Definition

Li-Fraumeni syndrome (LFS; OMIM #151623) is a highly aggressive cancer predisposition syndrome that often leads to malignancies in childhood. It predisposes to bone and soft tissue sarcomas, various brain tumors, premenopausal breast cancer, adrenocortical carcinoma (ACC), leukemia and other neoplasias.

Key Data

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Synonym Sarcoma Breast Leukemia and Adrenal Gland Cancer Syndrome
Gene TP53 (tumor protein 53, tumor suppressor gene)
Gene product p53
Role Transcription factor that is activated by cellular stress (e.g. DNA damage) and regulates multiple anti-tumor signalling pathways
Heredity autosomal dominant, new mutation (~ 7-25%)
Prevalence ~ 1:5,000, in Brazil sometimes much more often
Genotype-
Phenotype-
Correlation
Not yet fully understood. There is evidence that dominant negative mutations in the DNA-binding domain are associated with the highest risk of cancer. For the individual patient, no predictions can be made based on the genotype. There are also a number of modifying factors.
Penetrance Almost 100% cumulative tumor incidence up to the age of 70 (50% for women up to age 31. LJ; 50% for men up to 46. LJ)
– 4% in the first year of life
– 22% until the age of 5
– 41% until the age of 18
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Diagnosis

Classic Diagnostic Criteria

  • A patient with a diagnosis of sarcoma aged ≤ 45 years AND

  • A first-degree relative with cancer aged ≤ 45 years AND

  • A first- or second-degree relative with cancer aged ≤45 years or sarcoma, regardless of age of onset

Increasingly, LFS is equated with positive evidence of a TP53 germ line mutation.

Chompret Criteria

The so-called “Chompret” criteria were last revised in 2015 to define four different clinical constellations for which TP53 mutational analysis should be offered:

  • Familial presentation: Proband with a tumor of the LFS Tumor spectrum (premenopausal breast cancer, soft tissue sarcoma, brain tumor, ACC) before 46 years of age AND at least one first- or second-degree relative with an LFS tumor (except breast cancer, if the patient has breast cancer himself/herself) before 56 years of age or with multiple tumors

  • Multiple tumors: Subject with multiple tumors (excluding multiple breast cancers), two of which are in the LFS spectrum, before age 46

  • Rare tumors: patients with ACC, choroid plexus carcinoma, embryonal anaplastic subtype rhabdomyosarcoma, regardless of family history

  • Breast cancer before the age of 31

Further Suspicions

In addition to the Chompret criteria, there is a suspicion of the existence of an LFS in:

  • Children with low hypodiploid ALL

  • Children with medulloblastoma of the Sonic Hedghog subtype

  • Patients with osteosarcoma (recent studies indicate that constitutional TP53 changes can be detected in about 10% of those affected)

  • Children with ALL recurrence with TP53 mutation in the leukemic cells

In tumors of patients with LFS often a characteristic somatic mutation spectrum can be detected. Therefore, such signatures should lead to TP53 germ line analysis or genetic counseling. An example is the phenomenon of chromothripsis in LFS-associated medulloblastomas.

Differential Diagnoses

  • Hereditary Breast-Ovarian Cancer Syndrome (BRCA1 and BRCA2 mutation)

  • Constitutional Mismatch Repair Deficiency (CMMRD)

Clinical Presentation

The most common LFS-associated neoplasms are referred to as “core cancers,” including soft tissue sarcomas, osteosarcomas, premenopausal breast cancers, brain tumors (choroid plexus tumors, sonic hedgehog medulloblastomas, gliomas), and adrenocortical carcinoma.

Typical Presentation in Childhood

  • Sarcomas (osteosarcomas, soft tissue sarcomas)

  • ACC

  • CNS tumors (choroid plexus tumors, SHH medulloblastoma)

  • ALL (especially hypodiploid), AML, MDS

  • ALL-relapses

Typical Presentation in Adulthood

  • Breast cancer, especially young women

  • Soft tissue sarcomas

Other Common Tumors

  • Melanomas

  • Lung carcinomas

  • Tumors of the gastrointestinal tract

  • Neuroblastomas

  • Lymphomas

  • Nephroblastomas

  • Thyroid carcinomas

Therapeutic Considerations

So far, no detailed recommendations are available for the treatment of individuals with LFS and cancer. It is treated according to the current treatment protocols for the respective tumor diagnosis. There are a few exceptions: For example, in LFS-associated breast cancer mastectomy is preferred to lumpectomy to reduce the risk of a second primary breast tumor and avoid radiotherapy.

For patients with medulloblastoma and LFS, a new therapy concept adapted to LFS will be offered. Please contact the HIT Study Center for more information.

If a curative therapy approach is possible, radiotherapy should be avoided. Alkylating substances and other genotoxic substances should also be avoided where acceptable. The primary treatment success remains superior to the secondary consequences.

Surveillance Recommendations

Surveillance Recommendations for Children (birth up to 18 years)

For patients with LFS, starting from clinical or genetic Diagnosis, lifelong (examination recommendations of AACR 2016)

General

  • Detailed physical examination every 3-4 months, including blood pressure measurement, collection of anthropometric data on percentile curve (attention to rapid increase in weight or height; percentile buckling), cushingoides appearance, signs of virilization (pubic hair, axillary moisture, adult body odor, androgenic hair loss, clitoral hypertrophy or penile growth) and complete neurological status

  • Immediate registration of any medical concerns with primary physician (pediatrician)

ACC

  • Abdominal and pelvic ultrasound every 3 to 4 months

  • In case of insufficient availability or quality of sonography -> laboratory (BE¹,²) every 3-4 months: total testosterone, dehydroepiandrosterone sulphate and androstenedione

CNS Tumor

  • Annual cranial MRI (first MRI with contrast medium, then without contrast medium with previous normal findings)

Soft Tissue and Osteosarcoma

  • Annual whole-body MRI

Surveillance Recommendations for Adults

For patients with LFS, starting from clinical or genetic diagnosis, lifelong (examination recommendations of AACR 2016)

General

  • Complete physical examination every 6 months

  • Immediate registration of any medical concerns with primary physician (family doctor, internist)

Breast Cancer

  • Risk awareness (18 years and older)

  • Clinical breast examination twice a year (from 20 years)

  • Annual breast MRI screening (20-75 years)³

  • Consider risk-minimising bilateral mastectomy

CNS Tumor (from 18 years)

  • Annual cranial MRI (first MRI with contrast medium, then without contrast medium with previous normal findings)

Soft Tissue and Osteosarcoma (from 18 years)

  • Annual whole-body MRI³

  • Abdominal and pelvic ultrasound every 12 months

Gastrointestinal Tumors (from 25 years)

  • Upper endoscopy and colonoscopy every 2-5 years

Melanoma (from 18 years)

  • Annual dermatological examination

Notes

Whole-body MRI: head to toe, including upper and lower extremities

¹ Serial blood collection drawn at the same time of day and processed in the same laboratory

² The effectiveness of biochemical monitoring for the detection of adrenocortical carcinomas has not been demonstrated.

³ Alternate breast MRI/abdominal and pelvic ultrasound with annual whole-body MRI (at least one scan every 6 months).