Cancer Risks Associated With TP53 Pathogenic Variants: Maximum Likelihood Analysis of Extended Pedigrees for Diagnosis of First Cancers Beyond the Li-Fraumeni Syndrome Spectrum.
Level 3 - non-randomized controlled study
Multicenter retrospective extended pedigree penetrance analysis with ascertainment adjustment
PubMed 38412388 · doi:10.1200/PO.23.00453
What was done
Researchers conducted a maximum likelihood penetrance analysis using complete pedigree data from 146 TP53-positive families across Australia, Spain, and the United States (4,028 individuals with phenotypic data). The model adjusted for ascertainment bias and population-specific background cancer risks to estimate age-related cancer penetrance for core Li-Fraumeni syndrome (LFS) and other cancer types.
What was found
Core LFS cancers (breast, adrenocortical carcinoma, brain cancer, osteosarcoma, and soft tissue sarcoma) exhibited the highest hazard ratios. Significantly increased lifetime risks were also identified for non-core cancers: colorectal, gastric, lung, pancreatic, and ovarian. By age 50, the cumulative risk of developing any cancer was 92.4% (95% CI, 82.2 to 98.3) for females and 59.7% (95% CI, 39.9 to 81.3) for males. The cumulative breast cancer risk by age 50 among females was 63.3% (95% CI, 35.6 to 90.1).
Why it matters
These findings expand the recognized phenotypic spectrum of TP53 pathogenic variants beyond classic Li-Fraumeni cancers. The resulting ascertainment-adjusted risk figures can refine clinical cancer surveillance guidelines and assist in interpreting TP53 variants of uncertain significance.
Limits
Specific hazard ratios and numeric risk estimates for individual non-core cancer types were omitted from the abstract. Confidence intervals for cumulative risks were wide, and pedigree-based analyses remain susceptible to family history recall bias and unmeasured modifier genes.