Clinical implications of p53 gene defects

General information about the P53 gene

The p53 gene is found on chromosome 17p13.1 and encodes the tumor protein p53 (PT53). This is an oncoprotein that plays a major role in the fate of cells containing altered DNA. The roles of PT53 are to enable the repair of damaged DNA by delaying the cell cycle, or initiating programmed cell death (apoptosis).

More than 300 defects in the p53 gene have been identified, which lead to a lack of the normally activated p53 protein, thus allowing cells containing altered DNA to proliferate uncontrollably, favoring the appearance of neoplasia. These cancers appear since childhood and are grouped in the Li-Fraumeni syndrome. The syndrome is characterized by autosomal dominant transmission and brings together a multitude of neoplasias, such as sarcoma, breast cancer, leukemia and adrenal cancer, being also known as SBLA syndrome (Sarcoma, Breast, Leukemia and Adrenal Gland cancer syndrome).

What are the symptoms associated with P53 gene defects

Children with p53 gene mutations can most commonly develop osteosarcomas, adrenal carcinoma, central nervous system tumors (choroid plexus carcinoma, medulloblastoma, and glial tumors), and soft tissue sarcomas. In adults, breast neoplasms (all female), soft tissue sarcomas (rhabdomyosarcoma), leukemias, brain tumors, adrenal carcinoma, and to a lesser extent colorectal carcinoma, melanoma, gastric cancer, Wilms’ tumor, and lymphoma have been found.

Alteration of the p53 gene increases the risk of secondary neoplasia (57% within 30 years of the first cancer1), with cases being cited where affected patients developed 3 or even 4 distinct successive cancers.

There is a close link between Li-Fraumeni syndrome and radiation-induced cancers.

The risk of developing neoplasia in the female sex is 100% during life and 90% at the age of 60 years. In men, the risk is lower, being 73% throughout life.

Types of cancers

Sarcoma represents 25% of Li-Fraumeni syndrome cancers. All types of soft tissue neoplasia can occur in families with Li-Fraumeni syndrome, except Ewing’s sarcoma. The average age of appearance is around 15 years. Rhabdomyosarcoma occurs most frequently at ages under 5 years.

Breast cancer is common in females with p53 mutations, especially in the premenopausal period, with the average age of onset being 33 years. Treatment is mastectomy, not radiation therapy, given the risk of new radiation-induced tumors. The risk of contralateral breast cancer in women with p53 mutations is 4-7% per year, double that of BRCA carriers.

Brain tumors such as gliomas, astrocytomas, medulloblastomas, choroid plexus carcinomas have often been described in patients with Li-Fraumeni syndrome, children or adults.

Adrenal carcinomas are strongly associated with congenital mutations of the p53 gene in both children and adults.

What are the ways of diagnosis?

The definitive diagnosis of Li-Fraumeni syndrome is represented by the objectification of mutations in the p53 gene (deletions, duplications, etc.). Several diagnostic criteria have been described:

Classic Li-Fraumeni syndrome criteria (all):

• a proband with sarcoma diagnosed at age less than 45 years;
• a first-degree relative diagnosed with any type of cancer under the age of 45;
• a first or second degree relative diagnosed with any type of cancer under the age of 45 or sarcoma at any age.

Birch criteria (all):

• a person with any pediatric cancer, sarcoma, brain tumor or adrenal tumor diagnosed before the age of 45;
• a first or second degree relative diagnosed at any age with a cancer specific to Li-Fraumeni syndrome such as sarcoma, breast cancer, brain cancer, adrenal tumors, or leukemia;
• a first or second degree relative diagnosed with any cancer before the age of 60.

Chompret criteria (one of the following):

• a proband with:
  • a tumor belonging to the Li-Fraumeni syndrome (soft tissue sarcoma, osteosarcoma, premenopausal breast cancer, brain tumors, adrenal carcinoma, leukemia or bronchoalveolar cancer) before the age of 45;
  • at least one first- or second-degree relative with tumors belonging to Li-Fraumeni syndrome (excluding breast cancer if the proband has breast cancer) before age 56 or with multiple tumors.
• one proband with multiple tumors (excluding multiple breast cancers), 2 belonging to Li-Faumeni syndrome and the first occurring before 46 years of age.
• a proband who is diagnosed with adrenal carcinoma or choroid plexus tumor, independent of family history.

