About 50% of children with adrenocortical tumors (ACT) test positive for a germline TP53 mutation. This inherited mutation can be passed down from parent to child, even if the parent does not have cancer. It is recommended that pediatric patients with ACT and their families are counseled on genetic testing.
TP53 and cancer
TP53 is a gene that codes for a protein called p53 that plays an important role in cell cycle control and functions as a tumor suppressor. The name is due to its molecular mass: it is in the 53 kilodalton fraction of cell proteins. In normal cells, the p53 protein level is low.
DNA damage and other stress signals may trigger the increase of p53 proteins, which have three major functions: growth arrest, DNA repair and apoptosis (cell death). The growth arrest stops the progression of cell cycle, preventing replication of damaged DNA. During the growth arrest, p53 may activate the transcription of proteins involved in DNA repair. Apoptosis, or the signal to start the cell death, is the "last resort" to avoid proliferation of cells containing abnormal DNA.
If the TP53 gene is damaged, tumor suppression is severely reduced. Defective TP53 could allow abnormal cells to proliferate, resulting in cancer. People who inherit only one functional copy of TP53 will most likely develop tumors in early adulthood, a disease known as Li-Fraumeni syndrome (LFS). Germline mutations in the TP53 tumor suppressor gene are associated with the LFS. This autosomal dominant syndrome is characterized by a high incidence of early-onset cancers comprising mostly breast cancer, sarcoma, adrenocortical tumors, choroid plexus carcinoma, anaplastic rhabdomyosarcoma, leukemia and brain tumors.
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TP53 can also be damaged in cells by mutagens (chemicals, radiation or viruses), increasing the likelihood that the cell will begin uncontrolled division. More than 50% of human tumors acquire a mutation or deletion of the TP53 gene during tumor progression.
Mutation in TP53 is observed in about 50% of pediatric ACT. However, family history of cancer in families having an inherited TP53 mutation will vary, some of them with several affected members and others without a history of cancer.
TP53 Structure
In most cases, the mutation is located in the DNA-binding core domain of the protein. According to the latest version of the TP53 mutation database of the International Agency for Research on Cancer (version R18 at p53.iarc.fr), about 30,000 cancer-related TP53 mutations have been reported. The functional consequences of TP53 mutations are complex and several systematic studies have shown that while some mutants result in complete loss of p53 function, others still retain function. It is, therefore, crucial to understand the molecular basis of p53 inactivation in cancer by different types of mutation, so as to predict the biological outcome or the response to drug treatment.
The 393-amino acid p53 protein has a complex structure, which comprises well-defined domains and natively unfolded regions that undergo a reversible equilibrium to form tetramers.
The N-terminal region contains the transactivation domain (amino acids 1–50), followed by a proline-rich region (amino acids 63–92). The transactivation domain interacts with a number of proteins which regulates cellular levels of p53. The proline-rich region is thought to have a regulatory role for this protein. The central core domain (amino acids 100-300) binds specifically to double-stranded target DNA, particularly to the recognition elements of genes involved in cell cycle arrest and apoptosis. The C-terminal region includes the tetramerization domain (amino acids 323-358), which regulates the oligomerization state of p53, and the negative auto-regulatory domain at the extreme C-terminus, which contains acetylation sites and binds DNA non-specifically (amino acids 363-393).
Despite the huge diversity in the genes implicated in the development of tumors, the human gene TP53 stands out as a key tumor suppressor and a master regulator of various signaling pathways involved in this process. Indeed, TP53 mutations were reported to occur in almost every type of cancer at rates varying between 10% (hematopoietic malignancies) and close to 100% (high-grade serous carcinoma of the ovary). The importance of p53 as a cardinal player in protecting against cancer development is further emphasized by Li-Fraumeni syndrome (LFS), a rare type of cancer predisposition syndrome associated with germline TP53 mutations. Unlike the majority of tumor suppressor genes, such as RB, APC or BRCA1, which are usually inactivated during cancer progression by deletions or truncating mutations, the TP53 gene in human tumors is often found to undergo missense mutations, in which a single nucleotide is substituted by another. Consequently, a full-length protein containing only a single amino acid substitution is produced. The cancer-associated TP53 mutations are very diverse in their locations within the p53 coding sequence and their effects on the stability of the p53 protein. However, the vast majority of the mutations result in loss of p53’s ability to bind DNA in a sequence-specific manner and work properly.
TP53 mutations are distributed in all coding exons of the TP53 gene, with a strong predominance in exons 4-9, which encode the DNA-binding domain of the protein. Of the mutations in this domain, about 30% fall within six “hotspot” residues (residues R175, G245, R248, R249, R273 and R282) and are frequent in almost all types of cancer. To translate basic research findings into clinical practice, it is essential that information about mutations and variations in the TP53 are communicated easily and unequivocally.
TP53 mutations are frequently followed by loss of heterozygosity (LOH) during cancer progression. LOH is often seen in the case of tumor suppressors where, at a particular locus heterozygous for a mutant and WT allele, the WT or normal copy allele is either deleted or mutated. The LOH of the short arm of chromosome 17, where TP53 is located, implies a selective force driving the inactivation of the remaining WT allele.
Testing for the presence of a TP53 mutation
Diagnostic testing for germline TP53 mutations in families with suspected Li-Fraumeni syndrome (LFS) through direct DNA sequencing of all coding region of TP53 (exons 2–11) has been validated in a large clinical cohort. Moreover, it has been proposed that childhood ACT should prompt a request for diagnostic TP53 testing by molecular screening independent of family history of cancer.
Although the TP53 gene testing is medically indicated in many instances, there are many things to consider when thinking about TP53 testing for relatives of these patients. Learning the results of a genetic test can affect an entire family. Before a family undergoes genetic testing, they should think carefully about how knowing the test results might affect them, their child and other family members. Once a child tests positive for a TP53 mutation, adult family members may want to know if they have the same mutation. If the child’s blood test does not show the TP53 mutation, other family members will not benefit from testing. The individual might have sporadic ACT.
Knowing family medical history can help individuals make changes to lower their cancer risk. If they have a higher risk of certain cancers, they may be encouraged to undergo tests like mammograms or colonoscopies earlier than usual or more often. They might need other tests and regular clinical checkups. Recommending healthy foods, regular exercise and quitting smoking can lower their chances of getting heart disease, cancer and other diseases.
Following IPACTR recommendations, and because of the strong association between pediatric ACT and constitutional TP53 mutations, parents will be informed that they may carry a TP53 mutation, which is usually inherited in a Mendelian fashion (de novo TP53 mutations occur in less than 20% of the cases). They also will be informed that most of the TP53 mutation carriers have a life-long increased risk of developing different types of cancer. Moreover, that the risk of cancer appears to be highest in instances in which the TP53 function (protein) is severely compromised. Finally, they will be informed that there is a DNA test (TP53 sequencing) that reveals whether an individual carries a TP53 mutation. TP53 sequencing detects about 95% of the abnormalities associated with cancer. This is done by a blood or others tissue sample send off to a laboratory where the DNA will be sequenced. The remaining 5% of TP53 abnormalities (deletions/duplications) are detected by Multiplex Ligation-Dependent Probe Amplification (MLPA). This technique allows detecting small deletions or duplications that cannot be detected by sequencing.
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