Clinical and molecular characterization of patients fulfilling Chompret criteria for Li-Fraumeni syndrome in Southern Brazil

Abstract

Li-Fraumeni syndrome (LFS) is an autosomal dominant cancer predisposition syndrome caused by pathogenic germline variants in the TP53 gene, characterized by a predisposition to the development of a broad spectrum of tumors at an early age. The core tumors related to LFS are bone and soft tissue sarcomas, premenopausal breast cancer, brain tumors, adrenocortical carcinomas (ACC), and leukemias. The revised Chompret criteria has been widely used to establish clinical suspicion and support TP53 germline variant testing and LFS diagnosis. Information on TP53 germline pathogenic variant (PV) prevalence when using Chompret criteria in South America and especially in Brazil is scarce. Therefore, the aim of this study was to characterize patients that fulfilled these specific criteria in southern Brazil, a region known for its high population frequency of a founder TP53 variant c.1010G>A (p.Arg337His), as known as R337H. TP53 germline testing of 191 cancer-affected and independent probands with LFS phenotype identified a heterozygous pathogenic/likely pathogenic variant in 26 (13.6%) probands, both in the DNA binding domain (group A) and in the oligomerization domain (group B) of the gene. Of the 26 carriers, 18 (69.23%) were R337H heterozygotes. Median age at diagnosis of the first tumor in groups A and B differed significantly in this cohort: 22 and 2 years, respectively (P = 0.009). The present study shows the clinical heterogeneity of LFS, highlights particularities of the R337H variant and underscores the need for larger collaborative studies to better define LFS prevalence, clinical spectrum and penetrance of different germline TP53 pathogenic variants.

Breast Cancer Phenotype Associated With Li-Fraumeni Syndrome: A Brazilian Cohort Enriched by TP53 p.R337H Carriers

“…Brazilian LFS carriers are mostly represented by p.R337H carriers, even though other TP53 germline variants are also found in this population ( 25 , 36 , 37 ). Likewise, although the majority of the LFS carriers in this study harbored the p.R337H variant, 17.2% of the cohort harbored other TP53 germline P/LP variants.…”

Vantagens vs. Custos Dos Diagnósticos Genético-Moleculares Da Síndrome De Li-Fraumeni No Brasil:

“…O espectro tumoral é semelhante ao de outros portadores de outras mutações em TP53, porém, há maior ocorrência de carcinomas adrenocorticais, câncer papilífero de tireoide, câncer renal e adenocarcinoma pulmonar. O câncer de mama é o tumor mais frequente em mulheres portadoras de TP53 p.R337H, com idade média de início de 40 anos, enquanto a média de início do diagnóstico na LFS clássica ocorre aos 32 anos (5,6) .…”

A qualitative study to assess the psychological experiences and coping strategies of families affected with Li-Fraumeni syndrome in the Indian population

“…The Chompret criteria for clinical diagnosis of LFS are proposed recently to identify affected families beyond the Classic criteria. 4 Generally, an individual with suspected or diagnosed LFS, in his thirties has a 50% risk of developing cancer, and further this risk increases to 100% by the age of 70 years 1,5 Due to the high risk of occurrence of multiple cancers, patients with LFS may have overbearing psychosocial problems. 6,7 Some of these individuals might have lost a parent or any close relative, which could intensify their emotional distress.…”

“…The Chompret criteria for clinical diagnosis of LFS are proposed recently to identify affected families beyond the Classic criteria. 4…”