In southern Brazil, the frequent presence of a variant of a gene called TP53 predisposes to adrenocortical tumors (TCS) in children with low penetrance.
In an article published in The Lancet Regional Healthscientists are developing a method to discover other genetic variants that increase the risk of TCS in variant carriers TP53. These methods could be applied to identify risk factors in other types of cancer.
Pathogenic gene variants TP53which plays a very important role as a tumor suppressor, are common in many types of cancer. When people inherit certain harmful changes to this gene, especially if its function is severely impaired, they can develop multiple, recurring tumors at a young age. This condition is called Li-Fraumeni syndrome (LFS). These variants are rare because they reduce reproductive success. However, some variants only partially affect gene function TP53thus reducing the probability to develop a cancer in their carriers.
A specific variant of TP53 (p.R337H) is common in the population of the south and southeast from Brazil. Early studies linked this variant to a specific type of childhood cancer, adrenocortical tumors (TCS), which are much more common in this geographic region than in the rest of the world. Other research has also linked this variant to LFS and a similar condition called Li-Fraumeni-like syndrome (LFL).
In families where carriers of this variant are present, we observe approximately 5 times more cancers than in non-carriers. In children and adolescents with this variant, the most common cancers are TCS and a specific type of brain cancer (choroid plexus carcinoma). In adults, carriers have a higher likelihood of developing breast and stomach cancers.
However, the probability of developing cancer in carriers of the variant TP53 p.R337H is much lower than in people carrying variants TP53 more severe. In addition, this variant does not affect the reproductive healthbecause most carriers do not develop cancer until old age and remain healthy during their reproductive years.
In addition to newborn screening for carrier status TP53 p.R337H, it is crucial to identify the genetic and environmental factors influencing TCS penetrance in carriers of this variant pathogenic. This represents an issue of public health very important for about 100 million people living in southern and southeastern Brazil and neighboring countries (Paraguay and possibly Argentina).
In this study, carried out within the framework of the International Research Network CNRS “Immunobiology and immunopathology of pediatric adrenal tumors” (IIPACT), in collaboration with theHospital Pequeno Principe de Curitiba (Brazil), scientists sought to identify additional genetic factors that may increase the risk of developing TCS in children carrying TP53 p.R337H by analyzing the data genomics of trios composed of a carrier child, a carrier parent without cancer and a non-carrier parent.
By analyzing exome DNA sequencing data genomics of the blood of the members of the trios, using algorithmslearning profoundly, we found a significant enrichment of non-coding variants in genes involved in the cyclic AMP pathway in children with TCS carrying TP53 p.R337H. One of these variants (rs2278986 in the gene SCARB1) was confirmed to be significantly enriched in a validation cohort of carriers TP53 p.R337H with TCS compared to carriers without TCS.
Figure: Genetic variants increase the risk of developing adrenocortical tumors in children with the TP53 p.R337H mutation.
A. Hypothesis 1: A protective variant (P) is present in the germline of the parent carrying the TP53 p.R337H mutation and absent in the other parent. The affected child does not carry the P variant.
B. Hypothesis 2: A damaging variant (D) is present in the germline of the parent that does not carry TP53 p.R337H and is absent in the carrier parent. The child is a carrier of D. Each bar represents the genome haploid.
C. Gene Oncology terms differentially enriched in the protective variant model (hypothesis 1: PVM) and the damaging variant model (hypothesis 2: DVM). The log10 probability scale is shown.
This study therefore demonstrated that it is possible to identify variants associated with an increased risk of developing TCS through AI-guided analysis of exome sequencing data from a small number of trios. If these results are validated on a larger scale, the use of rs2278986 profiling in a clinical context could become a useful tool for stratifying the risk of developing TCS in carriers of the pathogenic variant. TP53 p.R337H. Additionally, our methods could also be applied to other pediatric and adult cancers associated with germline pathogenic variants in oncogenes or tumor suppressor genes.
References:
AI-guided identification of risk variants for adrenocortical tumours in TP53 p.R337H carrier children: a genetic association study.
The Lancet Regional Health – AmericasDOI: 10.1016/j.lana.2024.100863 (2024)
