The TP53 gene is associated with autosomal dominant Li-Fraumeni syndrome (LFS) (MedGen UID: 322656).
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TP53: Deletion/duplication analysis covers the promoter region.
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TP53 is a tumor suppressor gene encoding a protein that responds to diverse cellular stresses to regulate expression of target genes, thereby inducing cell cycle arrest, apoptosis, senescence, DNA repair, or changes in metabolism. Loss of TP53 function due to mutations enables cells with DNA damage to grow unchecked, increasing the risk of tumor formation.
MedGen UID: 322656
Li-Fraumeni syndrome (LFS) is a rare cancer predisposition condition. Cancers often develop during childhood or early adulthood, with a 30-40% risk of cancer within the first two decades of life and an over 90% lifetime risk (PMID: 11219776, 7713397, 26014290). In addition to early-onset cancer, affected individuals may also develop multiple primary tumors (PMID: 26014290). The cancers most often associated with LFS (often referred to as the classic or core cancers) are:
Several other types of cancer also occur more frequently in this condition:
Additionally, many other cancer types have been described in individuals with LFS (PMID: 21601526). There is data to suggest there may be an increased risk of thyroid and skin cancer; however, the evidence is limited and emerging (PMID: 20301488, 20522432).
TP53 is a tumor suppressor gene whose encoded protein responds to diverse cellular stresses to regulate expression of target genes, thereby inducing cell cycle arrest, apoptosis, senescence, DNA repair, or changes in metabolism (NCBI Gene. Gene ID: 7157. http://www.ncbi.nlm.nih.gov/gene/7157. Accessed January 2017). Because TP53 is essential for regulating cell division and preventing tumor formation, it has been nicknamed the “guardian of the genome” (National Library of Medicine, Genetics Home Reference: TP53. http://ghr.nlm.nih.gov/gene/TP53. Accessed January 2017). If there is a pathogenic variant in this gene that prevents it from normally functioning, there may be an increased risk to develop certain cancers.
Hereditary predisposition to cancer due to pathogenic variants in the TP53 gene has autosomal dominant inheritance. This means that an individual with a pathogenic variant has a 50% chance of passing the condition on to his/her offspring. With this result, it is now possible to identify at-risk relatives who can pursue testing for this specific familial variant. While the vast majority of cases are inherited from a parent, 7-20% occur spontaneously (PMID: 20301488, 19556618). This means that the individual did not inherit the pathogenic variant from either parent, but now has a 50% risk of passing it on to future offspring.
Management Guidelines for individuals with pathogenic TP53 variants have been developed by the National Comprehensive Cancer Network® (NCCN®) (National Comprehensive Cancer Network. Genetic/Familial High-Risk Assessment: Breast and Ovarian. Version 2.2017, accessed January 2017):
NCCN breast cancer surveillance:
In addition, NCCN recommends the following for both males and females:
Villani et al. proposed similar management guidelines that additionally include screening for adrenocortical carcinoma and hematologic malignancies and avoidance of therapeutic radiation for cancer (see below for details) (PMID: 21601526):
Villani et al. breast cancer surveillance:
Villani et al. adrenocortical carcinoma surveillance:
In addition, Villani et al. recommends the following for both males and females:
Sensitivity to radiation-induced cancers has been reported in clinical studies of individuals with LFS (PMID: 9554443, 12619118, 11474498, 26014290, 9228960). Second, third, and fourth primary cancers have been identified within the radiation field years after radiotherapy (PMID: 9554443). A study by Heyman et al. looked at women with LFS and breast cancer as their first tumor event in the absence of any prior cytotoxic therapy (PMID: 21059199). They found an increased risk of radiation-induced secondary cancers, most of which were breast, but also included chest wall angiosarcoma, malignant histiocytofibroma, and papillary thyroid carcinoma (PMID: 21059199).
Discussions surrounding the medical management, particularly of breast cancer diagnoses, in individuals with LFS should take into account radiotherapy risks (PMID: 21059199). Adjuvant radiation therapy for localized breast cancer should be extensively discussed and avoided if the risk/benefit ratio is doubtful (PMID: 21059199, 25271877). Bilateral mastectomy versus conservative lumpectomy should be discussed as the former provides the added advantage of potentially avoiding radiation therapy (PMID: 21059199, 25271877).
There are a number of additional issues that should be considered when implementing medical surveillance for those with LFS. Concerns of anesthesia for young children undergoing MRI and the possibility of burnout associated with undergoing lifetime surveillance should be raised and addressed. A close relationship and regular follow-up with an engaging and supportive multidisciplinary team may assist in individuals’ adherence to medical management recommendations (PMID: 21601526).
An individual’s cancer risk and medical management are not determined by genetic test results alone. Overall cancer risk assessment incorporates additional factors including personal medical history, family history, as well as available genetic information that may result in a personalized plan for cancer prevention and surveillance.
It is advantageous to know if a TP53 pathogenic variant is present as medical management recommendations can be implemented. At-risk relatives can be identified, allowing pursuit of a diagnostic evaluation. In addition, the available information regarding hereditary cancer susceptibility genes is constantly evolving and more clinically relevant TP53 data is likely to become available in the near future. Awareness of this cancer predisposition allows patients and their providers to be vigilant in maintaining close and regular contact with their local genetics clinic in anticipation of new information, inform at-risk family members, and diligently follow condition-specific screening protocols.
Special Considerations: TP53 and Acquired Mosaicism
Recent studies have shown that clonal hematopoiesis increases with age, with somatic variants detected in 10-25% of individuals 65 years of age and older (PMID: 25426837, 25426838). TP53 was reported as one of the genes in which these somatic variants have been commonly identified (PMID: 25426837, 25426838, 25487151).
Cells can acquire DNA sequence changes throughout the course of development and may result in mosaicism (while a variant is present in some cells, it may be absent from others). Individuals with a pathogenic variant in TP53, or a pathogenic result suggestive of TP53 mosaicism, may consider pursuing further testing of other family members or analysis of other sample types such as genomic DNA (gDNA) from cultured fibroblasts (skin cells) to assist in clarifying if the finding is heritable or likely acquired in a clonal population of cells in the blood.
Invitae offers select complimentary variant testing for cases with pathogenic or likely pathogenic variants in TP53, to aid in determining whether a variant is heritable or likely acquired in a clonal population of cells in the blood. If you have questions or would like more information about the Invitae TP53 Variant Program, please email firstname.lastname@example.org.
Review date: January 2017
Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Genetic/Familial High-Risk Assessment: Breast and Ovarian V.1.2017. © National Comprehensive Cancer Network, Inc 2016. All rights reserved. Accessed October 24, 2016. To view the most recent and complete version of the guideline, go online to NCCN.org. National Comprehensive Cancer Network®, NCCN®, NCCN Guidelines®, and all other NCCN content are trademarks owned by the National Comprehensive Cancer Network, Inc.
Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).
Our sequence analysis covers clinically important regions of each gene, including coding exons, +/- 10 base pairs of adjacent intronic sequence, and select noncoding variants. Our assay provides a Q30 quality-adjusted mean coverage depth of 350x (50x minimum, or supplemented with additional analysis). Variants classified as pathogenic or likely pathogenic are confirmed with orthogonal methods, except individual variants that have high quality scores and previously validated in at least ten unrelated samples.
Our analysis detects most intragenic deletions and duplications at single exon resolution. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. If you are requesting the detection of a specific single-exon copy number variation, please contact Client Services before placing your order.
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*TP53: Deletion/duplication analysis covers the promoter region.