frequent malignant tumor of the rib is Ewing's sarcoma. Osteosarcomas of the rib are very rare. Osteosarcoma has a predilection for rapidly growing long bones including the femur, tibia and humerus in adolescents. In this paper, we present an adolescent girl who presented with chest pain and dyspnea with osteosarcoma that originated from the rib and extended to the right hemithorax.

Osteosarcoma After Hematopoietic Stem Cell Transplantation in Children and Adolescents: Case Report and Review of the Literature.

Osteosarcoma as a secondary malignancy after hematopoietic stem cell transplantation (HSCT) is very rare. We present a case and review of 18 other cases reported to date. Our patient underwent HSCT for myelodysplastic syndrome at the age of 4 years. She developed osteosarcoma 13 years later. She underwent surgery after three courses of neoadjuvant chemotherapy followed by chemotherapy and mifamurtide. She has no evidence of disease 28 months after termination of chemotherapy. In 18 other cases of secondary osteosarcoma in the literature, 15 had received total body irradiation, eight had received alkylating agents, and six had received etoposide. The median interval from HSCT to the onset of osteosarcoma was 6.5 years (range 2.5-15.3), which confirms that children undergoing HSCT should be followed up for many years. In conclusion, osteosarcoma must be included in the differential diagnosis among solid tumors that may develop following HSCT.