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Li-Fraumeni Syndrome

[SBLA Syndrome (Sarcoma, Breast, Leukemia, and Adrenal Gland)]

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.

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.

Table 1. Molecular Genetic Testing Used in Li-Fraumeni Syndrome Test Method Mutations Detected Mutation Detection Rate  1 Test Availability Sequence analysis TP53 mutations ~95%  2 Clinical Chip-based TP53 mutation analysis >300 single base pair mutations in TP53 90-98% Research only

1. In the 70% of families with a detectable mutation 2. The mutation detection rate for sequence assay that includes exons 4 through 9 is approximately 95%; sequencing that does not include exons 4-9 has lower mutation detection rates.

Interpretation of test results.  For issues to consider in interpretation of sequence analysis results, click here.

Genetically Related (Allelic) Disorders

TP53.  Although mutations in TP53 are observed in numerous acquired tumors, no other inherited phenotypes are associated with mutations in this gene. Somatic TP53 mutations are found in about 50% of tumors, making it one of the most frequently altered genes in human cancers [Levine 1997].

CHEK2

• Somatic CHEK2 mutations have been reported in a variety of tumor types, although somatic CHEK2 mutations appear to be most common in osteosarcomas [Miller et al 2002].
• Germline CHEK2 mutations have been identified in a few families with classic LFS and several families with LFL [Lee et al 2001 , Varley 2003a]. Several reports suggest that CHEK2 may act as a low-penetrance tumor-suppressor gene in breast cancer [Vahteristo et al 2002 , Ingvarsson et al 2002 , Varley 2003a].

Clinical Description

Natural History

Cancer types.  Families with LFS were originally noted to have osteosarcomas, soft-tissue sarcomas, premenopausal breast cancer, brain tumors, adrenal cortical tumors, and acute leukemias inherited in an autosomal dominant manner [Li & Fraumeni 1969 , Li et al 1988]. Since the original description, published reports of families with LFS suggest excess rates of melanoma; cancer of the stomach, colon, pancreas, and esophagus; and gonadal germ cell tumors diagnosed at early ages [Strong & Williams 1987 ; Hartley et al 1989 ; Varley, Evans et al 1997]. A report on 24 kindreds with LFS revealed the following cancers in 151 blood relatives: 32 soft-tissue cancers, 23 bone cancers, 14 brain tumors, nine leukemias, and four adrenal gland tumors [Li et al 1988]. Adult women with LFS appear to have higher cancer risks than adult men because of the high frequency of breast cancer in women [Lustbader et al 1992 , Chompret 2002].

The spectrum of tumors in LFS is much broader than the original six component tumors; however, characterizing the specific tumors associated with LFS has been difficult. Chompret and colleagues (2001) assert that, in addition to the six component tumors, the most notable malignancies in individuals with LFS are melanoma, germ cell tumors, gastric carcinoma, and Wilms' tumor. Birch and colleagues (2001) catalogued the incidence of cancer in 28 families with LFS and reported that strongly associated cancers were breast carcinoma, soft tissue sarcoma, osteosarcoma, brain tumor, adrenocortical carcinoma, Wilms' tumor, and phyllodes tumor. Pancreatic cancer was moderately associated in this series and leukemia and neuroblastoma were weakly associated. Nichols and colleagues (2001) evaluated 738 cancers in individuals with known TP53 mutations and their first-degree relatives and found that the six component cancers accounted for only 77% of the cancer. The remaining 23% of cancers included lymphoma, melanoma, and cancers of the lung, stomach, ovary, colon/rectum, endometrium, thyroid, pancreas, prostate, and cervix.

