Emerging insights into ethnic-specific TP53 germline variants

Abstract

The recent expansion of human genomics repositories has facilitated the discovery of novel TP53 variants in populations of different ethnic origins. Interpreting TP53 variants is a major clinical challenge because they are functionally diverse, confer highly variable predisposition to cancer (including elusive low-penetrance alleles), and interact with genetic modifiers that alter tumor susceptibility. Here, we discuss how a cancer risk continuum may relate to germline TP53 mutations on the basis of our current review of genotype-phenotype studies and an integrative analysis combining functional and sequencing datasets. Our study reveals that each ancestry contains a distinct TP53 variant landscape defined by enriched ethnic-specific alleles. In particular, the discovery and characterization of suspected low-penetrance ethnic-specific variants with unique functional consequences, including P47S (African), G334R (Ashkenazi Jewish), and rs78378222 (Icelandic), may provide new insights in terms of managing cancer risk and the efficacy of therapy. Additionally, our analysis highlights infrequent variants linked to milder cancer phenotypes in various published reports that may be underdiagnosed and require further investigation, including D49H in East Asians and R181H in Europeans. Overall, the sequencing and projected functions of TP53 variants arising within ethnic populations and their interplay with modifiers, as well as the emergence of CRISPR screens and AI tools, are now rapidly improving our understanding of the cancer susceptibility spectrum, leading toward more accurate and personalized cancer risk assessments.

Figure 1.

The landscape of TP53 mutations in cancer and variants in the general population. A) The proportion of each type of mutation is represented within the following populations: tumors with somatic TP53 mutations (27 217 tumors; data from The TP53 Database), carriers of germline TP53 mutations (1384 carriers; data from The TP53 Database), and TP53 variants in the general population without cancer history (310 081 variants from 76 156 genome samples; data from gnomAD version 3 noncancer selection mapped against the canonical transcript [Ensembl transcript ID ENST00000269305.9]). B) The occurrence of nonsynonymous mutations affecting the coding region. CTD = C-terminal domain; DBD = DNA-binding domain; OD = oligomerization domain; PRD = proline-rich domain; T1/T2 = transactivation domain 1 and 2. In these populations, data are from the noncancer dataset of gnomAD version 3 for Africans and version 2 for the rest.

Figure 2.

The functional diversity of TP53 mutations in cancer and in variants found in the general population without cancer history. Violin plots with overlaid box plots display the functional distributions of the variants observed in Figure 1, B in terms of transcriptional activity (ability to transactivate p53-responsive promoter elements) (17), dominant-negative activity (ability to reduce the sensitivity of wild-type p53 to nutlin-3 inhibition) (13), loss-of-function (loss of sensitivity to nutlin-3 inhibition) (13), and relative fitness (selective advantage in a competitive growth culture; only measured for alterations in the DNA-binding domain [DBD]) (14). Each data point represents a different variant and its frequency within the population. Values of wild-type p53 are shown as horizontal dashed lines. Carriers of the predominant single nucleotide polymorphisms at codon 72 (72P and 72R; both considered wild-type alleles) were excluded from the plots but represented as colored symbols. P-values were obtained using the Kruskal-Wallis test.

Figure 3.

The landscapes of TP53 exonic variants across different ethnic groups and world regions. The top upwards-facing histograms compare TP53 variant allele counts in 20 744 Africans, 456 Amish, 5185 Ashkenazi Jewish, 9977 East Asians, 64 603 European non-Finnish, 12 562 Finnish, 17 720 Latino/admixed Americans, 158 Middle Eastern, 15 308 South Asians, and 3614 Others (data from the noncancer dataset of gnomAD version 3 for Africans and version 2 for the rest). The down-facing histograms below compare verified pathogenic germline TP53 mutations within populations of the indicated world regions (data from The TP53 Database).