Genetic Predisposition to Breast Cancer and Genetic Counseling and Testing
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Cancer syndrome
Li–Fraumeni syndrome
Genetic predisposition
Cowden syndrome
Genetic predisposition
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Whole-Body MRI Screening in Children With Li-Fraumeni and Other Cancer Predisposition Syndromes.Patrick R. Benusiglio1, Laurence Brugières1 and Olivier Caron1Audio Available | Share
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Abstract Although cancer predisposition syndromes are rare and malignancies arising in this context account for only 1–10% of childhood tumors, studies performed in affected patients and their families have been of unique value for the understanding of cancer development. Three classes of genes (tumor suppressor genes, oncogenes and stability genes) have been identified and shown to be involved in the pathogenesis of familial, as well as sporadic tumors. Cancer has long been recognized as a genetic disease of somatic cells. Despite improved understanding of the molecular basis of predisposition to cancer and better diagnostic tools, the care of these patients and their families remains a major challenge for the clinician. Medical, psychological, ethical and legal issues have to be considered. This review focuses on examples of each class of inherited cancer predisposition syndromes with special implications for patients in the pediatric age group, including retinoblastoma predisposition, Li‐Fraumeni syndrome, multiple endocrine neoplasia disorders and Fanconi anemia. The genetic basis of cancer predisposition is discussed as well as the major concepts and controversies in the clinical management of these patients and their families. © 2006 Wiley‐Liss, Inc.
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Li-Fraumeni syndrome (LFS) is a hereditary tumor that exhibits autosomal dominant inheritance. LFS develops in individuals with a pathogenic germline variant of the cancer-suppressor gene, TP53 (individuals with TP53 pathogenic variant). The number of individuals with TP53 pathogenic variant among the general population is said to be 1 in 500 to 20,000. Meanwhile, it is found in 1.6% (median value, range of 0-6.7%) of patients with pediatric cancer and 0.2% of adult patients with cancer. LFS is diagnosed by the presence of germline TP53 pathogenic variants. However, patients can still be diagnosed with LFS even in the absence of a TP53 pathogenic variant if the familial history of cancers fit the classic LFS diagnostic criteria. It is recommended that TP53 genetic testing be promptly performed if LFS is suspected. Chompret criteria are widely used for the TP53 genetic test. However, as there are a certain number of cases of LFS that do not fit the criteria, if LFS is suspected, TP53 genetic testing should be performed regardless of the criteria. The probability of individuals with TP53 pathogenic variant developing cancer in their lifetime (penetrance) is 75% for men and almost 100% for women. The LFS core tumors (breast cancer, osteosarcoma, soft tissue sarcoma, brain tumor, and adrenocortical cancer) constitute the majority of cases; however, various types of cancers, such as hematological malignancy, epithelial cancer, and pediatric cancers, such as neuroblastoma, can also develop. Furthermore, approximately half of the cases develop simultaneous or metachronous multiple cancers. The types of TP53 pathogenic variants and factors that modify the functions of TP53 have an impact on the clinical presentation, although there are currently no definitive findings. There is currently no cancer preventive agent for individuals with TP53 pathogenic variant. Surgical treatments, such as risk-reducing bilateral mastectomy warrant further investigation. Theoretically, exposure to radiation could induce the onset of secondary cancer; therefore, imaging and treatments that use radiation should be avoided as much as possible. As a method to follow-up LFS, routine cancer surveillance comprising whole-body MRI scan, brain MRI scan, breast MRI scan, and abdominal ultrasonography (US) should be performed immediately after the diagnosis. However, the effectiveness of this surveillance is unknown, and there are problems, such as adverse events associated with a high rate of false positives, overdiagnosis, and sedation used during imaging as well as negative psychological impact. The detection rate of cancer through cancer surveillance is extremely high. Many cases are detected at an early stage, and treatments are low intensity; thus, cancer surveillance could contribute to an improvement in QOL, or at least, a reduction in complications associated with treatment. With the widespread use of genomic medicine, the diagnosis of LFS is unavoidable, and a comprehensive medical care system for LFS is necessary. Therefore, clinical trials that verify the feasibility and effectiveness of the program, comprising LFS registry, genetic counseling, and cancer surveillance, need to be prepared.