Cancer risk.  LFS is a highly penetrant cancer syndrome. A segregation analysis conducted on families with LFS revealed cancer risks of 50% by age 40 years and up to 90% by age 60 years [Lustbader et al 1992]. Another study, based on five families with LFS, estimated age-specific cancer risks (and standard errors) as 42% (0.14) at 0-16 years of age, 38% (0.14) at ages 17-45 years, and 63% (0.27) after age 45 years; overall lifetime cancer risk was calculated at 85% [Le Bihan et al 1995]. Another study compared ages of cancer diagnoses in families with LFS and LFL. In this series, 56% of the cancers in families with LFS occurred prior to age 30 years and 100% were diagnosed by age 50 years. In families with LFL, 44% were diagnosed before age 30 years and 78% by age 50 years [Varley, Evans et al 1997]. These findings suggest that in some families LFL may result from genetic heterogeneity and/or chance associations.

Individuals with LFS are also at increased risk for developing multiple primary tumors. A retrospective study on 200 affected members of families with LFS found that 15% had developed a second cancer, 4% a third cancer, and 2% a total of four cancers. In this cohort, survivors of childhood cancers were found to have the highest risks for developing additional malignancies [Hisada et al 1998].

Genotype-Phenotype Correlations

Nearly 250 distinct germline TP53 mutations have been described in the literature [Varley 2003b]. A database of TP53 mutations has been established and can be accessed at www.iarc.fr/p53 [Olivier et al 2003]. While frame shift mutations have consistently been associated with high cancer risks, certain missense TP53 mutations may confer lower cancer risks.

• In a series of individuals with childhood adrenocortical carcinoma (ACC) and no significant cancer histories, 35 of 36 children were found to have the identical R337H germline mutation. The authors found no evidence for a founder effect and conjecture that the R337H germline mutation is a low-penetrance TP53 allele [Ribeiro et al 2001]. Other potential low-penetrance TP53 mutations have been reported among individuals with childhood ACC with noncontributory family histories [Varley et al 1999].
• In a series of individuals with breast cancer, the 13964^GC mutation in intron 6 was identified in three of 42 individuals with breast cancer, making it yet another possible low-penetrance mutation [Lehmann et al 2000].
• In the CHEK2 gene, the 1100delC mutation has been reported to confer low-penetrance breast cancer susceptibility [Varley & Haber 2003].

Nomenclature

LFS was initially referred to as sarcoma, breast, leukemia, and adrenal gland (SBLA) syndrome.

Prevalence

LFS is a rare hereditary cancer syndrome, with fewer than 400 families reported worldwide.

Differential Diagnosis

For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.

Certain families with LFS and LFL resemble families with hereditary breast cancer, who are candidates for BRCA1 or BRCA2 testing (see BRCA1/BRCA2 Hereditary Breast Cancer). Other families with LFS or LFL can resemble kindreds with familial brain tumors.

Germline TP53 mutations are thought to account for fewer than 1% of total cases of breast cancer. Series of individuals with other specific malignancies (irrespective of family history) have reported the following TP53 mutation frequencies:

• 2-10% of childhood brain tumors [Felix et al 1995 , Li et al 1995]
• 50-100% of childhood adrenocortical carcinomas (ACC) [Wagner et al 1994 ; Varley, Evans et al 1997 ; Ribeiro et al 2001]
• 2-3% of osteosarcomas [McIntyre et al 1994]
• 9% of rhabdomyosarcomas [Diller et al 1995]
• 7-20% of multiple primary tumors occurring at early ages [Malkin et al 1992]

Management

Prevention of Primary Manifestations

Females with a germline TP53 mutation have the option of prophylactic mastectomy to reduce the risk of breast cancer [Thull & Vogel 2004].

Surveillance

No surveillance measures, with the possible exception of breast cancer monitoring, have been shown to be effective in reducing morbidity or mortality among individuals with LFS or LFL. Routine mammograms and clinical breast exams are effective in women over age 40 years, but have not been proven to be beneficial for younger women with LFS or LFL.

Surveillance strategies have been suggested for individuals at risk for LFS or LFL [Varley, Evans et al 1997 ; NCCN 1999].

