Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2022 Aug 16;15(1):107.
doi: 10.1186/s13045-022-01332-1.

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

Judith Penkert  1   2 , Farina J Strüwe  1 , Christina M Dutzmann  1 , Beate B Doergeloh  1 , Emilie Montellier  3 , Claire Freycon  3   4 , Myriam Keymling  5 , Heinz-Peter Schlemmer  5 , Birte Sänger  1 , Beatrice Hoffmann  1 , Tanja Gerasimov  1 , Claudia Blattmann  6 , Sebastian Fetscher  7 , Michael Frühwald  8 , Simone Hettmer  9 , Uwe Kordes  10 , Vita Ridola  11 , Sabine Kroiss Benninger  12 , Angela Mastronuzzi  13 , Sarah Schott  14 , Juliane Nees  14 , Aram Prokop  15   16   17 , Antje Redlich  18 , Markus G Seidel  19 , Stefanie Zimmermann  20 , Kristian W Pajtler  21   22   23 , Stefan M Pfister  21   22   23 , Pierre Hainaut  3 , Christian P Kratz  24
Affiliations

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

Judith Penkert et al. J Hematol Oncol. .

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.

Keywords: Cancer predisposition; Genotype; Li-Fraumeni syndrome; Phenotype; TP53.

PubMed Disclaimer

Conflict of interest statement

The authors declare that they have no competing financial interests.

Figures

Fig. 1
Fig. 1
Spectrum of TP53 germline variants and statistically significant genotype-phenotype correlations. Colored spheres refer to different patients harboring the corresponding variant. Note: Y103* is based on two different nucleotide substitutions; whole gene deletions include two gross deletions with differing breakpoints. The genotype–phenotype correlation was based on data from 94 families. CNV, Copy number variation
Fig. 2
Fig. 2
Tumor spectrum in patients with LFS or attenuated LFS. Depicted are all neoplasms reported in the cohort’s individuals (not their families), including subsequent neoplasms occurring in patients with multiple tumors. “Miscellaneous” neoplasms include gastrointestinal, renal, lung, ovarian/tube, melanoma, prostate, and single other (lymphoma, cervical, parotis, basalioma, laryngeal) neoplasms. ACC Adrenocortical carcinoma, BC Breast cancer, CML Chronic myeloid leukemia, CNS Central nervous system, CPC Choroid plexus carcinoma, hematol. Hematological, MB Medulloblastoma, NB Neuroblastoma, NRSTS Non-rhabdomyosarcoma soft tissue sarcoma, OS Osteosarcoma, RMS Rhabdomyosarcoma
See this image and copyright information in PMC

References

    1. Li FP, Fraumeni JF., Jr Rhabdomyosarcoma in children: epidemiologic study and identification of a familial cancer syndrome. J Natl Cancer Inst. 1969;43(6):1365–1373. - PubMed
    1. Li FP, Fraumeni JF, Jr, Mulvihill JJ, Blattner WA, Dreyfus MG, Tucker MA, Miller RW. A cancer family syndrome in twenty-four kindreds. Cancer Res. 1988;48(18):5358–5362. - PubMed
    1. Malkin D, Li FP, Strong LC, Fraumeni JF, Jr, Nelson CE, Kim DH, Kassel J, Gryka MA, Bischoff FZ, Tainsky MA, et al. Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science. 1990;250(4985):1233–1238. doi: 10.1126/science.1978757. - DOI - PubMed
    1. Bougeard G, Renaux-Petel M, Flaman JM, Charbonnier C, Fermey P, Belotti M, Gauthier-Villars M, Stoppa-Lyonnet D, Consolino E, Brugieres L, et al. Revisiting Li-Fraumeni syndrome from TP53 mutation carriers. J Clin Oncol. 2015;33(21):2345–2352. doi: 10.1200/JCO.2014.59.5728. - DOI - PubMed
    1. Kratz CP, Freycon C, Maxwell KN, Nichols KE, Schiffman JD, Evans DG, Achatz MI, Savage SA, Weitzel JN, Garber JE, et al. 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 Oncol. 2021;7(12):1800–1805. doi: 10.1001/jamaoncol.2021.4398. - DOI - PMC - PubMed

Publication types

MeSH terms

Substances