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Beim Thema genetische Prädisposition für Krebserkrankungen im Kindesalter ist eine enge Kooperation zwischen Pathologen, behandelnden Kinderonkologen und Humangenetikern erforderlich. Dabei geht es nicht nur um die präzise Diagnose und möglichst effektive Behandlung der Krebserkrankung, sondern auch darum, weitere Krebserkrankungen bei den Betroffenen und ihren Familienmitgliedern zu verhindern bzw. möglichst früh zu diagnostizieren. Anhand von Beispielen wie dem Li-Fraumeni-Syndrom, der konstitutionellen Mismatch-Repair-Defizienz (CMMRD), dem Medullo- und Neuroblastom sowie hämatologischen Neoplasien werden die Kriterien für genetische Tumorprädispositionssyndrome, der Zusammenhang zwischen somatischen Varianten und Keimbahnvarianten sowie die unmittelbaren klinischen Konsequenzen erörtert. Bei einigen genetischen Tumorprädispositionssyndromen hat die Diagnose unmittelbare Konsequenzen für die Behandlung, z. B. den Verzicht auf eine Strahlentherapie beim Li-Fraumeni-Syndrom. Es besteht eine deutlich erhöhte Wahrscheinlichkeit für sekundäre, unabhängig entstandene Tumoren. Durch die prädiktive Diagnostik können die Familienmitglieder identifiziert werden, die die pathogene Variante tragen und aufgrund ihres erhöhten Tumorrisikos das Angebot einer intensivierten Früherkennung oder ggf. prophylaktischer Operationen erhalten sollten. Evidenzbasierte Daten zeigen, dass Programme zur intensivierten Früherkennung zu einer signifikanten Verbesserung der Überlebenswahrscheinlichkeit führen.
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PTEN hamartoma tumor syndrome/Cowden syndrome (CS) is a rare autosomal dominant syndrome containing a germline PTEN mutation that leads to the development of multisystem hamartomas and oncogenesis. Benign tumors such as Lhermitte-Duclos disease and malignant tumors involving the breast, thyroid, kidneys, and uterus are seen in CS. Radiologists have an integral role in the comanagement of CS patients. We present the associated imaging findings and imaging screening recommendations. Knowledge of the types of cancers commonly seen in CS and their imaging findings can aid in early tumor recognition during cancer screening to help ensure near-normal life spans in CS patients.
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Heterozygote advantage
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‘Familial tumour syndromes’ reviews some of the genetic syndromes associated with an increased incidence of nervous system tumours, including neurofibromatosis 1, neurofibromatosis 2, schwannomatosis, rhabdoid tumour predisposition, Li–Fraumeni syndrome, Turcot syndrome, Gorlin syndrome, and Cowden syndrome. The chapter reviews the epidemiology of these rare conditions with discussion of current diagnostic criteria. It reviews the genetic basis and pathogenesis of the conditions as well as the availability of genetic testing. It covers the clinical aspects of these conditions, including clinical presentation, associated nervous system tumours, and recommended management of these syndromes with a discussion of the role of imaging. The review is written for the practising neuro-oncologist and other specialists who care for patients with genetic syndromes affecting the nervous system.
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Li–Fraumeni syndrome
Neurofibromatosis type 2
Neurofibromatoses
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Hereditary syndromes that increase the risk of breast cancer are not common, but it is critical to recognize and manage them appropriately. This paper reviews the management of patients with the most common hereditary breast cancer syndromes, ie, hereditary breast and ovarian cancer syndrome, hereditary diffuse gastric cancer, Cowden syndrome (PTEN hamartoma tumor syndrome), Peutz-Jeghers syndrome, and Li-Fraumeni syndrome.
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