For at-risk children, on an annual basis:

• Complete physical examination
• Urinalysis
• Complete blood count
• Abdominal ultrasound examination
• Additional organ-targeted surveillance based on family history (e.g., imaging studies of the head if a relative has had a childhood brain tumor)

For at-risk adults:

• Complete physical examination every 12 months
• Dermatologic examination every 12 months
• Urinalysis and complete blood count every 12 months
• Women only: clinical breast examination every six months
• Women only: annual mammograms and annual breast MRI examination starting at age 20-25 years. Controversy exists regarding the use of routine mammograms in women with LFS, because of possible radiation sensitivity associated with TP53 mutations [Varley, Evans et al 1997 ; Eng et al 2001].
• Additional organ-targeted surveillance based on family history (e.g., colonoscopies at regular intervals if a relative has had colorectal cancer)
• Full-body MRI examination or PET scan has been suggested. However, no evidence supporting the benefit of such testing exists; in fact, it is possible that such testing leads to unnecessary biopsies or other follow-up tests.

Perhaps most importantly, at-risk individuals and their physicians are urged to pay greater attention to lingering symptoms and illnesses, particularly headaches, bone pain, or abdominal discomfort, and to schedule diagnostic tests promptly.

Agents/Circumstances to Avoid

Individuals with TP53 mutations should avoid or minimize exposure to radiation whenever possible [Varley 2003a]. The TP53 gene is recognized as having a crucial role in genomic repair [Wang et al 2003] and p53-deficient mouse cells have been shown to be radiation sensitive and prone to cancer [Mitchel et al 2004].

Radiation-induced second malignancies have been reported among individuals with TP53 mutations [Hisada et al 1998 , Nutting et al 2000 , Limacher et al 2001].

Testing of Relatives at Risk

Relatives of a proband known to have LFS may also be at increased risk; it is appropriate to offer genetic counseling and testing. (See Risk to Family Members .)

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory. —ED.

Mode of Inheritance

LFS is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• Although de novo germline mutations in TP53 have been reported, most individuals diagnosed as having LFS based on clinical criteria have an affected parent.
• The frequency of de novo mutations is not established; however, in one series, four of 17 germline TP53 mutations were reported as de novo [Chompret et al 2000].
• Recommendations for the evaluation of parents of a child with LFS and no known family history of LFS include molecular genetic testing for the TP53 mutation found in their child, followed by appropriate medical surveillance if either parent is identified as having the mutation.

Note: The family history may also appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent.

Sibs of a proband

• The risk to sibs of the proband depends on the genetic status of the proband's parents.
• If a parent has the same disease-causing mutation as the proband, then each sib of the proband has a 50% risk of having the familial mutation.
• If neither parent has the same disease-causing mutation as the proband, then the proband is assumed to have a de novo (new) mutation and the risk to the sibs appears to be low. However, the risk may be slightly greater than that of the general population because of the possibility of germline mosaicism.
• No instances of germline mosaicism have been reported, but it remains a theoretical possibility.
  • If the proband does not have a specific disease-causing mutation, then the estimates of risk for sibs depend on the pattern of cancer in the family
  • If the family meets clinical criteria for LFS, then sibs are assumed to be at 50% risk despite the inability to identify the exact genetic mutation for the family
  • If the family meets LFL criteria, then sibs may have some increased risk of cancer, but the level of risk is lower than that of families with LFS.
  • If the family does not meet LFL or LFS criteria, then failure to detect a mutation in the proband suggests that it is less likely that sibs are at increased risk for LFS-related malignancies.

Offspring of a proband

• Each child of an individual with a disease-causing mutation is at 50% risk of inheriting the familial mutation.
• It is estimated that 90% of individuals with a TP53 mutation will develop an LFS-related malignancy.

Other family members of a proband.  The risk to other family members depends upon the genetic status of the proband's parents. If a parent is found to be affected and/or to have a disease-causing mutation, his or her family members are at risk.

Related Genetic Counseling Issues

Considerations in families with an apparent de novo mutation.  When the parents of a proband with an autosomal dominant condition are genetically unaffected, it is likely that the child has a de novo mutation. However, possible nonmedical explanations, including alternate paternity or undisclosed adoption, should also be explored.

