Personalized screening strategies for TP53 R337H carriers: a retrospective cohort study of tumor spectrum in Li-Fraumeni syndrome adult carriers

Abstract

Background: Li-Fraumeni Syndrome (LFS) is a predisposition associated with early onset malignant tumors caused by germline pathogenic variants in the TP53 gene. Although rare worldwide, LFS is prevalent in Southern Brazil due to the founder pathogenic variant R337H. Here, we assessed tumor patterns and temporal trends, cancer risk, and sex differences of adult R337H carriers and carriers of other LFS-associated variants.

Methods: We retrospectively analyzed 708 adults, combining data from two sources: the Brazilian Li-Fraumeni Syndrome Study cohort and the NCI TP53 database. We assessed the clinical characteristics of 303 adults with R337H and compared them with those associated with 405 carriers of other TP53 variants.

Findings: R337H carriers, compared to adult carriers of other TP53 variants typical of LFS, had a lower cumulative risk of developing cancer (54% vs 78%). Female R337H carriers were at a higher risk than males (65% vs 30%) and had a higher risk of developing a second primary cancer, underscoring a strong sex bias not observed in carriers of other variants. The most common cancers were breast cancer and soft tissue sarcoma in females, and soft tissue sarcoma and prostate cancer in males. Common second malignancies were breast cancer in females and lung cancer in males.

Interpretation: This study shows that R337H is associated with a lifetime risk of multiple LFS-spectrum cancers but with incomplete penetrance, particularly in males. Our findings suggest that R337H carriers would benefit from tailored surveillance and risk reduction strategies.

Funding: São Paulo Research Foundation, Conselho Nacional de Pesquisa, and Hospital Sírio-Libanês.

Keywords: Germline; Li-Fraumeni syndrome; R337H variant; TP53.

Fig. 1

Overview of R337H and non-R337H study cohorts. A) Study flowchart showing the selected R337H (n = 303) and non-R337H (n = 405) individuals. B) Frequency of TP53 variants included in our study and affected TP53 domains. Variations found in at least 1% of individuals (corresponding to 286 of the 405) are shown. Number of non-R337H carriers only from the BLiSS cohort is shown in parenthesis when appropriate.

Fig. 2

Comparison of cancer onset, tumor types, and patient demographics between R337H and non-R337H carriers. A) Kaplan–Meier curves showing the cumulative risks of R337H and non-R337H carriers of developing a (first) primary tumor; B) Cancer patterns in R337H and non-R337H carriers; C) Proportions of male (M) and female (F) carriers without reported tumors, diagnosed with 1 primary tumor or with 2 or more primary tumors in R337H and non-R337H cohorts.

Fig. 3

Comparison of cancer characteristics between R337H and non-R337H carriers by sex. A) Ages at last follow-up of male and female individuals carrying TP53 R337H or non-R337H variants. B) Ages of male and female individuals at first tumor diagnosis (Wilcoxon tests); C) Kaplan–Meier curves showing the cumulative risks of male and female individuals (R337H and non-R337H carriers) of developing a first tumor (pairwise log-rank tests; FDR adjusted p-values); D) Tumor profile in male and female individuals carrying TP53 R337H or non-R337H variants; E) Temporal patterns of tumor occurrence in male and female individuals (Wilcoxon tests). P-value representation: “∗”: p < 0.05; “∗∗”: p < 0.01; “∗∗∗∗”: p < 0.0001; ns: not significant.

Fig. 4

Lifetime risk of developing a second tumor in R337H and non-R337H males and females. A) Ages of male and female individuals at second tumor diagnosis (Wilcoxon tests); B) Kaplan–Meier curves showing the cumulative risks of male and female individuals (R337H and non-R337H carriers) of developing a second tumor (pairwise log-rank tests; FDR adjusted p-values); C) and D) Proportions of additional tumors diagnosed in R337H and non-R337H C) female and D) male carriers (from second to last diagnosis). P-value representation: “∗”: p < 0.05; “∗∗”: p < 0.01; ns: not significant.

Fig. 5

Spectrum of second and third primary tumors in adult R337H carriers and non-R337H carriers. Sankey diagrams show the patterns of occurrence of the first, second, and third tumor types diagnosed in A) female and B) male individuals carrying the TP53 R337H and non-R337H variants.

Fig. 6

A summary of the tumor spectrum and cumulative cancer risks in adult R337H carriers by sex and age. A) Pie/donut charts showing percentages of first (central pie charts) and second (outer pie charts) tumor types diagnosed in R337H carriers. Carriers with no second malignancies (in gray) were further stratified into: dead (D), alive for up to 5 years of follow-up (≤5) or more than 5 years (>5); B) Schematic representation of a decision tree to support clinical decisions on screening of R337H adult carriers based on our findings.