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Erschienen in:
28.09.2020 | Editorial
New surveillance guidelines for Li-Fraumeni and hereditary TP53 related cancer syndrome: implications for germline TP53 testing in breast cancer
Erschienen in: Familial Cancer | Ausgabe 1/2021
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Heterozygous pathogenic germline variants were identified in TP53 in 1990 as a cause of Li-Fraumeni syndrome (LFS) [1]. LFS was originally labelled SBLA syndrome to reflect the predominance of Sarcoma, Breast/Brain, Leukaemia/Lung cancer and Adrenal carcinoma in the original families [2, 3]. LFS is typically characterized by familial aggregations of very early-onset malignancies covering many tumour sites. These include the characteristic core LFS tumours: soft-tissue sarcomas (STS), osteosarcomas (OS), adrenocortical carcinomas (ACC), central nervous system (CNS) tumours and very early-onset female breast cancers, typically occurring ≤ 30 years. Germline testing for variants in TP53 has been most frequently employed in individuals with core LFS malignancies who fulfil clinical criteria such as classical LFS or “Chompret criteria” (Table 1a/b) [4, 5]. Nevertheless testing for individual tumours without a family history has been carried out in childhood malignancy [6‐8] or among adult females with extremely early-onset breast cancers with germline TP53 mutations being identified in apparently isolated cases [5, 9]. Such findings have led to the idea being posited that a heritable TP53-related cancer (hTP53rc) syndrome would be a better term than LFS [10, 11]. Very recently two Europe based guidelines for surveillance in hTP53rc syndrome that include intensive surveillance with annual whole body MRI (WBMRI), brain MRI, breast MRI in women from age 20 years and blood testing (for ACC hormones) have been published [12, 13], to add to an American guideline [14]. The guidelines are based around the so-called ‘Toronto’ protocol that has been associated with a reported survival advantage [15]. The introduction of these intensive surveillance programmes, together with the increased availability of cancer predisposition gene testing, means it is particularly timely to understand both accurate variant interpretation and the clinical features where a genuinely pathogenic germline TP53 mutation is likely to be present.
Table 1
Clinical diagnostic criteria for Li Fraumeni syndrome and TP53 testing
|
Criteria
|
Description
|
Reference
|
|---|---|---|
|
(A) Classic
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Proband diagnosed with a sarcoma before age 45 AND; One first-degree relative with any malignant tumour diagnosed before age 45 AND; Another first- or second-degree relative diagnosed with any malignant tumour before age 45 or a sarcoma at any age
|
[4]
|
|
(B) Chompret 2009, modified 2015
|
Proband with a typical LFS tumor diagnosed before age 46 AND; At least one first- or second-degree relative diagnosed with a typical LFS tumor (except breast cancer if the proband is/was affected by breast cancer) before age 56 or with multiple primary tumours OR; Proband with multiple primary tumours (other than multiple breast tumors)—including at least two from LFS tumor spectrum - with the first diagnosed before age 46 OR; Proband diagnosed with ADR or CPC , or RMS of embryonal anaplastic subtype* at any age irrespective of family history; OR
Female proband with breast cancer < 31*
|
[8]
|