Gene test interpretation: TP53

INTRODUCTION — The TP53 gene encodes the tumor suppressor protein p53, which has been designated the guardian of the genome. It is responsible for much of the modern understanding of tumor suppressor function.

Of all the genes associated with inherited cancer syndromes, TP53 may be the most challenging to address clinically, for reasons discussed below. Other considerations such as somatic TP53 mutations in cancer and indications for testing are discussed separately [1]. (See 'UpToDate topics' below.)

OVERVIEW

How to read the report — Germline TP53 testing has major implications for clinical care. Early involvement of an expert in hereditary cancer syndromes is essential.

The tables define terms used in genetic test reports (table 1) and list general caveats to consider when reviewing results (table 2).

Important caveats specific to TP53 include:

●Results should be reviewed to ensure accurate sequence data and interpretation before the implications are reviewed with the tested individual, since potential consequences of a positive or negative result are especially meaningful (algorithm 1).

●The entire TP53 gene should be sequenced, rather than testing for selected variants.

•Sometimes sequencing of coding regions may be adequate; in others, sequencing of coding and noncoding regions may be required.

•Sensitive techniques should be used to test for copy number variants, as single and multiple exon deletions (and rarely, duplications) also occur.

•One exception is a known familial disease variant; at-risk relatives can be tested exclusively for the specific variant (algorithm 1). (See 'First-degree relatives (testing and counseling)' below.)

●Somatically acquired TP53 variants carry substantially different implications from germline (constitutional) variants.

•Somatic TP53 variants are common in many solid tumor types, as the p53 tumor suppressor plays a major role in coupling DNA damage with cell cycle delay and apoptosis [2].

•Somatic TP53 variants frequently arise in bone marrow, especially in older individuals, and these can lead to clonal hematopoiesis. Clonal hematopoiesis of indeterminate potential (CHIP) can produce allele frequencies as high as 50 percent in lymphocytes [3,4]. (See "Clonal hematopoiesis of indeterminate potential (CHIP) and related disorders of clonal hematopoiesis".)

If the first identification of a variant is from tumor tissue or CHIP, at least two tissues need to be tested to establish whether a germline variant exists (peripheral blood lymphocytes plus skin fibroblasts or tumor plus a somatic tissue).

●De novo germline TP53 variants and mosaicism can also occur, further emphasizing the need for careful assessment by a specialist. (See "Genetics: Glossary of terms", section on 'Mosaicism'.)

Classification of variants — Variants identified by genetic testing are classified into one of five categories of pathogenicity (table 3), depending on the confidence in their association with a disorder [5]. The classification is based on research demonstrating the variant can cause disease, not the likelihood that an individual with the variant will develop disease (ie, strength of association, not disease penetrance).

Stricter criteria are used to further parse TP53 variant interpretation. The ClinGen working group criteria require at least two functional tests that support pathogenicity, supportive clinical pathology data, and association with a positive personal or family history of heritable TP53-related cancer syndrome [6]. All individuals in a particular category should not be lumped together, as not all findings in a category carry the same management implications. A genetics professional or hereditary cancer expert should be involved.

●Pathogenic and likely pathogenic – Pathogenic variants (PV) and likely pathogenic variants (LPV) reflect >90 percent confidence of disease association. LPV are treated the same as PV.

PV and LPV must be stringently assessed against American College of Medical Genetics (ACMG) criteria and (when they become available) ACMG/Association for Molecular Pathology (AMP) criteria, so as not to misdiagnose a TP53 syndrome. Using looser criteria, as many as 1 in 500 variants in the population gnomAD database could be considered PV or LPV, whereas a more stringent approach reduces this to approximately 1 in 5000 [7,8].

TP53 PV and LPV are further subdivided by their effect on p53 function. Dominant-negative mutations can have more severe phenotypes than variants that do not block normal p53 function. (See "Genetics: Glossary of terms", section on 'Dominant negative'.)

●VUS – Variants of uncertain significance (VUS) lack sufficient evidence to determine disease causation. VUS may be reclassified as pathogenic or benign as family studies and bench research accrue.

