New surveillance guidelines for Li-Fraumeni and hereditary TP53 related cancer syndrome: implications for germline TP53
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EDITORIAL
New surveillance guidelines for Li‑Fraumeni and hereditary TP53 related cancer syndrome: implications for germline TP53 testing in breast cancer D. Gareth Evans1 · Emma R. Woodward1
© Springer Nature B.V. 2020
Keywords Breast cancer · Heritable TP53-related cancer · Li-fraumeni syndrome · Penetrance · TP53 · Sarcoma · Variant · MRI Abbreviations ACC Adrenocortical carcinoma ACMG American College of Medical Genetics and Genomics AMP Association for Molecular Pathology CNS Central nervous system ERN European reference network GBCA Gadolinium based contrast agents HCP Heath care professional hTP53rc Heritable TP53-related cancer LFS Li-Fraumeni syndrome STS Soft-tissue sarcoma WBMRI Whole
Introduction 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 * D. Gareth Evans [email protected] 1
Division of Evolution and Genomic Sciences, Manchester Centre for Genomic Medicine, University of Manchester, Manchester Academic Health Sciences Centre (MAHSC), St Mary’s Hospital, Manchester University Hospitals NHS Foundation Trust, Manchester, UK
(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 p
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