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Analysis of the Li-Fraumeni spectrum based on an international germline TP53 variant data set: An international agency for research on cancer TP53 database analysis

JAMA Nov 03, 2021

Kratz CP, Freycon C, Maxwell KN, et al. - Researchers sought to describe the phenotypic spectrum of Li-Fraumeni syndrome and conduct phenotype-genotype correlations across the phenotypic spectrum.

  • The germline variant data set of the International Agency for Research on Cancer TP53 database that accommodates data on a cohort of 3,034 persons from 1,282 families were analyzed and classified.

  • The term Li-Fraumeni spectrum involved (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 who does not meet 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.

  • Patients who met vs those who did not meet Li-Fraumeni syndrome testing criteria differed meaningfully in the TP53 variant distribution.

  • There were significant differences in tumor spectra, with patients who met Li-Fraumeni syndrome genetic testing criteria (n = 2,139) having more early adrenal, brain, connective tissue, and bone tumors.

  • There were more breast and other cancers among carriers who did not meet Li-Fraumeni syndrome genetic testing criteria (n = 678); 45% of these occurred after age 45 years. Both groups had the presence of hotspot variants.

  • Patients with Li-Fraumeni syndrome exclusively exhibit several variants, while patients with attenuated Li-Fraumeni syndrome exclusively exhibit other variants.

  • Most TP53 variants in patients who met Li-Fraumeni syndrome genetic testing criteria were classified as pathogenic/likely pathogenic (1,757 of 2,139, 82.2%), whereas in patients who did not meet the Li-Fraumeni syndrome genetic testing criteria, 40.4% (404 of 678) of identified TP53 variants were classified as variants of uncertain significance, conflicting results, likely benign, benign, or unknown.

  • The new classification, Li-Fraumeni spectrum, is suggested to be a step toward attaining insight into the factors that result in phenotypic disparities and may serve as a model for other cancer predisposition syndromes.

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