LFS is caused by germline mutations (also called genetic variants) in the TP53tumor suppressor gene,[5] which encodes a transcription factor (p53) that normally regulates the cell cycle and prevents genomic mutations. The variants can be inherited, or can arise from mutations early in embryogenesis, or in one of the parent's germ cells.
LFS is thought to occur in about 1 in 5,000 individuals in the general population. In Brazil there is a common founder variant, p.Arg337, that occurs in about 1 in every 375 people.[6] LFS is inherited in an autosomal dominant fashion which means that a person with LFS has a 50% chance to pass the syndrome on in every pregnancy (and a 50% chance to not pass on the syndrome).[7]
Clinical presentation
Li–Fraumeni syndrome is characterized by early onset of cancer, a wide variety of types of cancers, and development of multiple cancers throughout one's life.[8]
LFS: Mutations in TP53
TP53 is a tumor suppressor gene on chromosome 17 that normally assists in the control of cell division and growth through action on the normal cell cycle. TP53 typically becomes expressed due to cellular stressors, such as DNA damage, and can halt the cell cycle to assist with either the repair of repairable DNA damage, or can induce apoptosis of a cell with irreparable damage. The repair of "bad" DNA, or the apoptosis of a cell, prevents the proliferation of damaged cells and the development of cancer.[9]
Pathogenic and likely pathogenic variants in the TP53 gene can inhibit its normal function and allow cells with damaged DNA to continue to divide. If these DNA mutations are left unchecked, some cells can divide uncontrollably, forming tumors (cancers). Many individuals with Li–Fraumeni syndrome have been shown to be heterozygous for a TP53 variant. Recent studies have shown that 60% to 80% of classic LFS families harbor detectable germ-line TP53 mutations, the majority of which are missense mutations in the DNA-binding domain.[10] These missense mutations cause a decrease in the ability of p53 to bind to DNA, thus inhibiting the normal TP53 mechanism.[11]
LFS-Like (LFS-L):
Families who do not conform to the criteria of classical Li–Fraumeni syndrome have been termed "LFS-Like".[10] LFS-L individuals generally do not have any detectable TP53 variants, and tend to meet either the Birch or Eeles criteria.
Clinical
The classical LFS malignancies—sarcoma, cancers of the breast, brain, and adrenal glands—comprise about 80% of all cancers that occur in this syndrome.
The risk of developing any invasive cancer (excluding skin cancer) is about 50% by age 30 (1% in the general population) and is 90% by age 70. Early-onset breast cancer accounts for 25% of all the cancers in this syndrome. This is followed by soft-tissue sarcomas (20%), bone sarcoma (15%), and brain tumors—especially glioblastomas—(13%). Other tumours seen in this syndrome include leukemia, lymphoma, and adrenocortical carcinoma.
The table below depicts tumor site distribution of variants for families followed in the LFS Study at the National Cancer Institute's (NCI) Division of Cancer Epidemiology and Genetics (DCEG):
About 95% of females with LFS develop breast cancer by age 60 years; the majority of these occur before age 45 years lending females with this syndrome to have almost a 100% lifetime risk of developing cancer.
A proband with a tumor belonging to the LFS tumor spectrum (premenopausal breast cancer, soft tissue sarcoma, osteosarcoma, central nervous system (CNS) tumor, adrenocortical carcinoma) before age 46 years AND at least one first- or second-degree relative with an LFS tumor (except breast cancer if the proband has breast cancer) before age 56 years or with multiple tumors; OR
A proband with multiple tumors (except multiple breast tumors), two of which belong to the LFS tumor spectrum and the first of which occurred before age 46 years; OR
A proband with adrenocortical carcinoma, choroid plexus tumor, or rhabdomyosarcoma of embryonal anaplastic subtype, irrespective of family history; OR
A proband with any childhood cancer, sarcoma, brain tumor, or adrenal cortical carcinoma diagnosed before age 45, AND
A first- or second-degree relative with a typical LFS malignancy (sarcoma, leukemia, or cancers of the breast, brain or adrenal cortex) regardless of age at diagnosis, AND
A first- or second-degree relative with any cancer diagnosed before age 60
Two different tumors that are part of extended LFS in first- or second-degree relatives at any age (sarcoma, breast cancer, brain tumor, leukemia, adrenocortical carcinoma, melanoma, prostate cancer, and pancreatic cancer).
If an individual has a personal or family history concerning for LFS, they should discuss the risks, benefits, and limitations of genetic testing with their healthcare provider or a genetic counselor.
Management
Genetic counseling and genetic testing for the TP53 gene can confirm a diagnosis of LFS.[18] People with LFS require early and regular cancer screening following the "Toronto Protocol":[18][19][20]
Children and adults undergo comprehensive annual physical examinations every 6 to 12 months
All patients consult a physician promptly for evaluation of lingering symptoms and illnesses
Ultrasound of abdomen and pelvis every 3 to 4 months from birth to age 18 years
Colonoscopy and upper endoscopy every 2 to 5 years beginning at age 25 or 5 years before the earliest known GI cancer in the family
Annual dermatological exam starting at age 18 years
Annual whole-body MRI
Annual brain MRI and neurological exam
Annual prostate-specific antigen (PA) starting at age 40
Breast awareness beginning at age 18
Clinical breast exam every 6 to 12 months starting at age 20
Annual breast MRI age 20 to 29; annual breast MRI alternating with mammogram age 30 to 75
Consideration of risk-reducing mastectomy (surgery to remove the breast tissue)
Families and individuals should consider participating in a peer-support group[21][22]
^Malkin D, Li FP, Strong LC, Fraumeni JF, Nelson CE, Kim DH, et al. (November 1990). "Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms". Science. 250 (4985): 1233–1238. doi:10.1126/science.1978757. PMID1978757.
^Srivastava S, Zou ZQ, Pirollo K, Blattner W, Chang EH (December 1990). "Germ-line transmission of a mutated p53 gene in a cancer-prone family with Li-Fraumeni syndrome". Nature. 348 (6303): 747–749. doi:10.1038/348747a0. PMID2259385.
^Li FP, Garber JE, Dreyfus MG, Blattner WA, Fraumeni JF, Sandberg AA (January 1990). "Follow-up of cancer family with in-vitro radioresistance". Lancet. 335 (8682): 176–177. doi:10.1016/0140-6736(90)90056-b. PMID1967474.
^Bougeard G, Renaux-Petel M, Flaman JM, Charbonnier C, Fermey P, Belotti M, et al. (July 2015). "Revisiting Li-Fraumeni Syndrome From TP53 Mutation Carriers". Journal of Clinical Oncology. 33 (21): 2345–2352. doi:10.1200/JCO.2014.59.5728. PMID26014290.
^Eeles RA (January 1993). "Predictive testing for germline mutations in the p53 gene: are all the questions answered?". European Journal of Cancer. 29A (10): 1361–1365. doi:10.1016/0959-8049(93)90001-v. PMID8398258.
^Villani A, Shore A, Wasserman JD, Stephens D, Kim RH, Druker H, et al. (September 2016). "Biochemical and imaging surveillance in germline TP53 mutation carriers with Li-Fraumeni syndrome: 11 year follow-up of a prospective observational study". The Lancet. Oncology. 17 (9): 1295–1305. doi:10.1016/S1470-2045(16)30249-2. PMID27501770.
