Abstract
Importance Li-Fraumeni syndrome is a cancer predisposition syndrome that is associated with a high, lifelong risk of a broad spectrum of cancers, 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.
Objective To define the phenotypic spectrum of Li-Fraumeni syndrome and to conduct phenotype-genotype correlations across the phenotypic spectrum.
Design, Setting, Participants We propose the term "Li-Fraumeni spectrum" to encompass (1) phenotypic Li-Fraumeni syndrome, defined by the absence of a pathogenic/likely pathogenic TP53 variant in persons/families meeting clinical Li-Fraumeni syndrome criteria; (2) Li-Fraumeni syndrome, defined by the presence of a pathogenic/likely pathogenic TP53 variant in persons/families meeting Li-Fraumeni syndrome testing criteria; (3) attenuated Li-Fraumeni syndrome, defined by the presence of a pathogenic/likely pathogenic TP53 variant in a person/family with cancer not meeting Li-Fraumeni syndrome testing criteria; and (4) incidental Li- Fraumeni syndrome, defined by the presence of a pathogenic/likely pathogenic TP53 variant in a person/family without a history of cancer. We analyzed the germline variant dataset of the International Agency for Research on Cancer TP53 database
that contains 3034 persons from 1282 families.
Results Tumor spectra showed significant differences with a higher proportion of early adrenal, brain, connective tissue and bone tumors in patients meeting Li-Fraumeni syndrome genetic testing criteria, whereas carriers not meeting Li-Fraumeni syndrome genetic testing criteria had a higher proportion of breast and other cancers, 50% 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 meeting Li-Fraumeni syndrome genetic testing criteria, most TP53 variants classified as pathogenic/likely pathogenic (80.7%), whereas about 38.8% of TP53 variants identified in patients not meeting the Li-Fraumeni syndrome genetic testing criteria were classified as variants of uncertain significance, conflicting results, likely benign, or benign.
Conclusions and Relevance The new classification is a step towards understanding the factors leading to phenotypic differences and may serve as a model for other cancer predisposition syndromes.
Objective To define the phenotypic spectrum of Li-Fraumeni syndrome and to conduct phenotype-genotype correlations across the phenotypic spectrum.
Design, Setting, Participants We propose the term "Li-Fraumeni spectrum" to encompass (1) phenotypic Li-Fraumeni syndrome, defined by the absence of a pathogenic/likely pathogenic TP53 variant in persons/families meeting clinical Li-Fraumeni syndrome criteria; (2) Li-Fraumeni syndrome, defined by the presence of a pathogenic/likely pathogenic TP53 variant in persons/families meeting Li-Fraumeni syndrome testing criteria; (3) attenuated Li-Fraumeni syndrome, defined by the presence of a pathogenic/likely pathogenic TP53 variant in a person/family with cancer not meeting Li-Fraumeni syndrome testing criteria; and (4) incidental Li- Fraumeni syndrome, defined by the presence of a pathogenic/likely pathogenic TP53 variant in a person/family without a history of cancer. We analyzed the germline variant dataset of the International Agency for Research on Cancer TP53 database
that contains 3034 persons from 1282 families.
Results Tumor spectra showed significant differences with a higher proportion of early adrenal, brain, connective tissue and bone tumors in patients meeting Li-Fraumeni syndrome genetic testing criteria, whereas carriers not meeting Li-Fraumeni syndrome genetic testing criteria had a higher proportion of breast and other cancers, 50% 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 meeting Li-Fraumeni syndrome genetic testing criteria, most TP53 variants classified as pathogenic/likely pathogenic (80.7%), whereas about 38.8% of TP53 variants identified in patients not meeting the Li-Fraumeni syndrome genetic testing criteria were classified as variants of uncertain significance, conflicting results, likely benign, or benign.
Conclusions and Relevance The new classification is a step towards understanding the factors leading to phenotypic differences and may serve as a model for other cancer predisposition syndromes.
| Original language | English |
|---|---|
| Journal | JAMA oncology |
| Publication status | Accepted/In press - 13 Jul 2021 |
