Paired Tumor-Normal Sequencing Provides Insights into TP53-Related Cancer Spectrum in Li-Fraumeni Patients
Menée à partir du séquençage de l'ADN extrait d'échantillons sanguins et d'échantillons tumoraux prélevés sur 17 922 patients atteints d'un cancer, cette étude identifie les caractéristiques des variants du gène TP53 dans les cancers liés au syndrome de Li-Fraumeni
Background : Li-Fraumeni syndrome (LFS) genetic testing is performed using blood specimens from patients selected based on phenotype-dependent guidelines. This approach is problematic for understanding LFS clinical spectrum, because patients with non-classical presentations are missed, clonal hematopoiesis (CH)-related somatic blood mutations cannot be distinguished from germline variants, and unrelated tumors cannot be differentiated from those driven by germline TP53 defects.
Methods : To provide insights into LFS-related cancer spectrum, we analyzed paired tumor-blood DNA sequencing results in 17,922 cancer patients, and distinguished CH-related, mosaic, and germline TP53 variants. Loss-of-heterozygosity (LOH) and TP53 mutational status were assessed in tumors, followed by immunohistochemistry for p53 expression on a subset to identify those lacking biallelic TP53 inactivation.
Results : Pathogenic/likely pathogenic TP53 variants were identified in 50 patients, 12 (24.0%) of which were CH-related and four (8.0%) were mosaic. Twelve (35.3%) of 34 patients with germline TP53 variants did not meet LFS testing criteria. LOH of germline TP53 variant was observed in 96.0% (95% CI = 79.7–99.9%) of core LFS-spectrum type tumors versus 45.5% (95% CI = 16.8–76.6%) of other tumors, and 91.3% (95% CI = 72.0–98.9%) of tumors from patients who met LFS testing criteria versus 61.5% (95% CI = 31.6–86.1%) of tumors from patients who did not. Tumors retaining wild-type TP53 allele exhibited wild-type p53 expression.
Conclusions : Our results indicate that some TP53 variants identified in blood-only sequencing are not germline and a substantial proportion of LFS patients are missed by current testing guidelines. Additionally, a subset of tumors from LFS patients do not have biallelic TP53 inactivation and may represent cancers unrelated to their germline TP53 defect.
Journal of the National Cancer Institute , résumé, 2020