Age-specific risks of leukemia in Li Fraumeni syndrome in children, adolescents, young adults, and adults.

Abstract

e22653 Background: Leukemia is a well-recognized risk in Li Fraumeni Syndrome (LFS), but age-specific risks in males and females estimated using modern genetic epidemiology analyses within the world’s largest study of LFS families have not been reported. Methods: Pedigree data from 1,610 families with LFS from the LiFT UP study comprised of 47,393 family members were analyzed by Kaplan Meier methods and modified segregation analysis using a Bayesian framework. All families included had germline TP53 mutations. Age-specific and lifetime risks were calculated. Standardized incidence ratios were calculated to estimate relative risk using observed leukemia cases in pedigrees vs. SEER data for expected counts. Missing ages in family members were imputed. To minimize ascertainment bias, we excluded information from probands who were ascertained because of a leukemia diagnosis (conditioning on the proband). Results: Leukemia was reported in 165 females, 191 males (356 individuals) from a total of 289 families. Among these, leukemia was diagnosed in 30 female probands and 21 male probands, who were excluded as part of the ascertainment adjustment. The youngest age-at-diagnosis was <1 in females and 1 in males and the average age of diagnosis was 27.5 years in females and 27.4 years in males. Among individuals with recorded diagnosis age, 50 females and 46 males with leukemia were TP53 carriers, and 5 females and 10 males with leukemia were non-carriers, with the remaining 81 females and 93 males untested. The lifetime risk of leukemia is 9.9% in TP53+ females, compared to a SEER risk of 1.6% (Standardized Incidence Ratio (SIR)=11.7, confidence interval (CI)=8.8-15.4) and 16.4% in TP53+ males compared to a SEER risk of 2.9% (SIR = 12.7, CI=9.4-16.8). Age-specific SIRs are high especially in children, adolescents, and young adults, with the highest SIR in females aged 10-14 (SIR=23.2, CI=14.5-35.1) and highest SIR in males aged 15-19 (SIR=23.6 CI=14.4-36.4). Cumulative leukemia risks in children & adolescents (≤19 years) old are 1.5% in females and 2.1% in males. Conclusions: TP53 carriers with LFS have elevated risk of leukemia, especially in young carriers compared to population risks. Pediatric, adolescent, and young adults are at the highest relative risk of leukemia in LFS, although risks remain elevated throughout the lifetime of TP53 carriers in both females and males.