TP53 

 TP53 -Related Cancer Risk

Germline pathogenic mutations in the TP53 gene are associated with an increased risk for developing certain types of cancer in both men and women. For example, women who have a germline pathogenic  TP53  mutation are up to 6 times more likely to develop breast cancer as compared to the general population. People with a germline pathogenic mutation in the  TP53  gene have a hereditary condition called Li-Fraumeni syndrome.

The main types of cancers that have been linked to Li-Fraumeni syndrome include, sarcomas (tumors of the bones or connective tissue), brain tumors, adrenocortical carcinomas (cancer of the outer layer of the adrenal glands), multiple breast cancers, and childhood cancers. A variety of other cancers, such as leukemias (cancers of the blood), gastrointestinal (colorectal, stomach), genitourinary (kidney, endometrial, ovarian, prostate), lung cancers, and others have been described in individuals with Li-Fraumeni syndrome. The lifetime risk of individuals with Li-Fraumeni syndrome developing cancer is high, and many individuals experience multiple cancer diagnoses. A large number of the cancer diagnoses in people with Li-Fraumeni syndrome occur early in life, during infancy, childhood, and early adulthood.

Recent data indicates that some families with germline  TP53  mutations may have lower cancer risks and later onset of cancer compared to what has historically been described in Li-Fraumeni syndrome. Further research is needed to understand the importance of certain germline  TP53  mutations and family history on lifetime cancer risk.

Importantly, at this time, all individuals found to have a germline pathogenic  TP53  mutation are recommended to follow Li-Fraumeni syndrome medical management recommendations (described below), even in the absence of strong personal and family cancer histories.

 TP53 cancer screening and risk-reducing options

The best long-term medical management for individuals who carry a germline mutation in the TP53 gene is a topic of on-going research. The below recommendations are based upon a recent expert panel review (reference 4).

Children:

  • Complete physical examination every 3–4 months, including:
    • blood pressure
    • growth measurements (with attention to rapid increase in weight or height)
    • physical appearance assessment
    • full neurologic assessment
  • Prompt assessment with primary care physician for any medical concerns
  • Ultrasound of abdomen and pelvis every 3–4 months
  • Possible blood tests performed every 3–4 months:
    • total testosterone
    • dehydroepiandrosterone sulfate
    • androstenedione
  • Annual brain Magnetic Resonance Imaging (MRI)
  • Annual Whole Body MRI

Adults:

  • Complete physical examination every 6 months
  • Prompt assessment with primary care physician for any medical concerns
  • Annual brain MRI
  • Upper endoscopy and colonoscopy every 2–5 years beginning by age 25 years
  • Annual dermatologic examination beginning by age 18 years

For women:

  • breast self-awareness beginning at age 18.
  • clinical breast examination by a healthcare provider twice a year starting by age 20 years
  • annual breast MRI (performed 6 months after annual Whole Body MRI – see below).
  • risk-reducing mastectomy may also be considered
  • Annual Whole Body MRI (as mentioned above, in women this exam should be separated from the annual breast MRI by 6 months)
  • Annual Ultrasound of abdomen and pelvis (separated from the annual Whole Body MRI by 6 months)
  • Avoid radiation exposure given the potential association with increased risk for new cancer diagnoses.

 TP53 associated therapeutic/ treatment implications

Individuals who have a cancer diagnosis and an identified germline pathogenic  TP53  mutation should speak with their treating physician about the availability of targeted/personalized treatment options.

Clinical trials for individuals who have a pathogenic mutation in the  TP53  gene might be available now or in the future.

 TP53 testing in other family members

Genetic testing in family members is recommended. It is also recommended that family members discuss the risks, benefits, and limitations of genetic testing with their physician and/or genetic counselor.  Family members found to carry a germline pathogenic TP53 gene mutation should consider the increased cancer screening and risk reducing surgical options discussed above. Family members who do not carry the  TP53  mutation known to be in their family should speak with their medical providers regarding remaining risks for cancer.

Family members who are considering having children should speak with a genetic counselor to discuss risks of passing on a germline pathogenic  TP53  mutation to offspring before conceiving. Genetic test results may be used by some individuals for reproductive decision-making including the use of pre-implantation genetic diagnosis (PGD), donor gametes, or adoption.

Future considerations

As research continues to evolve, physicians and researchers will gain a better understanding of how a germline pathogenic  TP53  mutation will guide medical care. Because the information provided to patients will almost certainly change, those with a germline pathogenic  TP53 mutation are encouraged to keep in touch with their medical providers in order to receive updates.

References:

  1. Ruijs MW, Verhoef S, Rookus MA et al. TP53 germline mutation testing in 180 families suspected of Li-Fraumeni syndrome: Mutation detection rate and relative frequency of cancers in different familial phenotypes. J Med Genet. 2010; 47:421-428.
  2. Schneider K, Zelley K, Nichols KE, Garber J. Li-Fraumeni syndrome.    Last updated 4/11/2013.  Accessed 4/5/2018. https://www.ncbi.nlm.nih.gov/books/NBK1311/.
  3. Rana HQ, GelmanR, LaDuca H, et al. Differences in TP53 Mutation Carrier Phenotypes Emerge from Panel-Based Testing. JNCI 2018. doi: 10.1093/jnci/djy001. [Epub ahead of print]
  4. Kratz CP, Achatz MI, Brugieres L, et al. Cancer Screening Recommendations for Individuals with Li-Fraumeni syndrome. Clin Cancer Res 2017; 23:e38-e45.