Genetic cancer risk assessment and counseling.  Families with LFS or LFL present with a wide variety of medical, psychological, and familial issues making effective counseling a challenge [Chompret 2002 , Varley 2003b]. For comprehensive descriptions of the medical, psychosocial, and ethical ramifications of identifying at-risk individuals through cancer risk assessment with or without molecular genetic testing, see:

• Genetic Cancer Risk Assessment and Counseling: Recommendations of the National Society of Genetic Counselors
• Elements of Cancer Genetics Risk Assessment and Counseling (part of PDQ^®, National Cancer Institute)

Cancer risk assessment modification based on age.  For the asymptomatic at-risk relative, the risk of having inherited the disease-causing allele is the a priori risk based on the person's position in the pedigree. If the at-risk individual is older than age 50 years and has never had cancer, this risk gradually decreases with age.

Testing of at-risk asymptomatic adults.   Testing of at-risk asymptomatic adults for germline mutations in the TP53 gene is available using molecular genetic testing (see Molecular Genetic Testing).

Predisposition testing for germline TP53 mutations is available clinically; CHEK2 testing is not clinically available. Uptake of predisposition testing for TP53 mutations in one research program was 39%, indicating that many at-risk individuals choose not to be tested [Patenaude et al 1996]. Individuals undergoing genetic testing should receive pre- and post-test genetic counseling, including discussion of the accuracy and limitations of results, the medical and psychological implications of results to individuals and their families, the logistics of testing (including cost), and potential risks and benefits of testing. Potential risks include possible problems with health, life, and disability insurance coverage, employment and educational discrimination, and changes in social and family interaction. Other issues to consider are implications for the at-risk status of other family members. Informed consent should be procured and records kept confidential. Individuals with a positive test result need arrangements for long-term follow-up and evaluation.

Some individuals seek genetic counseling because they are puzzled by the excess of childhood cancers in their family; others already know that there is LFS in their family and wish to learn about their options for genetic testing. It is important to determine motivations for the genetic counseling visit and the individual's level of understanding regarding LFS. Individuals who have struggled with the seemingly unrelated cancer diagnoses in their family may welcome the diagnosis of LFS as an explanation. Others, especially those initially referred for BRCA1 or BRCA2 testing (see BRCA1/BRCA2 Hereditary Breast Cancer), may be surprised and distressed to learn that they have a syndrome that includes diverse tumor types and childhood malignancies.

Perception of cancer risks varies widely among at-risk individuals and is influenced by a person's previous experiences with cancer and loss, his/her adaptive or maladaptive strategies for dealing with increased risk, and presence or absence of social support.

Molecular genetic status can be used for testing of at-risk relatives only if a disease-causing TP53 mutation has been identified in an affected family member. Such testing is not useful in predicting whether symptoms will occur, or if they do, what the age of onset, severity and type of symptoms, or rate of disease progression in asymptomatic individuals will be. Because of the lack of proven surveillance methods or prevention strategies, testing of at-risk individuals cannot be justified for management reasons and many at-risk individuals may choose not to be tested [Patenaude et al 1996]. However, some at-risk asymptomatic adult family members seek testing in order to make personal decisions regarding such issues as reproduction, financial matters, and career planning. Others may simply "need to know" their genetic status.

Testing of at-risk asymptomatic individuals during childhood.  Although LFS-related malignancies can occur during childhood or adolescence, predisposition testing programs have for the most part confined testing to individuals 18 years of age or older. There are legitimate concerns about testing children for TP53 mutations, including issues of informed consent among minors, the lack of proven surveillance or prevention strategies, and concerns about stigmatization and discrimination. However, as pediatric-onset cancers may occur as part of the syndrome, genetic testing programs are exploring how best to provide genetic testing and counseling to minors. (See also the National Society of Genetic Counselors resolution on genetic testing of children and the American Society of Human Genetics and American College of Medical Genetics points to consider : ethical, legal, and psychosocial implications of genetic testing in children and adolescents.)

