Cancer Risks Associated With TP53 Pathogenic Variants: Maximum Likelihood Analysis of Extended Pedigrees for Diagnosis of First Cancers Beyond the Li-Fraumeni Syndrome Spectrum

Abstract

PURPOSE Establishing accurate age-related penetrance figures for the broad range of cancer types that occur in individuals harboring a pathogenic germline variant in the TP53 gene is essential to determine the most effective clinical management strategies. These figures also permit optimal use of cosegregation data for classification of TP53 variants of unknown significance. Penetrance estimation can easily be affected by bias from ascertainment criteria, an issue not commonly addressed by previous studies. MATERIALS AND METHODS We performed a maximum likelihood penetrance estimation using full pedigree data from a multicenter study of 146 TP53-positive families, incorporating adjustment for the effect of ascertainment and population-specific background cancer risks. The analysis included pedigrees from Australia, Spain, and United States, with phenotypic information for 4,028 individuals. RESULTS Core Li-Fraumeni syndrome (LFS) cancers (breast cancer, adrenocortical carcinoma, brain cancer, osteosarcoma, and soft tissue sarcoma) had the highest hazard ratios of all cancers analyzed in this study. The analysis also detected a significantly increased lifetime risk for a range of cancers not previously formally associated with TP53 pathogenic variant status, including colorectal, gastric, lung, pancreatic, and ovarian cancers. The cumulative risk of any cancer type by age 50 years was 92.4% (95% CI, 82.2 to 98.3) for females and 59.7% (95% CI, 39.9 to 81.3) for males. Females had a 63.3% (95% CI, 35.6 to 90.1) cumulative risk of developing breast cancer by age 50 years. CONCLUSION The results from maximum likelihood analysis confirm the known high lifetime risk for the core LFS-associated cancer types providing new risk estimates and indicate significantly increased lifetime risks for several additional cancer types. Accurate cancer risk estimates will help refine clinical recommendations for TP53 pathogenic variant carriers and improve TP53 variant classification.

Breast Cancer Risk for Women With a TP53 Pathogenic Variant

“…Specifically, (1) half of their families were from Australian resources that focused on hereditary cancers, especially breast cancer (they did not mention the selection criteria for the families from Spain and the United States), and (2) all family members' phenotypes were used in the adjustment for ascertainment in their statistical analysis. Considering previous studies, the same pattern is also observed: The risk estimate from women unselected for breast cancer family history 3 is consistent with our estimate, whereas the risk estimates from Li-Fraumeni Syndrome families 4,5 are consistent with those of Fortuno et al 1 From an etiological perspective, the existence of a risk difference between members of high-risk families and members of unselected families implies that breast cancer risk associated with TP53 PVs, or the PVs themselves, is inherently different for these two populations, and/or the risks are modified by other factors shared within families, genetic, or environmental. Such potential differences and/or modifications have also been observed for carriers of PVs in other breast cancer susceptibility genes such as BRCA1, BRCA2, and PALB2.…”

“…This could be misleading, especially for the public without relevant knowledge and for clinicians who are not aware of the complexity related to penetrance interpretation. We believe that the relevance of the risk estimates, both Fortuno's and ours, should be emphasized so that women with different circumstances can be advised about the most relevant risk estimate, and the dedicated breast screening for women from a young age, as suggested by Fortuno et al, 1 No potential conflicts of interest were reported.…”

“…The difference is likely due to that the families for these two studies were selected using different criteria. The families in our study were ascertained via breast cancer case probands unselected for breast cancer family history, whereas in the study by Fortuno et al, 1 although not explicitly stated, family history contributed to the families' ascertainment. Specifically, (1) half of their families were from Australian resources that focused on hereditary cancers, especially breast cancer (they did not mention the selection criteria for the families from Spain and the United States), and (2) all family members' phenotypes were used in the adjustment for ascertainment in their statistical analysis.…”