Dados do Trabalho

Título

GENOTYPING OF THE GERMLINE PATHOGENIC VARIANT R337H TP53 AND ITS GENETIC PREDISPOSITION TO SARCOMAS IN THE ABSENCE OF PHENOTYPES ASSOCIATED WITH LI-FRAUMENI SYNDROME

Introdução

Although they usually occur sporadically, genetic susceptibility is a risk factor for several types of sarcomas. In particular, the occurrence of familial sarcoma has been the basis of the clinical definition of Li-Fraumeni syndrome (LFS) (involving variations in the TP53 gene) since its first description in 1969, consequently, most investigations of the pathogenic variant TP53 R337H in patients diagnosed with sarcomas occurs in the context of the syndrome. However, cancer histories associated with this allele range from isolated cases to those associated with LFS families. This is explained by the fact that de novo TP53 variants are not uncommon and the penetrance of variants is incomplete.

Objetivo

To date, we have screened the TP53 R337H variant in 57 patients (out of 426) diagnosed with any histological subtype of sarcoma between the years 2010 to 2021, regardless of age at diagnosis and family history of cancer in an attempt to explain the frequency and penetrance of the variant in this type of cohort.

Método

Genomic DNA was extracted from peripheral blood leukocytes and exon 10 of the TP53 gene was amplified by conventional PCR using oligonucleotides flanking the TP53 R337H variant region. The generated amplicons were genotyped by the Sanger method.

Resultado

We identified two heterozygous patients (GA genotype) for the TP53 R337H variant, resulting in a frequency of 3.5% (2/57), all being germline. Adult age (considering those over 46 years old) was the representative age group for the onset of the tumor in those patients with the TP53 R337H variant. Among the carriers, we observed an apparently sporadic phenotypic pattern of cancer presentation in one of the patients, while the other showed a more aggressive phenotype and family history of cancer similar to LFS, although it did not meet the syndrome criteria. It was not possible to prove whether the pathogenic variant that both patients carry was due to inheritance, as their first-degree relatives were not tested. However, due to the patient's presentation with sporadic phenotype, a de novo variant case is suspected.

Conclusão

The identification of individuals with this condition makes it possible to guide physicians in counseling and to outline specific targeted prevention strategies, as well as to apply surveillance protocols with the aim of early detection of neoplasms that will contribute to their prognosis, in addition to helping to determine morbidity.

Palavras-chave

Sarcoma; Li–Fraumeni syndrome; TP53 R337H