Analysis of the Li-Fraumeni Spectrum Based on an International Germline <i>TP53</i> Variant Data Set
Authors: Christian P. Kratz, Claire Freycon, Kara N. Maxwell, Kim E. Nichols, Joshua D. Schiffman, D. Gareth Evans, Maria I. Achatz, Sharon A. Savage, Jeffrey N. Weitzel, Judy E. Garber, Pierre Hainaut, David Malkin
Journal: JAMA Oncology (2021)

<h3>Importance</h3> Li-Fraumeni syndrome is a cancer predisposition syndrome that is associated with a high, lifelong risk of a broad spectrum of cancers that is caused by pathogenic<i>TP53</i>germline variants. A definition that reflects the broad phenotypic spectrum that has evolved since the gene discovery is lacking, and mechanisms leading to phenotypic differences remain largely unknown. <h3>Objective</h3> To define the phenotypic spectrum of Li-Fraumeni syndrome and conduct phenotype-genotype associations across the phenotypic spectrum. <h3>Design, Setting, and Participants</h3> We analyzed and classified the germline variant data set of the International Agency for Research on Cancer<i>TP53</i>database that contains data on a cohort of 3034 persons from 1282 families reported in the scientific literature since 1990. We defined the term<i>Li-Fraumeni spectrum</i>to encompass (1)<i>phenotypic Li-Fraumeni syndrome</i>, defined by the absence of a pathogenic/likely pathogenic<i>TP53</i>variant in persons/families meeting clinical Li-Fraumeni syndrome criteria; (2)<i>Li-Fraumeni syndrome</i>, defined by the presence of a pathogenic/likely pathogenic<i>TP53</i>variant in persons/families meeting Li-Fraumeni syndrome testing criteria; (3)<i>attenuated Li-Fraumeni syndrome</i>, defined by the presence of a pathogenic/likely pathogenic<i>TP53</i>variant in a person/family with cancer who does not meet Li-Fraumeni syndrome testing criteria; and (4)<i>incidental Li-Fraumeni syndrome</i>, defined by the presence of a pathogenic/likely pathogenic<i>TP53</i>variant in a person/family without a history of cancer. Data analysis occurred from November 2020 to March 2021. <h3>Main Outcomes and Measures</h3> Differences in variant distribution and cancer characteristics in patients with a germline<i>TP53</i>variant who met vs did not meet Li-Fraumeni syndrome testing criteria. <h3>Results</h3> Tumor spectra showed significant differences, with more early adrenal (n = 166, 6.5% vs n = 0), brain (n = 360, 14.17% vs n = 57, 7.46%), connective tissue (n = 303, 11.92% vs n = 56, 7.33%), and bone tumors (n = 279, 10.98% vs n = 3, 0.39%) in patients who met Li-Fraumeni syndrome genetic testing criteria (n = 2139). Carriers who did not meet Li-Fraumeni syndrome genetic testing criteria (n = 678) had more breast (n = 292, 38.22% vs n = 700, 27.55%) and other cancers, 45% of them occurring after age 45 years. Hotspot variants were present in both groups. Several variants were exclusively found in patients with Li-Fraumeni syndrome, while others where exclusively found in patients with attenuated Li-Fraumeni syndrome. In patients who met Li-Fraumeni syndrome genetic testing criteria, most<i>TP53</i>variants were classified as pathogenic/likely pathogenic (1757 of 2139, 82.2%), whereas 40.4% (404 of 678) of<i>TP53</i>variants identified in patients who did not meet the Li-Fraumeni syndrome genetic testing criteria were classified as variants of uncertain significance, conflicting results, likely benign, benign, or unknown. <h3>Conclusions and Relevance</h3> The findings of this cohort study suggest that this new classification, Li-Fraumeni spectrum, is a step toward understanding the factors that lead to phenotypic differences and may serve as a model for other cancer predisposition syndromes.