Deciphering dual clinical entities associated with TP53 pathogenic variants: Insights from 53,085 HBOC panel analyses in French laboratories

Abstract

TP53 is included in most cancer predisposition multigene panels, especially those exploring Hereditary Breast and Ovarian Cancer (HBOC) predisposition. The purpose of this study was to define the contribution of TP53 pathogenic variants (PV) to the HBOC phenotype by collecting genotypes and phenotypes of 398 patients harboring a TP53 variant identified by 53,085 HBOC panel sequencing in 15 French laboratories. Heterozygous TP53 variants were identified in 0.44% of HBOC panels, evenly distributed between PV and VUS. Breast cancers associated with TP53 were predominantly triple positive, particularly Her2+ breast cancer, in situ cancer, or phyllodes tumors (p < 0.0001 for both). Interestingly, TP53 PV were identified across all ages in breast cancer patients, with enrichment before 36y. We demonstrated that null variants were linked with the HBOC phenotype, and missense variants, especially with a dominant negative effect, with the LFS phenotype (p = 0.0096). Patients with breast cancer harboring null variants displayed an earlier age of onset compared to missense (p = 0.0030). Surprisingly, we identified, in late-onset cancer patients, TP53 hotspot PV usually identified in classic LFS, which underlines variable penetrance. Thus, this study suggests the existence of two phenotypic entities associated with TP53 PV: clinical LFS and TP53-related breast cancer. The type of TP53 variant, as well as modifying factors reflected in family history, may influence these phenotypes, and both should be considered to define the clinical follow-up of patients and relatives.

Keywords: Li–Fraumeni syndrome; TP53; breast cancer; genotype–phenotype correlation.

FIGURE 1

Study flow diagram.

FIGURE 2

Phenotypes of patients harboring a TP53 variant. Phenotypes of the 124 patients with a TP53 PV (A) and of the 110 patients with a TP53 VUS (B).

FIGURE 3

LOF TP53 variants are associated with HBOC‐associated variants and with early onset breast cancer. (A) Percentage of the different types of TP53 variants according to their proteic impact in patients with a LFS associated variant or a HBOC associated variant. We observe a significantly higher proportion of LOF variants in the HBOC associated variants group of patients compared to missense variants and particularly to DNE missense variants which seem associated to the LFS associated variants group of patients. (B) and (C) Age of first cancer (B) or first breast cancer (C) development in HBOC patients carrying a LOF, DNE missense or other missense TP53 PV. Patients with LOF variants (green) develop cancer sooner than those carrying a DNE missense variant (blue) or other missense variant (orange).

FIGURE 4

Cancer distribution according to the age in patients carrying a null or missense TP53 PV. Density plots representing the cancer risk depending on age for null (in pink) and missense (in blue) TP53 variants. This graph has been obtained from collected data in this series and data from the Rouen laboratory local TP53 database. We reported the age of the first cancer for 324 patients carrying one of the 95 missense variants identified in this study and for 42 patients with one of the 18 null variants documented in this work.