Gradations in TP53 VUS have major implications for risk. A genetics expert will review these details to determine optimal management. Per ACMG/AMP criteria, several factors can be reviewed, including segregation studies, functional studies, and in silico analysis. A ClinGen TP53 Variant Curation Expert Panel has published guidance on how to apply criteria [9].

●Benign and likely benign – Benign and likely benign variants carry high confidence of no disease association. These typically are not reported (or are reported as negative).

Laboratories vary in their expertise in interpreting TP53 variants, underscoring the importance of specialist input before making treatment decisions.

Disease associations — Germline PV and LPV in TP53 are associated with increased risk of several cancers including (but not limited to):

●Soft tissue sarcomas

●Osteosarcomas

●Adrenocortical carcinomas

●Central nervous system tumors (mainly glial, choroid plexus, and medulloblastoma)

●Breast cancers in young females (≤30 years)

●Acute leukemias or myelodysplastic syndromes (MDS), often following treatment for one of the above solid tumors

Affected individuals are heterozygous for a PV or LPV in TP53. Tumors typically show somatic loss or mutation of the second (normal) allele; other changes including loss of the germline PV can occur. The first cancer diagnosis is generally in childhood (one-fifth before 5 years; two-fifths before 18 years); often multiple cancers develop by adulthood [10]. The risks differ depending on the variant; it is important to review the results and personal and family history before determining an individual's personal risk spectrum. (See "Li-Fraumeni syndrome", section on 'Spectrum of malignancies and age at onset'.)

Prior to widespread availability of genetic testing, classic Li-Fraumeni syndrome (LFS) criteria included an autosomal dominant cancer syndrome with sarcoma before age 45 in the proband (table 4). The Chompret criteria (table 5) are broader but miss some individuals with a germline PV or LPV in TP53. Chompret criteria may also apply to individuals with early-onset breast cancer due to non-TP53 genetic cause. (See "Overview of hereditary breast and ovarian cancer syndromes".)

The diagnosis has since been broadened to heritable TP53-related cancer syndrome (hTP53rc), which includes a wider range of presentations, as outlined in a 2020 European Reference Network (ERN) guideline [10,11].

PREVENTIVE CARE

Cancer surveillance — Early identification of cancers is paramount to reduce disease and treatment morbidities and to increase the chance for curative therapy [10,12,13].

Individuals with a pathogenic variant (PV) or likely pathogenic variant (LPV) in TP53 require a comprehensive surveillance program to identify new cancers (algorithm 1). The same program may be offered to those with a family history consistent with heritable TP53-related cancer syndrome (hTP53rc) when a familial variant cannot be identified after review by a genetics clinician. Involvement of a hereditary cancer syndrome expert is essential.

Surveillance may differ depending on the specific TP53 variant and/or the family history and should be coordinated with a cancer geneticist, cancer genetic counselor, or hereditary cancer expert [10,12,13]. The table summarizes suggested screenings (table 6). These include:

●Physical examination; skin examination from 18 years onward

●Whole-body magnetic resonance imaging (MRI; without contrast), annually starting at birth (may require sedation or general anesthesia in young children)

●Brain MRI (first with contrast, subsequently without), annually starting at birth

●Abdominal ultrasound from birth to 18 years; biochemical testing for adrenocortical carcinoma if ultrasound is unsatisfactory

●Breast MRI for women, annually starting at 20 years

Some screenings vary regionally (colonoscopies are recommended in the United States but not Europe or Great Britain). Some screenings such as breast MRI may be decreased in older adults, but whole-body MRI is typically continued indefinitely.

Cancer risk reduction — No therapies have been clearly demonstrated to reduce cancer risk in individuals with hTP53rc. The following may be discussed:

●Consultation with a cancer genetics program will provide important insights on living with the condition and contemporary screening approaches. Patients are often approached to participate in studies to better understand this rare syndrome. (See 'First-degree relatives (testing and counseling)' below.)