Collecting a cancer history.  Collecting a cancer history for a family suspected of having LFS or LFL involves obtaining information on all childhood and adult-onset malignancies among first-, second-, and third-degree relatives. This includes type and site of cancer and age of onset. Obtaining written documentation of the reported cancer diagnoses is important. Details about relatives may be incomplete for a variety of reasons. For example, cancer may be a subject to be avoided, or the parent's death may have led to estrangement from relatives on that side of the family. In addition, collecting a cancer history for a family with possible LFS may be emotionally charged because of the number of cancer-related illnesses and deaths in close relatives.

DNA Banking.  DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. DNA banking is particularly relevant in situations in which the sensitivity of currently available testing is less than 100% or molecular genetic testing available on a research basis only. See DNA Banking for a list of laboratories offering this service.

Prenatal Testing

Prenatal diagnosis for pregnancies at 50% risk of LFS is possible by analyzing DNA extracted from fetal cells obtained by amniocentesis usually performed at about 15-18 weeks' gestation or chorionic villus sampling (CVS) at about 10-12 weeks' gestation. The familial TP53 (or CHEK2) mutation must be identified before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD).  Successful preimplantation genetic diagnosis has been reported for several single-gene diseases and is an option for families with LFS [Simpson 2001 , Kanavakis & Traeger-Synodinos 2002 , Rechitsky et al 2002]. PGD is performed in conjunction with in vitro fertilization (IVF). Sperm and egg specimens are collected from each parent and combined in vitro. A cell from the blastomere is then tested for the familial mutation. Blastomeres that do not contain the familial mutation are implanted in the womb. Although PGD is an accurate method of analysis and allows couples to avoid making difficult decisions about pregnancy termination, IVF is a time-intensive and expensive process with only a 20% success rate for each attempt.

Molecular Genetics

Information in the Molecular Genetics tables may differ from that in the text; tables may contain more recent information. —ED.

TP53

Normal allelic variants: In 1990, germline mutations in the TP53 gene were recognized as the underlying cause of LFS [Malkin et al 1990]. The TP53 gene is a tumor suppressor gene that is 20 kilobases (kb) in genomic length. The gene, which consists of one noncoding and ten coding regions, has five highly conserved domains that show little variation across species [Soussi et al 1990]. Domain I is responsible for transactivation properties, while the remaining domains (II-V) make up the core DNA-binding domain [Varley, Evans et al 1997].

Pathologic allelic variants: The majority of reported TP53 mutations are missense mutations. Most TP53 mutations have been reported within exons 5-8, which reside in the core DNA-binding region of the gene. However, 20% of mutations may be outside this region [Greenblatt et al 1994]. Mutations affecting splice site junctions have been reported, emphasizing the need to examine both coding and noncoding regions for germline mutations [Verselis et al 2000 , Varley et al 2001 , Olivier et al 2003]. (For more information, see Genomic Databases table above.)

Normal gene product: The TP53 gene, first identified in 1979, encodes a protein that complexes to the large T antigen of SV40 [Lane & Crawford 1979]. The cellular tumor antigen p53 protein functions as a tetramer, which is actually a dimer of dimers [Varley, Evans et al 1997]. Nicknamed the "guardian of the genome" [Lane & Crawford 1979], the cellular tumor antigen p53 protein plays a major role in determining whether cells undergo arrest for purposes of DNA repair or programmed cell death (apoptosis) [Fisher 2001]. The cellular tumor antigen p53 protein acts as a checkpoint control following DNA damage, helping delay cell cycle progression until the damaged DNA can be repaired or proceed with programmed cell death. Upon recognizing damaged DNA, the normal cellular tumor antigen p53 protein either: 1) transcriptionally activates the downstream genes (p21, MDM-2, GADD45, Bax, IGF-BP and cyclin-G) to repair the DNA or 2) directly signals a "sensor" molecule which confirms the damage and proceeds with apoptosis. The ability to arrest the cell cycle, a key regulatory function, occurs with proper activation of the RB pathway, which is p53-mediated [Levine 1997]. The cellular tumor antigen p53 protein may also have a direct role in the DNA repair process [Varley, Evans et al 1997].

