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Genotype-phenotype associations within the Li-Fraumeni spectrum: a report from the German Registry.

ABSTRACT: Li-Fraumeni syndrome (LFS) is a cancer predisposition syndrome caused by pathogenic TP53 variants. The condition represents one of the most relevant genetic causes of cancer in children and adults due to its frequency and high cancer risk. The term Li-Fraumeni spectrum reflects the evolving phenotypic variability of the condition. Within this spectrum, patients who meet specific LFS criteria are diagnosed with LFS, while patients who do not meet these criteria are diagnosed with attenuated LFS. To explore genotype-phenotype correlations we analyzed 141 individuals from 94 families with pathogenic TP53 variants registered in the German Cancer Predisposition Syndrome Registry. Twenty-one (22%) families had attenuated LFS and 73 (78%) families met the criteria of LFS. NULL variants occurred in 32 (44%) families with LFS and in two (9.5%) families with attenuated LFS (P value < 0.01). Kato partially functional variants were present in 10 out of 53 (19%) families without childhood cancer except adrenocortical carcinoma (ACC) versus 0 out of 41 families with childhood cancer other than ACC alone (P value < 0.01). Our study suggests genotype-phenotype correlations encouraging further analyses.

SUBMITTER: Penkert J

PROVIDER: S-EPMC9382737 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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Genotype-phenotype associations within the Li-Fraumeni spectrum: a report from the German Registry.

Penkert Judith J Strüwe Farina J FJ Dutzmann Christina M CM Doergeloh Beate B BB Montellier Emilie E Freycon Claire C Keymling Myriam M Schlemmer Heinz-Peter HP Sänger Birte B Hoffmann Beatrice B Gerasimov Tanja T Blattmann Claudia C Fetscher Sebastian S Frühwald Michael M Hettmer Simone S Kordes Uwe U Ridola Vita V Kroiss Benninger Sabine S Mastronuzzi Angela A Schott Sarah S Nees Juliane J Prokop Aram A Redlich Antje A Seidel Markus G MG Zimmermann Stefanie S Pajtler Kristian W KW Pfister Stefan M SM Hainaut Pierre P Kratz Christian P CP

Journal of hematology & oncology 20220816 1

Li-Fraumeni syndrome (LFS) is a cancer predisposition syndrome caused by pathogenic TP53 variants. The condition represents one of the most relevant genetic causes of cancer in children and adults due to its frequency and high cancer risk. The term Li-Fraumeni spectrum reflects the evolving phenotypic variability of the condition. Within this spectrum, patients who meet specific LFS criteria are diagnosed with LFS, while patients who do not meet these criteria are diagnosed with attenuated LFS. ...[more]

PMID: 35974385

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Project description:BackgroundLi-Fraumeni syndrome (LFS) is a rare autosomal hereditary predisposition to multiples cancers, mainly affecting young individuals. It is characterized by a broad tumor spectrum. To our best knowledge, only one Tunisian study with a confirmed LFS was published.MethodsOur study focused on the clinical, histopathological and genetic results of two patients with rare tumor phenotype and tried to establish genotype-phenotype correlation. The clinical diagnosis was based on Chompret-Bonaiti criteria relative to LFS. Molecular study was assessed using Sanger sequencing of the hotspot germline variants of TP53 gene.ResultsWe report 2 Tunisian families fulfilling the clinical criteria of Chompret-Bonaiti. The tumor phenotype was bilateral breast cancer (BC) in 27-year-old woman and multiple tumors for the second proband, with an onset age of 14, 35 and 36 yo for osteosarcoma, BC and esophageal cancer respectively. Each of them had a rare histological type of breast cancer associated with LFS, phyllode tumor and intralobular carcinoma. Both patients had cancer family history. The molecular study showed deleterious heterozygous germline TP53 variants in each index case: The first had a well-known hotspot missense variation c.742C>T p.(R248W) with a rare histological association, explaining genotype phenotype correlation. The second case had a nonsense variation c.159G>A p.(W53*), rare worldwide, extending the phenotype spectrum in LFS. Immunohistochemistry study in tumor samples confirmed the lack of p53 protein expression.ConclusionsConclusively, germline TP53 testing is primordial in patients with a family history suggestive of LFS for clinical practice avoiding genotoxic treatments and adapting the surveillance. National database in LFS listing clinical and mutational data is important to set, particularly for variants rarely reported worldwide. Experience from different countries must be integrated to harmonize global protocols for cancer surveillance in LFS.

Dataset Information

Genotype-phenotype associations within the Li-Fraumeni spectrum: a report from the German Registry.

Publications

Genotype-phenotype associations within the Li-Fraumeni spectrum: a report from the German Registry.

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