When a differential diagnosis is recommended

Li-Fraumeni syndrome must be differentiated from:

• Pathogenic BRCA1 and BRCA2 variants: increased risk of premenopausal breast cancer or ovarian cancer, but also prostate cancer, melanoma or pancreatic cancer.
• Lynch syndrome: mutations in MLH1, MSH2, MSH6, PMS1, PMS2 cause hereditary non-polyposis colorectal carcinoma.

Neoplastic screening:

Patients at high risk of Li-Fraumeni syndrome, i.e. those who fulfill the classic Li-Fraumeni syndrome criteria or the Chompret criteria, those with a family history of neoplasia, or women with early-onset breast cancers (<31 years) and who do not have BRCA1 or BRCA2, patients with adrenal carcinoma, choroid plexus or sarcomas in the pediatric period (except Ewing's sarcoma), should be investigated extensively (including for the determination of pathogenic variants of p53).

Patients with a family history of p53 mutations require genetic testing for p53, and follow-up is recommended for early detection of various neoplasias.

Prenatal testing should be done when either parent has p53 mutations.

Neoplastic surveillance strategies have been developed for those who present a high risk, based on the history of cancers within the Li-Fraumeni syndrome, to identify p53 mutations, or of increased familial risk of Li-Fraumeni but without a positive genetic test.

Thus, pediatric screening in children with p53 mutations is performed by physical examination, ultrasound of the abdomen/pelvis (for adrenal carcinoma), brain MRI (for brain tumors), or total MRI (for soft tissue or bone sarcomas).

Breast cancer detection is carried out from the age of 20, through monthly self-examination of the mammary glands, biannually by a specialist and annual imaging. MRI without mammography is preferred, given the radiological susceptibility of this type of neoplasia.

For colorectal cancer, colonoscopy screening is initiated starting at age 25, once every 5 years.

Total (whole body) MRI should be done annually to detect soft tissue sarcomas or osteosarcomas.

MRI is recommended for brain tumor screening.

Thus, summarizing, the neoplastic screening methods are:

• Clinical examination at 6 months, from birth (to identify signs of precocious puberty, HTN in children);
• Total MRI, without contrast, annually, starting at birth, requiring sedation or general anesthesia in young children;
• Brain MRI (first with contrast substance, later without contrast substance), annually, starting from birth;
• Abdominal ultrasound, starting from birth to 18 years. In case of changes in the abdominal ultrasound, biochemical determinations are recommended for adrenal cancers (urinary steroids);
• Breast MRI for women starting in their 20s;
• Conoscopy, starting at age 18, every 5 years.

What are the treatment options?

The therapy of neoplasms in Li-Fraumeni syndrome does not differ from the same neoplasms of patients without this syndrome. However, the treatment of women with breast cancer is mastectomy, not radiation therapy, given the risk of radiation-induced carcinogenesis in patients with p53 mutations.

It is hoped that future treatment will include specific interventions at the level of p53, by actions on p53 mutant cells, but also by correcting the p53 mutation or the molecular cycle in which p53 is involved.

ConCluSIonS

• Li-Fraumeni syndrome is a syndrome characterized by the appearance at a young age of various neoplasias (breast, brain tumors, sarcomas and adrenal carcinomas) determined by mutations in the p53 tumor protein gene.
• The definitive diagnosis is based on the identification of pathogenic variants at the p53 level. Various criteria (classical, Birch and Chompret) have been proposed to identify susceptible individuals for molecular screening.
• Screening of individuals with pathogenic p53 variants should include MRI for breast cancer, and brain tumors, colonoscopy for colorectal cancer detection.
• Management of neoplasms in those with Li-Fraumeni syndrome should exclude radiotherapy, given the risk of radiation-induced neoplasia.

Bibliography

1. Multiple primary cancers in families with Li-Fraumeni syndrome. Hisada M, Garber JE, Fung CY, Fraumeni JF Jr, Li FP, J Natl Cancer Inst. 1998;90(8):606.
2. The relationship between radiation-induced G(1) arrest and chromosome aberrations in Li-Fraumeni fibroblasts with or without germline TP53 mutations. Boyle JM, Spreadborough A, Greaves MJ, Birch JM, Varley JM, Scott D, Br J Cancer. 2001;85(2):293.
3. Risk of Contralateral Breast Cancer in Women with and without Pathogenic Variants in BRCA1, BRCA2, and TP53 Genes in Women with Very Early-Onset (<36 Years) Breast Cancer. Hyder Z, Harkness EF, Woodward ER, Bowers NL, Pereira M, Wallace AJ, Howell SJ, Howell A, Lalloo F, Newman WG, Smith MJ, Evans DG, Cancers (Basel). 2020;12(2) Epub 2020 Feb 7.