Abnormal gene product: Mutant cellular tumor antigen p53 often gains the ability to cooperate with the RAS oncogene products and can block normal cellular tumor antigen p53 protein from appropriately binding. These dominant negative functions explain why the TP53 gene was initially thought to be an oncogene [Jenkins et al 1985] rather than a tumor suppressor gene. The inability to set off the appropriate chain of events when presented with damaged DNA can lead to the development or maturation of diverse tumor types.

A child with soft tissue sarcoma and a brain tumor was identified as having three separate deleterious TP53 mutations: one on the paternal allele and two on the maternal allele. Although this child had partial or complete loss of wild-type cellular tumor antigen p53 function, the child had completed normal embryonic development [Quesnel et al 1999]. This is consistent with animal studies in which TP53-deficient mice have been shown to undergo normal embryogenesis but have increased carcinogenic potential [Harvey et al 1995].

CHEK2

Normal allelic variants: CHEK2 is a putative tumor suppressor gene which lies in the TP53 pathway. CHEK2 is one of the checkpoint genes activated in response to DNA damage or other stressors.

Normal gene product: CHEK2 encodes a protein kinase required for DNA damage and replication checkpoints. The protein encoded by CHEK2 is capable of phosphorylating cellular tumor antigen p53, playing an important role in connecting the cellular tumor antigen p53 response to the double-stranded DNA breaks. The protein encoded by CHEK2 also binds to and regulates BRCA1 [Bell 1999 , Allinen 2001].

Abnormal gene product: Abnormal or absent serine/threonine-protein kinase Chk2 appears to hamper the cell's ability to halt mitosis so that DNA damage can be repaired [Bell et al 1999 , Miller et al 2002].

Resources

GeneReviews provides information about selected national organizations and resources for the benefit of the reader. GeneReviews is not responsible for information provided by other organizations. -ED.

References

Published Statements and Policies Regarding Genetic Testing

One set of guidelines specific to TP53 testing exists; five additional publications address issues relevant to TP53 testing:

• In 1992, an International Consortium of clinicians and researchers convened and developed recommendations regarding genetic testing for germline TP53 mutations [Li et al 1992]. These recommendations state that testing should be done voluntarily with appropriate pre- and post-test genetic counseling and education. They also advocate that testing cancer-free individuals be confined to families with known TP53 mutations and acknowledge that there may not be a medical benefit to learning one's TP53 results. Although this report was published several years ago, the majority of recommendations remain useful.
  
  
• The National Society of Genetic Counselors (1997) Statement regarding genetic testing for adult-onset disorders. These guidelines provide a detailed description of the pretest and post-test genetic counseling process as well as potential laboratory issues.
  
  
• The Ethical, Legal and Social Implications (ELSI) committee of the Human Genome Project assembled a Task Force to consider policy issues and make recommendations to safeguard all types of genetic tests, including predisposition testing [Holtzman & Watson 1999]. This report provides overarching principles and recommendations for action related to laboratory safety and effectiveness, genetic counseling issues and informed consent, and provider competence in understanding genetic tests. The laboratory and counseling issues for predisposition tests are relevant to TP53 testing.
  
  
• The American Society of Human Genetics (ASHG) has published a position statement regarding BRCA1 testing that urges that testing be offered to families with strong cancer histories rather than the general population [ASHG Ad Hoc Committee 1994]. This statement also outlines the issues that should be discussed with individuals as they consider testing and states the need for further research in the medical management of individuals with inherited susceptibilities to cancer.
  
  
• American Society of Clinical Oncology (2003) Policy statement update : Genetic testing for cancer susceptibility
  
  
• American Society of Human Genetics and American College of Medical Genetics (1995) Points to consider : ethical, legal, and psychosocial implications of genetic testing in children and adolescents

Literature Cited

• Allinen M, Huusko P, Mantyniemi S, Launonen V, Winqvist R (2001) Mutation analysis of the CHK2