●Individuals undergoing mastectomy for breast cancer may elect to have a bilateral mastectomy to avoid radiotherapy and reduce the very high risk of contralateral breast cancer [14-17]. Risk-reducing bilateral mastectomy may also be considered in young women without breast cancer. (See "Contralateral prophylactic mastectomy".)

●Metformin is under investigation as a possible chemoprevention approach. Clinicians may contact a hereditary cancer expert to seek updated information or possible enrollment in a clinical trial.

●Tamoxifen could be considered for breast cancer risk reduction, although its efficacy in individuals with hTP53rc is untested.

●Avoiding carcinogenic exposures such as smoking seems prudent, although data are limited. Patients should be advised on leading a healthy lifestyle.

●Certain therapies are avoided if possible (if an alternative exists) due to an increased risk of promoting second tumors. (See 'Cancer management' below.)

Psychosocial support — hTP53rc carries a significant psychological burden due to the unpredictability and potential morbidity of new cancer diagnoses. Psychosocial support may be needed to contend with this distress as well as bereavement linked to cancer diagnoses in the family.

Studies have shown reduced adherence to surveillance due to concerns about financial and insurance implications; genetic counseling can provide further information to ensure an informed decision has been made to reduce negative impacts [18-22]. (See 'Locating a genetics specialist or oncologist' below.)

CANCER MANAGEMENT — Optimal cancer treatment in individuals with a heritable TP53-related cancer syndrome (hTP53rc) is performed by a multidisciplinary team with expertise in hTP53rc and/or hereditary cancer syndromes in general. The following may apply [10]:

●Early detection may allow avoidance of more toxic therapies and extensive surgeries, especially since some individuals develop second tumors in the same tissue. (See 'Cancer surveillance' above.)

●Radiation is avoided when possible due to the increased risk of radiation-induced sarcoma, especially under age 30 years. (See "Li-Fraumeni syndrome", section on 'Radiation-associated cancers'.)

•Breast cancer can be treated with mastectomy rather than lumpectomy plus radiation.

•Sarcomas often require radiation. The efficacy may be reduced in individuals with hTP53rc.

•Lower-grade gliomas may be treated without radiation; higher-grade gliomas generally are treated with radiation.

●Crosslinking agents (nitrogen mustard, mitomycin, psoralen, platinum compounds) may increase the risk of secondary cancers. These should be avoided if possible (if an alternative exists).

FIRST-DEGREE RELATIVES (TESTING AND COUNSELING) — If a familial variant in TP53 has been identified, testing first-degree relatives is useful (algorithm 1). Testing as early as infancy is reasonable due to the early age of tumor onset.

●A positive finding can facilitate early initiation of cancer surveillance and treatment.

●Negative results allow avoidance of the burdens of surveillance and psychological stress related to increased cancer risk.

Testing should be coordinated with counseling from a specialist (genetic counselor, clinical geneticist, oncologist with expertise in hereditary cancer syndromes) who can provide information about potential results and their implications. In some countries, such as the United Kingdom, only a genetics specialist can request this testing.

RESOURCES

Locating a genetics specialist or oncologist — The following provide listings:

●Clinical geneticists – American College of Medical Genetics and Genomics (ACMG)

●Genetic counselors – National Society of Genetic Counselors (NSGC)

●National Institutes of Health (NIH) Cancer Genetics Services Directory

●British Society for Genetic Medicine (directory)

UpToDate topics

●Li-Fraumeni syndrome (LFS) – (See "Li-Fraumeni syndrome".)

●Hereditary breast cancer – (See "Overview of hereditary breast and ovarian cancer syndromes".)

●Sarcoma – (See "Pathogenetic factors in soft tissue and bone sarcomas" and "Overview of multimodality treatment for primary soft tissue sarcoma of the extremities and superficial trunk".)

●Brain tumors – (See "Classification and pathologic diagnosis of gliomas, glioneuronal tumors, and neuronal tumors" and "Overview of the management of central nervous system tumors in children" and "Initial treatment and prognosis of IDH-wildtype glioblastoma in adults" and "Treatment and prognosis of IDH-mutant astrocytomas in adults".)