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Guidlines for LiFraumeni syndrome and heritable TP53-related cancer syndromes
Guidelines for the Li–Fraumeni and heritable TP53-related cancer syndromes
—–> Guidlines for LiFraumeni syndrome
Onderstaand zijn de aanbevelingen uit dit document.
N.B In Nederland is dit afwijkend gegregeld.
Recommendations: Cancer patients who should be tested for germline disease-causing TP53 a
| Recommendation 1 | All patients who meet the modified ‘Chompret Criteria’ should be tested for germline TP53 variants: • Familial presentation: proband with a TP53 core tumour (breast cancer, soft-tissue sarcoma, osteosarcoma, central nervous system tumour, adrenocortical carcinoma) before 46 years AND at least one first- or second-degree relative with a core tumour before 56 years; or • Multiple primitive tumours: proband with multiple tumours, including 2 TP53 core tumours, the first of which occurred before 46 years, irrespective of family history; or • Rare tumours: patient with adrenocortical carcinoma, choroid plexus carcinoma, or rhabdomyosarcoma of embryonal anaplastic subtype, irrespective of family history; or • Very early-onset breast cancer: Breast cancer before 31 years, irrespective of family history |
| Recommendation 2 | Children and adolescents should be tested for germline TP53 variants if presenting with: • Hypodiploid acute lymphoblastic leukaemia (ALL); or • Otherwise unexplained sonic hedgehog-driven medulloblastoma; or • Jaw osteosarcoma |
| Recommendation 3 | Patients who develop a second primary tumour, within the radiotherapy field of a first core TP53 tumour which occurred before 46 years, should be tested for germline TP53 variants |
| Recommendation 4 | a. Patients older than 46 years presenting with breast cancer without personal or familial history fulfilling the ‘Chompret Criteria’ should not be tested for germline TP53 variants |
| b. Any patient presenting with isolated breast cancer and not fulfilling the ‘Chompret Criteria’, in whom a disease-causing TP53 variant has been identified, should be referred to an expert multi-disciplinary team for discussion | |
| Recommendation 5 | Children with any cancer from southern and south-eastern Brazilian families should be tested for the p.R337H Brazilian founder germline TP53 variant |
- aTesting for disease-causing TP53 variants should be performed before starting treatment in order to avoid in variant carriers, if possible, radiotherapy and genotoxic chemotherapy and to prioritise surgical treatments.
Pre-symptomatic testing recommendations
| Recommendation 6 | Adult first-degree relatives of individuals with germline disease-causing TP53 variants should be offered testing for the same germline TP53 variant |
| Recommendation 7 | The testing in childhood, from birth, of first-degree relatives of individuals with germline disease-causing TP53 variants should be systematically offered, if updated knowledge, based on databases and registries, shows that the variant can be considered as a high cancer risk TP53 variant conferring a high cancer risk in childhood: • The index case has developed a childhood cancer; or • Childhood cancers have been observed within the family; or • This variant has already been detected in other families with childhood cancers; or • This variant corresponds to a dominant-negative missense variant |
| Recommendation 8 | The testing in childhood of first-degree relatives of individuals with germline disease-causing TP53 variants should not be systematically offered, if updated knowledge, based on databases and registries, shows that the variant can be considered as a low cancer risk TP53 variant and does not confer a high cancer risk in childhood: • The index case has not developed a childhood cancer; and • Childhood cancers have not been observed within the family; and • This variant has not already been reported in other families with childhood cancers; and • This variant does not correspond to a dominant-negative missense variant |
| Recommendation 9 | The testing in childhood of first-degree relatives of individuals with germline disease-causing TP53 variants should be discussed with their parents if cancers have occurred in early adulthood (before the age of 31 years) within the family, or if there is insufficient evidence in the databases or registries to determine the childhood cancer risk. • This discussion should address the burden, and uncertain benefits, of surveillance in childhood, before a decision is made whether to test the child for germline disease-causing TP53 variants. |
Surveillance recommendations in carriers of germline disease-causing TP53 variants
| Recommendation 10 | In children, clinical examination should be performed every 6 months, with specific attention to signs of virilization or early puberty, and measurement of blood pressure |
| In adults, clinical examination should be performed annually with specific attention, in patients who received radiotherapy, to occurrence of basal cell carcinomas within the radiotherapy field | |
| Recommendation 11 | In adults, WBMRI without gadolinium enhancement should be conducted annually |
| Recommendation 12 | In individuals with high cancer risk TP53 variants or previously treated by chemotherapy or radiotherapy, WBMRI without gadolinium enhancement, should be conducted annually, from birth |
| Recommendation 13 | In female individuals, breast MRI should be conducted annually, from 20 years until 65 years |
| Recommendation 14 | In children, from birth, and in adolescents (<18 years), abdominal ultrasound for the detection of adrenocortical carcinoma should be conducted at least every 6 months |
| Recommendation 15 | In children, from birth, and in adolescents (<18 years), when abdominal ultrasound does not allow a proper imaging of the adrenal glands, measurement of urine steroids, for detection of ACC, should probably be conducted at least every 6 months |
| Recommendation 16 | In adults until 50 years, brain MRI should be conducted annually |
| Recommendation 17 | In individuals with high cancer risk TP53 variants, brain MRI should be conducted from birth, annually |
| Recommendation 18 | If surveillance includes brain MRI, at least the first (prevalence) scan should be conducted using dedicated brain MRI with Gadolinium enhancement |
| Recommendation 19 | In children, if surveillance includes annual brain MRI, this should alternate with the WBMRI, so that the brain is imaged at least every 6 months |
| Recommendation 20 | Colonoscopy should be performed, from 18 years, every 5 years, only if the carrier received abdominal radiotherapy for the treatment of a previous cancer, or if there is a familial history of colorectal tumours suggestive of an increased genetic risk |
Guideline summary: surveillance protocol in carriers of GERMLINE disease-causing TP53 variants
| Exam | Periodicity | Age to start | Age to end | Condition | Evidencea |
| Clinical examination with, in children, specific attention to signs of virilisation or early puberty and measurement of blood pressure and, in patients who received radiotherapy, to occurrence of basal cell carcinomas within the radiotherapy field | Every 6 months | Birth | 17 years | Moderate | |
| Annual | 18 years | – | Moderate | ||
| Whole-Body MRI without gadolinium enhancement | Annual | Birth | – | High cancer risk TP53 variantb or patient previously treated by chemotherapy or radiotherapy | Moderate |
| 18 years | – | Strong | |||
| Breast MRI | Annual | 20 years | Until 65 years | Strong | |
| Brain MRIc | Annual | Birth | 18 years | High cancer risk TP53variant | Moderate |
| 18 years | Until 50 years | Moderate | |||
| Abdominal ultrasound | Every 6 months | Birth | Until 18 years | Strong | |
| Urine steroids | Every 6 months | Birth | Until 18 years | When abdominal ultrasound does not allow a proper imaging of the adrenal glands | Weak |
| Colonoscopy | Every 5 years | 18 years | – | Only if the carrier received abdominal radiotherapy for the treatment of a previous cancer or if there is a familial history of colorectal tumours suggestive of an increased genetic risk | Weak |
- aThis grading is based on published articles and expert consensus.
- bA germline disease-causing TP53 variant should be considered as ‘high risk’ if the index case has developed a childhood cancer; or childhood cancers have been observed within the family; or this variant has already been detected in other families with childhood cancers; or this variant corresponds to a dominant-negative missense variant.
- cThe first scan should be conducted with I.V. Gadolinium enhancement; in children, brain MRI should alternate with the Whole-Body MRI, so that the brain is imaged at least every 6 months.
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