FaCD Online Syndrome Fact Sheet

Last updated: 14 Jan 2010

Name: Li-Fraumeni syndrome

Synonym: LFS, SBLA syndrome (Sarcoma Breast Leukemia Adrenal cancer), incl.: Cancer with In Vitro Radioresistence, Familial, Li-Fraumeni-like s.

Mode of Inheritance: AD

OMIM number: 151623 114450

Genes

BRCA2, mapped to 13q12.3
TP53, mapped to 17p13.1

Tumor features

adrenocortical cancer
astrocytoma
breast cancer
chondrosarcoma
choroid plexus carcinoma
choroid plexus papilloma
colorectal cancer
fibrosarcoma
glioblastoma (multiforme)
Hodgkin disease (Hodgkin's lymphoma)
leiomyosarcoma
leukemia, acute lymphoblastic (ALL)
leukemia, acute myeloid (AML, incl. ANLL)
liposarcoma
lung/bronchial cancer
malignant fibrous histiocytoma
medulloblastoma
non-Hodgkin lymphoma
osteosarcoma
primitive neuroectodermal tumor (PNET)
rhabdomyosarcoma

Tumor features (possible)

bone, giant cell tumor of
breast, phyllodes tumor of the
ependymoma
fibroadenoma with giant atypical cells of the breast
ganglioneuroblastoma
gastric cancer
hepatocellular cancer (hepatoma)
leukemia, chronic myeloid (CML)
melanoma, cutaneous
melanoma, uveal (choroidal, ciliary body, iris)/ocular
meningioma
neuroblastoma, adrenal
non-seminoma
ovarian germ cell tumor
pancreatic adenocarcinoma
prostate cancer
seminoma
Wilms' tumor (nephroblastoma)

Comment

Tumor spectrum
The LFS tumor spectrum includes soft-tissue and bone sarcomas, breast cancer (including that of the phyllodes type [51]), brain tumors, adrenocortical tumors, leukemia (particularly ALL) and lymphomas (particularly Hodgkin disease)[1-3,50], lung cancer[3;13], choroid plexus carcinoma[7,42,51] and papilloma[52], and colorectal cancer, particularly early onset types[3,41]. Other tumors have also been suggested to belong to the clinical spectrum of LF(like) syndrome, including melanoma of skin[46,51] and the eye[47], meningioma[43], germ cell tumors[4,50,51], Wilms tumor[5,50], primitive neuroectodermal tumors (PNET[6],(ganglio)neuroblastoma[8,9,37,50], gastric cancer[3;10-12], renal cell cancer[7], fibroadenoma with aytypical giant cells of the breast[44], phyllodes tumors of the breast[49,50] and pancreatic cancer[3,50]. Lynch et al[17] reported a patient from an extended LFS family with an predominance of brain tumors, who had been diagnosed with multiple primary tumors as well as Sturge-Weber syndrome.

Tumor risk
Patients with LFS have a high risk to develop additional primary tumors (at least 15 % in a series of 200 LFS patients[14]). Estimations of tumor risks in LFS are based on only a handful of families: 42 % up to 16 years, 38 % between 17-45 years and 63 % after 45 years; life-time risks: 85 %[15]. Chompret et al.[16] screened for germline TP53 mutations in a group of 268 children with cancer and a family history of early onset or multiple cancer. They calculated a life-time risk of cancer for 17 mutation carriers of 78% for males and 100% for females. Wu et al confirmed that women with germ-line p53 mutations have a much higher cancer risk than men[38].

Genotypes
Germline TP53 gene mutations have been detected in approximately 70 % in LFS and less than 25 % in LFS-like families[18;19]. Wang et al.[20] suggested that germline P53 mutations characterized a subset of LFS families with an increased risk of multiple primary tumors, sarcomas and breast cancer compared with the non-P53 LFS group of families. Although LFS is relatively rare, germline TP53 mutations may be detected with a comparatively high frequency in patients with specific types of cancer: childhood adrenocortical cancer (50-80%)[21;22] and childhood sarcomas (7-33 %)[23-25]. In families that do not meet the LFS or LFS-like criteria and present with a single case of sarcoma and one or more cases of breast cancer, TP53 mutations are only very rarely detected[40]. In a series of 95 BRCA1/2 negative women with breast cancer diagnosed before the age of 30 years, no germline TP53 mutation was detected[53].

Genotype-phenotype correlations have been observed for TP53 mutations[22,26,39,48]. Compound heterozygosity (each allele associated with complete or partial loss of P53 function) was reported in a severely affected LFS patient[28]. A few germline de novo TP53 mutations have been reported [16;29;30]. Although germline mutations in CHEK2 have been detected in a few LFS families[32], germline mutations in this gene are now not considered to be a cause of LFS[34,45]. In rare cases germline BRCA2 mutations may cause a LFS-like phenotype[35,36].

Chromosomal instability and radiosensitivity
Chromosome instability is a trait of fibroblasts from heterozygotes for germline TP53 mutations[27]. There is evidence to suggest an increased risk to develop tumors after radiotherapy or radiation exposure in general, in LFS patients. Bech-Hansen et al.[31] reported on a family with in-vitro radioresistance associated with a tumor spectrum fitting LFS (McKusick lists this as a separate entry, no. 114450 ).

Clinical criteria

Classic LFS criteria[33]

a) proband with sarcoma diagnosed <45 years, and

b) at least one first degree relative with any cancer diagnosed <45 years, and

c) at least one additional first- or second-degree relative in the same lineage with: any cancer diagnosed <45 years or sarcoma at any age

Criteria for LFS-like families[33]

a) proband with any childhood tumor or sarcoma or brain tumor or adrenocortical tumor, diagnosed <45 years, and
b) a first- or second-degree relative with a typical LFS tumor diagnosed at any age, and
c) an additional first- or second-degree relative with any cancer diagnosed <60 years

Updated "Chompret" criteria[48]

i) proband with a tumor belonging to the LFS spectrum (soft-tissue sarcoma, osteosarcoma, brain tumor, pre-menopausal breast cancer, adrenocortical cancer, leukemia, lung brochioalveolar cancer) diagnosed <46 years, and
at least one first- or second degree relative with LFS tumor (except pre-menopausal breast cancer if the proband listed under i) had that tumor type) <56 years or multiple primary LFS spectrum timors diagnosed at any age
ii) proband with at least two primary narrow LFS spectrum tumors, at least one of them diagnosed <46 years
iii) proband with adrenocortical carcinoma or with breast cancer diagnosed <36 years without BRCA1/2 mutation, irrespective of family history

References