Tumor Spectrum and Temporal Cancer Trends in adult carriers of Li-Fraumeni syndrome: Implications for Personalized Screening Strategies inTP53R337H carriers

Abstract

SUMMARYBackgroundLi-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 a founder pathogenic variant, c.1010G>A, p.Arg337His (R337H), discovered through its association with risk of childhood adrenal cortical carcinoma.MethodsHere, we have analyzed tumor patterns, cancer risk, sex differences and temporal tumor trends in a cohort of 303 adult R337H carriers and we have compared them with those of 405 adult carriers of otherTP53variants typical of LFS.FindingsCompared to the latter, R337H carriers had a lower cumulative risk of developing cancer (54% for R337H vs 78% for otherTP53variants at age 50 years). Female R337H carriers were at a higher risk than males (65% vs 30% at age 50 years) 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 (75%), soft tissue sarcoma (9%) and lung cancer (8%) in females, and soft tissue sarcoma (30%), prostate (13%) and lung cancer (12%) in males. Common second malignancies were breast cancer in females and lung cancer in males.InterpretationsOverall, this study confirms that R337H is associated with a lifetime risk of multiple cancers of the LFS spectrum but with incomplete penetrance, particularly in males. Our findings suggest that R337H carriers would benefit from adapted lifetime and surveillance strategies for risk reduction.FundingSão Paulo Research Foundation and Hospital Sírio-Libanês.