MOLECULAR DIAGNOSIS OF ORPHAN SYNDROMES ASSOCIATED WITH NUMEROUS TYPES OF CANCER IN CHILDREN

Abstract

Sarcomas and brain tumors in children are a heterogeneous group of tumors, more than 7% of which may be a component of the Li-Fraumeni and Li-Fraumeni-like syndromes. The recognition these syndromes prior the adequate molecular testing is not always possible. This leads to late the diagnosis of tumor and not always adequate treatment. There are presented results of the molecular genetics diagnosis of the disease in four children with neoplasm arising in different organs and different periods in their life, between 2000 and 2015. Based on next-generation sequencing (NGS), test systems multiplex ligation-dependent probe amplification, Segner’s sequencing were detected a germline mutations of ТР53 gene in all children and some their relatives. Mutation in the gene ТР53, exon 7, с.С742Т (р.R248W) was reviled in one of these children, which inherited from his father affected multiple primary tumors. Besides, in this child discovered the second germinal missense mutation in the gene PPARG с.С254А (pP85Q), which inherited from the mother. Two missense mutations in the TP53 gene, exon 6 [c.619G> A (P.D207N) and c.644G> T (P.S215I)] identified in the second child, that inherited from the unaffected mother. The TP53 mutation exon 4, s.C328T (P.R110C) was revealed in the third child and the same mutations were detected in the child's mother and her 4 years old sister, who were healthy. Detected variants mutations indicated incomplete penetrance. The disease of the fourth child with intragenic deletion of exon 10 [c. (+ 11196- 1195 (1302 + 1_1303-1) del, P. (Ile332 ProfsTer14)] had the most aggressive course, with the development of 6 primary neoplasm. All identified genotypes had led to varying severity of disease symptoms in children. It is showed that the basis for the testing of mutations in the TP53 gene in children is early age of sarcomas, brain tumors and multiple primary neoplasms. Genetic TP53 testing should be offered their first-degree relatives. Because carriers of TP53 mutations have the risk of the other primary malignancy, they should be under active medical observing for life.