Genotype–phenotype associations among panel-based TP53+ subjects

• Published in: Genetics in medicine Vol. 21; no. 11; pp. 2478 - 2484
• Main Authors: Rana, Huma Q., Clifford, Jacob, Hoang, Lily, LaDuca, Holly, Black, Mary Helen, Li, Shuwei, McGoldrick, Kelly, Speare, Virginia, Dolinsky, Jill S., Gau, Chia-Ling, Garber, Judy E.
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.11.2019; Elsevier Limited
• Subjects: Adult; Biomedical and Life Sciences; Biomedicine; Cancer; Cohort Studies; Female; Genetic Association Studies; Genetic counseling; Genetic Predisposition to Disease; Genetic Testing - methods; Genotype & phenotype; Germ-Line Mutation - genetics; Heterozygote; Human Genetics; Humans; Laboratory Medicine; Li-Fraumeni Syndrome - diagnosis; Li-Fraumeni Syndrome - genetics; Loss of Function Mutation - genetics; Male; Middle Aged; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; phenotype; loss-of-function; Li–Fraumeni syndrome; multigene panel testing; TP53
• ISSN: 1098-3600; 1530-0366; 1530-0366
• DOI: 10.1038/s41436-019-0541-y

Purpose Panel testing has led to the identification of TP53 pathogenic/likely pathogenic (P/LP) variant carriers ( TP53 +) who exhibit a broad range of phenotypes. We sought to evaluate and compare genotype–phenotype associations among TP53 + panel-ascertained subjects. Methods Between 2012 and 2017, 317 TP53 + subjects (279 females and 38 males) identified through panel testing at one testing laboratory were found to have evaluable clinical histories and molecular results. Subject cancer histories were obtained from test requisition forms. P/LP variants were categorized by type and were examined in relation to phenotype. Results Loss-of-function (LOF) variants were associated with the earliest age at first cancer, with a median age of 30.5 years ( P  = 0.014); increased frequency of a sarcoma diagnosis ( P  = 0.016); and more often meeting classic LFS testing and Chompret 2015 criteria ( P  = 0.004 and 0.002 respectively), as compared with dominant-negative missense, other missense, or miscellaneous (splice or in-frame deletion) P/LP variant categories. Conclusion Loss-of-function variants were more often associated with characteristic LFS cancer histories than other variant categories in TP53 + carriers ascertained through multigene panel testing. These findings require validation in other TP53 + cohorts. Genetic counseling for panel-ascertained TP53 + individuals should reflect the dynamic expansion of the Li–Fraumeni syndrome phenotype.