Prevalence of germline mutations in the TP53 gene in patients with early-onset breast cancer in the Mexican population

Abstract

BackgroundHeterozygous germline TP53 gene mutations result in Li-Fraumeni Syndrome (LFS). Breast cancer (BC) is the most frequent tumor in young women with LFS. An important issue related to BC in the Mexican population is the average age at diagnosis, which is approximately 11 years younger than that of patients in the United States (U.S.) and Europe. The aim of this study was to determine the prevalence of germline mutations in TP53 among young Mexican BC patients.MethodsWe searched for germline mutations in the TP53 gene using targeted next-generation sequencing (NGS) in 78 BC patients younger than 45 years old (yo) who tested negative for BRCA1/2 mutations. A group of 509 Mexican women aged 45yo or older without personal or family BC history (parents/grandparents) was used as a control.ResultsWe identified five patients with pathogenic variants in the TP53 gene, equivalent to 6.4% (5/78). Among patients diagnosed at age 36 or younger, 9.4% (5/55) had pathogenic TP53 mutations. Three of these variants were missense mutations (c.844C > T, c.517G > A, and c.604C > T), and the other two mutations were frameshifts (c.291delC and c.273dupC) and had not been reported previously. We also identified a variant of uncertain clinical significance (VUS), c.672G > A, which causes a putative splice donor site mutation. All patients with TP53 mutations had high-grade and HER2-positive tumors. None of the 509 patients in the healthy control group had mutations in TP53.ConclusionsAmong Mexican BC patients diagnosed at a young age, we identified a high proportion with germline mutations in the TP53 gene. All patients with the TP53 mutations had a family history suggestive of LFS. To establish the clinical significance of the VUS found, additional studies are needed. Pathogenic variants of TP53 may explain a substantial fraction of BC in young women in the Mexican population. Importantly, none of these mutations or other pathological variants in TP53 were found in the healthy control group.

High Prevalence of Somatic Oncogenic Driver Alterations in Patients With NSCLC and Li-Fraumeni Syndrome

“…It has been described that breast tumors associated with LFS are enriched in HER2-positive subtype, which is in line with our data. 8 These observations suggest that the development of tumors in TP53 variant carriers requires somatic driver alterations, with TP53 variants acting not as oncogenic but as permissive events. This oncogenic addiction might be specific of an EGFR and HER2 pathway belonging to the HER family.…”

p.Arg72Pro polymorphism of P53 and breast cancer risk: a meta-analysis of case-control studies

“…It should be noted that the incidence of breast cancer differs among different populations around the world [1]. Over the past decades, major advances have been made in understanding the pathology of breast cancer at the molecular level, including the involvement of certain genes associated with the development of the disease such as BRCA1, BRCA2 and P53 which produce tumor suppressor proteins and participate in damaged DNA repair [3][4][5]. P53 plays a key role in the regulation of cell proliferation and apoptosis.…”

Prevalence of germline TP53 variants among early-onset breast cancer patients from Polish population

“…All patients had a familial history suggestive of LFS. One of the variants (c.844C > T) was initially reported as a founder mutation in the French-Canadian population [ 34 ] and was detected in our study. Among 2 out of 133 Taiwanese patients (median age—44) were found to carry the germline pathogenic variant p.G245S and p.R248Q in TP53 , which results in the defective function of TP53 .…”