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.
Highlights
Heterozygous germline TP53 gene mutations result in Li-Fraumeni Syndrome (LFS)
Germline TP53 mutations cause Li-Fraumeni Syndrome (LFS) (Online Mendelian Inheritance in Man [OMIM] #151623) [15]; patients with this syndrome show a predisposition for a broad spectrum of tumors, including adrenocortical carcinoma, bone and soft-tissue sarcomas, brain tumors, and early-onset Breast cancer (BC) [16]
We identified a variant of uncertain clinical significance (VUS), c.672G > A, that caused a silent mutation in a splice donor site in a patient who met the Chompret criteria for LFS (Fig. 1)
Summary
Heterozygous germline TP53 gene mutations result in Li-Fraumeni Syndrome (LFS). Breast cancer (BC) is the most frequent tumor in young women with LFS. The lifetime risk of developing cancer in patients with LFS is > 90% by the age Gallardo-Alvarado et al BMC Cancer (2019) 19:118 of 60. This percentage differs depending on gender, at approximately 68% in males and 93% in females. This difference is due to the high rate of women with LFS who develop BC at an early age (pre-menopause), making BC the most common cancer in LFS carriers (24–31%) [3, 16,17,18,19,20]. Other researchers have revised these criteria by adding other factors that include more individuals at risk of having TP53 mutations
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