Cancer Risks Associated With TP53 Pathogenic Variants: Maximum Likelihood Analysis of Extended Pedigrees for Diagnosis of First Cancers Beyond the Li-Fraumeni Syndrome Spectrum
Authors: Fortuno Cristina , Feng Bing-Jian , Carroll Courtney , Innella Giovanni , Kohlmann Wendy , Lázaro Conxi , Brunet Joan , Feliubadaló Lidia , Iglesias Silvia , Menéndez Mireia , Teulé Alex , Ballinger Mandy L. , Thomas David M. , Campbell Ainsley , Field Mike , Harris Marion , Kirk Judy , Pachter Nicholas , Poplawski Nicola , Susman Rachel , Tucker Kathy , Wallis Mathew , Williams Rachel , Cops Elisa , Goldgar David ,   kConFab Investigators, James Paul A. , Spurdle Amanda B. , Amor David , Andrews Lesley , Antill Yoland , Balleine Rosemary , Beesley Jonathan , Bennett Ian , Bogwitz Michael , Bodek Simon , Botes Leon , Brennan Meagan , Brown Melissa , Buckley Michael , Burke Jo , Butow Phyllis , Caldon Liz , Campbell Ian , Cao Michelle , Chakrabarti Anannya , Chauhan Deepa , Chauhan Manisha , Chenevix-Trench Georgia , Christian Alice , Cohen Paul , Colley Alison , Crook Ashley , Cui James , Courtney Eliza , Cummings Margaret , Dawson Sarah-Jane , deFazio Anna , Delatycki Martin , Dickson Rebecca , Dixon Joanne , Edkins Ted , Edwards Stacey , Farshid Gelareh , Fellows Andrew , Fenton Georgina , Field Michael , Flanagan James , Fong Peter , Forrest Laura , Fox Stephen , French Juliet , Friedlander Michael , Gaff Clara , Gattas Mike , George Peter , Greening Sian , Harris Marion , Hart Stewart , Hayward Nick , Hopper John , Hoskins Cass , Hunt Clare , James Paul , Jenkins Mark , Kidd Alexa , Kirk Judy , Koehler Jessica , Kollias James , Lakhani Sunil , Lawrence Mitchell , Lee Jason , Li Shuai , Lindeman Geoff , Lippey Jocelyn , Lipton Lara , Lobb Liz , Loi Sherene , Mann Graham , Marsh Deborah , McLachlan Sue Anne , Meiser Bettina , Milne Roger , Nightingale Sophie , O'Connell Shona , O'Sullivan Sarah , Ortega David Gallego , Pachter Nick , Pang Jia-Min , Pathak Gargi , Patterson Briony , Pearn Amy , Phillips Kelly , Pieper Ellen , Ramus Susan , Rickard Edwina , Robinson Bridget , Saleh Mona , Skandarajah Anita , Salisbury Elizabeth , Saunders Christobel , Saunus Jodi , Savas Peter , Scott Rodney , Scott Clare , Sexton Adrienne , Shaw Joanne , Shelling Andrew , Srinivasa Shweta , Simpson Peter , Southey Melissa , Spurdle Amanda , Taylor Jessica , Taylor Renea , Thorne Heather , Trainer Alison , Tucker Kathy , Visvader Jane , Walker Logan , Williams Rachael , Winship Ingrid , Young Mary Ann , Zaheed Milita 
Published: February 2024

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.