In a study reported in JAMA Oncology, Kratz et al analyzed data from the International Agency for Research on Cancer (IARC) TP53 Database to define a phenotypic spectrum categorization for Li-Fraumeni syndrome.
As stated by the investigators, “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 TP53 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.”
Study Details
The study involved data from the IARC TP53 Database on a cohort of 3,034 persons from 1,282 families. The investigators defined the term “Li-Fraumeni spectrum” to include:
(1) Phenotypic Li-Fraumeni syndrome (defined as the absence of a pathogenic/likely pathogenic TP53 variant in persons/families meeting clinical Li-Fraumeni syndrome criteria)
(2) Li-Fraumeni syndrome (defined as the presence of a pathogenic/likely pathogenic TP53 variant in persons/families meeting Li-Fraumeni syndrome genetic testing criteria)
(3) Attenuated Li-Fraumeni syndrome (defined as the presence of a pathogenic/likely pathogenic TP53 variant in a person/family with cancer who does not meet Li-Fraumeni syndrome genetic testing criteria)
(4) Incidental Li-Fraumeni syndrome (defined as the presence of a pathogenic/likely pathogenic TP53 variant in a person/family without a history of cancer).
Key Findings
Compared with TP53 variant carriers who did not meet Li-Fraumeni syndrome genetic testing criteria (n = 678), patients who met the criteria (n = 2,139) were more likely to have early adrenal (6.5% vs 0%), brain (14.17% vs 7.46%), connective tissue (11.92% vs 7.33%), and bone tumors (10.98% vs 0.39%); in contrast, carriers who did not meet the criteria were more likely to have breast cancer (38.22% vs 27.55%) and other cancers (including lung, ovarian, kidney, and pancreatic cancers), with 45% of cancers occurring after age 45 years.
Several hotspot variants were present in both patients who did and did not meet genetic testing criteria (codons p.R175, p.G245, p.R248, p.R273, and p.R282), whereas others (p.M133T, p.P152L, p.C275Y, p.C275*, p.R337C, p.R342*, and p.R342P) were found exclusively in those in the Li-Fraumeni syndrome group, and one—p.R110L—was found exclusively in patients with attenuated Li-Fraumeni syndrome.
In patients who met genetic testing criteria, 82.2% of TP53 variants were classified as pathogenic/likely pathogenic, whereas 40.4% of variants identified in those who did not meet the criteria were classified as variants of uncertain significance, conflicting results, likely benign, benign, or unknown.
The investigators concluded: “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.”
Christian P. Kratz, MD, of the Pediatric Hematology and Oncology and Rare Disease Program, Hannover Medical School, Germany, is the corresponding author for the JAMA Oncology article.
Disclosure: The study was supported by the Deutsche Kinderkrebsstiftung, National Institutes of Health, National Cancer Institute, Burroughs Wellcome Fund, and others. For full disclosures of the study authors, visit jamanetwork.com.
