Abstract Background: Li-Fraumeni Syndrome (LFS), caused by pathogenic/likely pathogenic (P/LP) variants in TP53, is a cancer predisposition syndrome that increases the risk for numerous cancer types in both children and adults. Many studies have shown that cancer rates can vary between races and ethnicities. For example, the 2024 Cancer Statistics published by the American Cancer Society reported the incidence for breast cancer to be highest for White individuals and lowest for Hispanic/Latino individuals. One LFS study showed East Asian individuals were more frequently diagnosed with gastric cancer compared to North Americans and Europeans. Other studies identified P/LP TP53 variants associated with specific populations, such as the South and Southeast Brazil founder variant, p.Arg337His. However, there lacks extensive research on the variable expressivity of cancers within the LFS population, based on genotype, race, and/or ethnicity. This study aims to describe the specific TP53 germline variants, cancer rates, and cancer types among individuals of different racial and ethnic groups diagnosed with LFS. Methods: A retrospective chart review of individuals with germline P/LP TP53 variants at the University of Texas MD Anderson Cancer Center was completed. Data collected includes race, ethnicity, number of cancer diagnoses, cancer types, and location of the TP53 variant (exon and codon). Individuals with a suspected somatic TP53 variant were excluded from this study. Racial groupings included Asian, Black or African American, White, and Other/Unspecified. Ethnicity was categorized as Hispanic, Non-Hispanic, and Other/Unspecified. There were also six cancer type categories: adrenocortical carcinoma, brain cancer, breast cancer, osteosarcoma, soft tissue sarcoma, and non-core LFS cancers. Descriptive and statistical analyses, including chi-squared or Fisher’s exact tests and pairwise comparisons, were performed using R software (v4.4.1). Results: Two hundred and fifty individuals with a confirmed P/LP TP53 variant were included in the analysis. Breast cancer was the most common cancer type diagnosed for all ethnic and racial groups, except Asian individuals, who most frequently had non-core LFS cancer diagnoses. There was a significant difference in the rate of breast cancer across racial groups (p = 0.037), with Black or African American individuals with LFS having the highest rate of breast cancer at 76.5%. Additionally, individuals who identified as Black or African American were 1.87 times more likely to develop breast cancer in comparison to those who identified as White. For cancer rates, most individuals in each racial and ethnic group were diagnosed with one primary cancer. Statistical analysis did not identify a significant difference in cancer rates across groups defined by race or ethnicity. Regarding the location of variants within the TP53 gene, there was a significant difference in the rate of variants in exon four (p = 0.021) and exon six (p = 0.016) across racial groups, with variants in exon four being more common in Asian individuals (33.3%) and variants in exon six being more common in Black or African American individuals (35.3%). Conclusion: This study highlights similarities in the rates and types of cancers seen across racial and ethnic groups within a cohort of individuals with LFS. However, this study also identified potential differences in the rates of breast cancer and variant location across racial populations within the cohort. The results of this study provide information that can lead to more personalized counseling for patients and train risk models to accurately predict cancer risk for individuals with LFS of differing races and ethnicities. Citation Format: H. Esplen, B. Arun, C. DiNardo, H. Abdel-Salam, K. Richardson, C. Peterson, J. Corredor. Evaluating Cancer Rates, Cancer Types, and Variant Hotspots Across Races and Ethnicities in Individuals with Li-Fraumeni Syndrome abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS3-01-13.
Esplen et al. (Tue,) studied this question.