Li-Fraumeni综合征
一种罕见但有意义的家族性部综合征，与广谱的肿瘤，包括：乳腺癌、软组织肉瘤、白血病和脑吸瘤有关。对有危险的家族，在30岁以前发生某些侵袭性癌的机会接近50％。高百分率的LFS家族在一等位基因中携带种系p53突变。（由Federick P.Li和Joseph F.Fraumeni研究确定）。
Summary
Disease characteristics. Li-Fraumeni syndrome (LFS) is a cancer predisposition syndrome associated with soft-tissue sarcoma, breast cancer, leukemia, osteosarcoma, melanoma, and cancer of the colon, pancreas, adrenal cortex, and brain. Individuals with LFS are at increased risk for developing multiple primary cancers. Age-specific cancer risks have been calculated.
Diagnosis/testing. LFS is diagnosed in individuals meeting established clinical criteria. More than 50% of individuals diagnosed clinically have an identifiable disease-causing mutation in the TP53 gene. Of these mutations, 95% can be detected by sequence analysis, which is clinically available.
Genetic counseling. LFS is inherited in an autosomal dominant manner. Offspring of an affected individual have a 50% chance of inheriting the disease-causing mutation. Predisposition testing for at-risk family members is available in families in which the disease-causing mutation has been identified.
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Diagnosis
Clinical Diagnosis
Two forms of Li-Fraumeni syndrome are recognized: classic Li-Fraumeni syndrome (LFS) and Li-Fraumeni-like syndrome (LFL).
Classic LFS is defined by the following criteria:
A proband with a sarcoma diagnosed before 45 years of age AND
A first-degree relative with any cancer under 45 years of age AND
A first- or second-degree relative with any cancer under 45 years of age or a sarcoma at any age [Li & Fraumeni 1969].
LFL shares some, but not all of the features listed for LFS. Two definitions of LFL are listed below.
Birch's definition of LFL [Birch et al 1994]:
A proband with any childhood cancer or sarcoma, brain tumor, or adrenal cortical tumor diagnosed before 45 years of age AND
A first- or second-degree relative with a typical LFS cancer (sarcoma, breast cancer, brain tumor, adrenal cortical tumor, or leukemia) at any age AND
A first- or second-degree relative with any cancer under the age of 60 years
Eeles' definition of LFL [Eeles 1995]:
Two first- or second-degree relatives with LFS-related malignancies at any age
Molecular Genetic Testing
GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information. —ED.
Genes. The TP53 gene is the main gene associated with Li-Fraumeni syndrome (LFS). A few families with LFS and Li-Fraumeni-like syndrome (LFL) have been found to have mutations in the CHEK2 gene [Lee et al 2001 , Varley 2003a].
Molecular genetic testing: Clinical uses
Confirmatory diagnostic testing
Predisposition testing
Prenatal and preimplantation genetic diagnosis
Molecular genetic testing: Clinical method
Sequence analysis. A variety of TP53 sequence analysis panels, covering subsets of the total coding and noncoding gene regions, is offered on a clinical basis. In the 70% of families with LFS with detectable TP53 mutations, approximately 95% of the mutations can be detected by sequence analysis of exons 4 through 9. Because the vast majority of mutations occur in exons 4 through 9, panels that do not include these exons have lower mutation detection rates. Duplications, inversions, large deletions, and mutations in noncoding regions are not likely to be detected by sequence analysis [Bougeard et al 2003]. If the entire coding region of the TP53 gene is sequenced, the sensitivity may be increased to 98%.
Over 50% of families with Li-Fraumeni syndrome have an identifiable germline TP53 mutation [Nichols et al 2001].
The percent of families with Li-Fraumeni-like syndrome who have an identifiable TP53 mutation varies from 22% using Birch's definition to 8% using Eele's definition [Varley, Evans et al 1997].
TP53 deletions do not appear to be common, but have been reported, including one case with a complete heterozygous deletion of the TP53 gene [Bougeard et al 2003].
It is conjectured that mutations in the TP53 promotor may account for families with LFS and LFL who do not have an identifiable TP53 mutation. However, the one promotor deletion reported in two of 18 probands with LFS and LFL was concluded to be a rare polymorphism [Attwooll et al 2002].
Chompret and colleagues (2000 , 2001) suggest that individuals be offered TP53 analysis if they fulfill at least ONE of the following criteria:
Proband affected by sarcoma, brain tumor, breast cancer, or adrenocortical carcinoma (ACC) before 36 years of age with:
At least one first- or second-degree relative with cancer (other than breast cancer if the proband has breast cancer) before 46 years of age or
A relative with multiple primary tumors at any age
Proband with multiple primary tumors, two of which are sarcoma, brain tumor, breast cancer, and/or ACC, with the initial cancer occurring before 36 years of age, regardless of family history
Proband with ACC regardless of age of onset or family history
Using these criteria, it is estimated that 20% of individuals with LFS would be found to have germline TP53 mutations.
Molecular genetic testing: Research
Chip-based DNA mutation analysis. A chip-based DNA sequencing assay that can detect more than 300 single base pair mutations in TP53 is available on a research basis [Schaefer et al 2002]. This assay has a sensitivity of approximately 90%.
Germline CHEK2 mutations have been reported in only a few families with Li-Fraumeni syndrome or Li-Fraumeni-like syndrome. Missense variants of uncertain clinical significance have also been identified [Bell et al 1999 , Vahteristo et al 2001 , Varley 2003a]. Whether CHEK2 mutations confer cancer risks different from those associated with TP53 mutations remains unclear