Precision immuno-oncology approach for four malignant tumors in siblings with constitutional mismatch repair deficiency syndrome.

Constitutional mismatch repair deficiency (CMMRD) is a rare syndrome characterized by an increased incidence of cancer. It is caused by biallelic germline mutations in one of the four mismatch repair genes (MMR) genes: MLH1, MSH2, MSH6, or PMS2. Accurate diagnosis accompanied by a proper molecular genetic examination plays a crucial role in cancer management and also has implications for other family members. In this report, we share the impact of the diagnosis and challenges during the clinical management of two brothers with CMMRD from a non-consanguineous family harbouring compound heterozygous variants in the PMS2 gene. Both brothers presented with different phenotypic manifestations and cancer spectrum. Treatment involving immune checkpoint inhibitors significantly contributed to prolonged survival in both patients affected by lethal gliomas. The uniform hypermutation also allowed immune-directed treatment using nivolumab for the B-cell lymphoma, thereby limiting the intensive chemotherapy exposure in this young patient who remains at risk for subsequent malignancies.

Tazemetostat in the therapy of pediatric INI1-negative malignant rhabdoid tumors.

Rhabdoid tumors are aggressive tumors that may arise in the kidney, soft tissue, central nervous system, or other organs. They are defined by SMARCB1 (INI1) or SMARCA4 alterations. Often, very young children are affected, and the prognosis is dismal. Four patients with primary atypical teratoid rhabdoid tumor (AT/RT, a rhabdoid tumor in the central nervous system) were treated by resection and high dose chemotherapy. Tazemetostat was introduced after completion of chemotherapy. Three patients have achieved an event free survival of 32, 34, and 30 months respectively. One progressed and died. His overall survival was 20 months. One patient was treated for a relapsed atypical teratoid rhabdoid tumor. The treatment combined metronomic therapy, radiotherapy, tazemetostat and immunotherapy. This patient died of disease progression, with an overall survival of 37 months. One patient was treated for a rhabdoid tumor of the ovary. Tazemetostat was given as maintenance after resection, chemotherapy, and radiotherapy, concomitantly with immunotherapy. Her event free survival is 44 months. Only approximately 40% of patients with rhabdoid tumors achieve long-term survival. Nearly all relapses occur within two years from diagnosis. The event free survival of four of the six patients in our cohort has exceeded this timepoint. Tazemetostat has been mostly tested as a single agent in the relapsed setting. We present promising results when applied as maintenance or add on in the first line treatment.

Novel de novo pathogenic variant in the GNAI1 gene as a cause of severe disorders of intellectual development.

Pathogenic sequence variant in the GNAI1 gene were recently introduced as a cause of novel syndrome with a manifestation of variable developmental delay and autistic features. In our study, we report a case of monozygotic twins with severe intellectual disability and motor delay and developmental dysphasia. Both probands and their parents were examined using multi-step molecular diagnostic algorithm including whole-exome sequencing (WES), resulting in the identification of a novel, de novo pathogenic sequence variant in the GNAI1 gene, NM_002069.6:c.815 A>G, p.(Asp272Gly) in probands. Using WES we also verified the microarray findings of a familial 8q24.23q24.3 duplication and heterozygous 5q13.2 deletion, not associated with clinical symptoms in probands. Our results confirmed the role of the GNAI1 gene in the pathogenesis of syndromic neurodevelopmental disorders. They support trio- or quatro-based WES as a suitable molecular diagnostics method for the simultaneous detection of clinically relevant sequence variants and CNVs in individuals with neurodevelopmental disorders and rare diseases.

DICER1 Syndrome.

DICER1 syndrome is an inherited disorder that increases the risk of different types of malignant and benign tumors. The syndrome is caused by mutations in the DICER1 gene, which is located on the long arm of chromosome 14, region q32.13. Patients with DICER1 syndrome commonly develop pleuropulmonary blastoma (PPB), multinodular goiter, ovarian Sertoli-Leydig cell tumors, and/or other types of tumors. In approximately 35% of families with children manifesting PPB, further (and rather rare) malignancies may be observed, including cystic nephroma, nodular dysplasia of the thyroid gland, medulloepithelioma of the iris, embryonal rhabdomyosarcoma botryoid type, nasal epithelial hamartoma, pituitary blastoma, and/or pineoblastoma. Large studies report a high variability of tumors associated with DICER1. DICER1 syndrome, which is associated with an inherited predisposition to tumors, is inherited in an autosomal dominant pattern. Symptoms of DICER1 syndrome may vary, even within families. Preventive screening of carriers with causative mutations is complicated. Follow-up is undertaken as recommended by the 2016 International PPB Register. This work was supported by grant of Ministry of Health of the Czech Republic AZV 16-3329A. The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Submitted: 4. 6. 2019 Accepted: 6. 6. 2019.

Pre-treatment VD levels and VDR receptors as potential predictors of occurrence and overall survival in paediatric patients with solid tumours-a single institution pilot study.

Recently, vitamin D has been recognized as an important player in the immune system, and multiple studies suggested its involvement in cancer, too. The aims of this study were to investigate selected single nucleotide polymorphisms (SNPs) in the VDR gene, BsmI (rs1544410; A > G), FokI (rs 2228570; C > T), TaqI (rs731236; T > C), ApaI (rs 7975232; C > T) and Cdx-2 (rs11568820; A > G), and to evaluate their possible predictive role for outcomes in patients with paediatric solid tumours. A total of 111 children with paediatric solid tumours were enrolled at the Department of Paediatric Oncology, University Hospital Brno (Brno, Czech Republic) along with a control population of 787 adults; all study subjects were available for genotyping of selected SNPs, and the prediagnostic levels of 25-hydroxycholecalciferol (25(OH)D3) and 1,25-dihydroxycholecalciferol (1,25(OH)2D3) were measured in the cases, too. In FokI, the heterozygote CT genotype was weakly associated with a decreased risk of paediatric solid cancer occurrence 0.82 (0.53-1.28), while the CC genotype was associated with a decreased risk of 0.58 (0.30-1.09), p = 0.09. The 1,25(OH)2D3 prediagnostic levels were indicative of the overall survival in the cases (ß = -0.012, HR 0.988, 95 % CI (0.978-0.998), while higher prediagnostic levels of 1,25(OH)2D3 were associated with a statistically significant increase in overall mortality. We observed multiple effects of the alleles of the investigated polymorphisms and of 1,25(OH)2D3 on overall survival, regardless of the underlying disease.

[Vitamin D: Its physiology, pathophysiology and significance in etiopathogenesis of malignant diseases]. / Vitamin D - jeho fyziologie, patofyziologie a význam v etiopatogenezi nádorových onemocnení

Vitamin D is an endogenous product of mammalian organisms from which an active agent of a steroid hormone nature is synthesized. These hormones participate in a variety of key metabolic processes in every nuclear cell, whether on endocrine, paracrine and autocrine or subcellular level. Vitamin D represents a very interesting molecule which participates in a great deal of body processes. This review summarizes the findings about the metabolism of vitamin D focusing on pathophysiology of malignant diseases.