Cancer Risks Associated With <i>TP53</i> Pathogenic Variants: Maximum Likelihood Analysis of Extended Pedigrees for Diagnosis of First Cancers Beyond the Li-Fraumeni Syndrome Spectrum
Cristina Fortuño, Bing Feng, Courtney Carroll, Giovanni Innella, Wendy Kohlmann, Conxi Lázaro, Joan Brunet, Lídia Feliubadaló, Sílvia Iglesias, Mireia Menéndez, Àlex Teulé, Mandy L. Ballinger, David M. Thomas, Ainsley Campbell, Mike Field, Marion Harris, Judy Kirk, Nicholas Pachter, Nicola Poplawski, Rachel Susman, Kathy Tucker, Mathew Wallis, Rachel Williams, Elisa J. Cops, David E. Goldgar, kConFab Investigators, Paul A. James, Amanda B. Spurdle, David J. Amor, Lesley Andrews, Yoland Antill, Rosemary L. Balleine, Jonathan Beesley, Ian Bennett, Michael Bogwitz, Simon Bodek, Leon Botes, Meagan Brennan, Melissa A. Brown, Michael F. Buckley, Jo Burke, Phyllis Butow, Liz Caldon, Ian Campbell, Michelle Cao, Anannya Chakrabarti, Deepa Chauhan, Manisha Chauhan, Georgia Chenevix‐Trench, Alice Christian, Paul A. Cohen, Alison Colley, Ashley Crook, James Cui, Eliza Courtney, Margaret C. Cummings, Sarah‐Jane Dawson, Anna DeFazio, Martin Delatycki, Rebecca Dickson, Joanne Dixon, Ted Edkins, Stacey L. Edwards, Gelareh Farshid, Andrew Fellows, Georgina Fenton, Michael Field, James M. Flanagan, Peter C.C. Fong, Laura Forrest, Stephen B. Fox, Juliet D. French, Michael Friedländer, Clara Gaff, Mike Gattas, Peter George, Sian Greening, Marion Harris, Stewart Hart, Nick Hayward, John L. Hopper, Cass Hoskins, Clare Hunt, Paul A. James, Mark A. Jenkins, Alexa Kidd, Judy Kirk, Jessica Koehler, James Kollias, Sunil R. Lakhani, Mitchell Lawrence, Jason S. Lee, Shuai Li, Geoffrey J. Lindeman, Jocelyn Lippey, Lara Lipton, Liz Lobb, Sherene Loi, Graham J. Mann, Deborah J. Marsh
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.