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Originally published as JCO Early Release 10.1200/JCO.2009.22.7967 on August 3 2009 © 2009 American Society of Clinical Oncology.
2009 Version of the Chompret Criteria for Li Fraumeni SyndromeInserm U614, Faculty of Medicine, University of Rouen; and Department of Genetics, University Hospital, Institute for Medical Research, Rouen, France
Department of Medicine, Institut Gustave Roussy, Villejuif, France
Department of Genetics, Institut Gustave Roussy, Villejuif, France
Department of Genetics, Centre François Baclesse, Caen, France
Department of Genetics, University Hospital and Centre Eugène Marquis, Rennes, France
Inserm U535, Villejuif, France
Department of Genetics, Institut Curie; and University Paris Descartes, Paris, France
Inserm U614, Faculty of Medicine, University of Rouen; and Department of Genetics, University Hospital, Institute for Medical Research, Rouen, France To the Editor: We read with great interest the article by Gonzalez et al1 published in Journal of Clinical Oncology. This study confirms the clinical utility of the Chompret criteria, which the French Li Fraumeni syndrome (LFS) working group elaborated in 2001 to facilitate diagnosis of LFS.2 Gonzalez et al performed TP53 analysis in 341 clinically informative families, including 195 families fulfilling the Chompret criteria; obtained a mutation detection rate of 35% (69 of 195 families); and estimated the sensitivity and specificity of these criteria to be 92% and 53%, respectively. The authors were seemingly not aware of our study3 published last year, which had already validated the clinical utility of these criteria. We analyzed TP53 in 474 French families suggestive of LFS, including 232 families fulfilling the Chompret criteria; obtained a mutation detection rate of 29% (67 of 232 families); and estimated the sensitivity and specificity of the Chompret criteria to be 82% and 58%, respectively. We also proposed extending the Chompret criteria to cover the clinical presentation of the 82 families in which we identified germline TP53 mutations. The extended criteria would include the following: A proband with a tumor belonging to the narrow LFS tumor spectrum (eg, soft tissue sarcoma, osteosarcoma, brain tumor, premenopausal breast cancer, adrenocortical carcinoma, leukemia, and lung bronchoalveolar cancer) diagnosed before age 46 years, with at least one first- or second-degree relative with an LFS tumor (except breast cancer, if proband is affected by breast cancer) before age 56 years or with multiple tumors; or a proband with multiple tumors, two of which belong to the narrow LFS tumor spectrum (except multiple primary breast cancers) and the first of which occurred before age 46 years; or a patient with adrenocortical carcinoma or a choroid plexus carcinoma or a patient diagnosed with breast cancer before age 36 years without BRCA1 or BRCA2 mutation, irrespective of family history. Gonzalez et al1 indicated that patients with breast cancer younger than age 30 years with no first- or second-degree relative with cancer have a 7% chance of having a TP53 mutation. Therefore, we would like to highlight our recent experience of TP53 testing in patients with early-onset breast cancer. Our group has now performed a complete analysis of TP53—on the basis of sequencing the 11 exons and screening for genomic rearrangements using quantitative multiplex polymerase chain reaction of short fluorescent fragments—in 161 female patients presenting with breast cancer before age 36 years without detectable BRCA1 or BRCA2 mutation. In this group of patients, we identified 12 deleterious mutations and one unclassified variant (a translationally silent exonic variation) corresponding with a mutation detection rate of 7% to 8%. Among the 161 patients with breast cancer analyzed, 25 belonged to families fulfilling the familial LFS Chompret criteria; we identified a TP53 mutation in four (16%) of the 25. Eight patients without familial history suggestive of LFS presented not only with breast cancer but also with other LFS-related tumors; three (38%) of the eight were found to have a TP53 mutation. The 128 remaining patients were selected for TP53 analysis only on the basis of the development of breast cancer before age 36 years and absence of BRCA1 or BRCA2 mutation; a TP53 mutation or unclassified variant was detected in only five (4%) of the 128. We conclude that the TP53 mutation detection rate in patients with early-onset breast cancer without familial history of cancer or multiple primary tumors is less than 5%. Considering this low mutation detection rate with regard to the psychologic distress induced by TP53 genetic testing, we think that avoidance of TP53 testing in patients with early-onset breast cancer without familial history of cancer or multiple primary tumors would be appropriate. On the basis of our experience in TP53 testing and the study by Gonzalez et al,1 highlighting in particular the predictive value of choroid plexus tumors, we propose a 2009 version of the Chompret criteria to help clinicians to recognize Li Fraumeni syndrome (Table 1).
AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. ACKNOWLEDGMENT We thank the members of the Groupe Génétique et Cancer for fruitful discussion and Mario Tosi for critical review of the manuscript. This work was supported by the French National Cancer Institute. REFERENCES
1. Gonzalez KD, Noltner KA, Buzin CH, et al: Beyond Li Fraumeni syndrome: Clinical characteristics of families with p53 germline mutations. J Clin Oncol 27:1250–1256, 2009. 2. Chompret A, Abel A, Stoppa-Lyonnet D, et al: Sensitivity and predictive value of criteria for p53 germline mutation screening. J Med Genet 38:43–47, 2001. 3. Bougeard G, Sesboüé R, Baert-Desurmont S, et al: Molecular basis of the Li-Fraumeni syndrome: An update from the French LFS families. J Med Genet 45:535–538, 2008.
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Copyright © 2009 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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