Li–Fraumeni syndrome is a rare,

autosomal dominant In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...

hereditary disorder A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene (monogenic) or multiple genes (polygenic) or by a chromosomal abnormality. Although polygenic disorders ...

that predisposes carriers to cancer development. It was named after two American physicians,

Frederick Pei Li Frederick Pei Li (; May 7, 1940 – June 12, 2015) was a Chinese-American physician. He is most famous for his discovery, together with his colleague Joseph Fraumeni, of Li–Fraumeni syndrome, which is caused by germline mutations of the p53 t ...

and Joseph F. Fraumeni, Jr., who first recognized the syndrome after reviewing the medical records and death certificates of 648 childhood

rhabdomyosarcoma Rhabdomyosarcoma (RMS) is a highly aggressive form of cancer that develops from mesenchymal cells that have failed to fully differentiate into myocytes of skeletal muscle. Cells of the tumor are identified as rhabdomyoblasts. There are four subt ...

patients. This syndrome is also known as the sarcoma, breast, leukaemia and adrenal gland (SBLA) syndrome. The syndrome is linked to

germline mutation A germline mutation, or germinal mutation, is any detectable variation within germ cells (cells that, when fully developed, become sperm and ova). Mutations in these cells are the only mutations that can be passed on to offspring, when either a m ...

s of the

p53 p53, also known as Tumor protein P53, cellular tumor antigen p53 (UniProt name), or transformation-related protein 53 (TRP53) is a regulatory protein that is often mutated in human cancers. The p53 proteins (originally thought to be, and often s ...

tumor suppressor gene A tumor suppressor gene (TSG), or anti-oncogene, is a gene that regulates a cell during cell division and replication. If the cell grows uncontrollably, it will result in cancer. When a tumor suppressor gene is mutated, it results in a loss or re ...

, which encodes a transcription factor (p53) that normally regulates the cell cycle and prevents genomic mutations. The mutations can be inherited, or can arise from mutations early in

embryogenesis An embryo is an initial stage of development of a multicellular organism. In organisms that reproduce sexually, embryonic development is the part of the life cycle that begins just after fertilization of the female egg cell by the male spe ...

, or in one of the parent's

germ cell Germ or germs may refer to: Science * Germ (microorganism), an informal word for a pathogen * Germ cell, cell that gives rise to the gametes of an organism that reproduces sexually * Germ layer, a primary layer of cells that forms during embr ...

Presentation

Li–Fraumeni syndrome is characterized by early onset of cancer, a wide variety of types of cancers, and development of multiple cancers throughout one's life.

Pathology

LFS1: Mutations in ''TP53'' * Normal conditions: ''TP53 ''is a

on chromosome 17 that normally assists in the control of cell division and growth through action on the normal

cell cycle The cell cycle, or cell-division cycle, is the series of events that take place in a cell that cause it to divide into two daughter cells. These events include the duplication of its DNA (DNA replication) and some of its organelles, and sub ...

. TP53 typically become expressed due to cellular stressors, such as DNA damage, and can halt the cell cycle to assist with either the repair of repairable DNA damage, or can induce

apoptosis Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes ( morphology) and death. These changes in ...

of a cell with irreparable damage. The repair of "bad" DNA, or the apoptosis of a cell, prevents the proliferation of damaged cells. * Mutant conditions:

Mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, m ...

s of ''TP53'' can inhibit its normal function, and allow cells with damaged DNA to continue to divide. If these DNA mutations are left unchecked, some cells can divide uncontrollably, forming tumors (cancers). Further mutations in the DNA could lead to

malignant Malignancy () is the tendency of a medical condition to become progressively worse. Malignancy is most familiar as a characterization of cancer. A ''malignant'' tumor contrasts with a non-cancerous ''benign'' tumor in that a malignancy is not s ...

cells that can travel to, and develop cancer in, different areas of the body. Many individuals with Li–Fraumeni syndrome have been shown to be heterozygous for a ''TP53'' mutation. Recent studies have shown that 60% to 80% of classic LFS families harbor detectable germ-line ''TP53'' mutations, the majority of which are

missense mutations In genetics, a missense mutation is a point mutation in which a single nucleotide change results in a codon that codes for a different amino acid. It is a type of nonsynonymous substitution. Substitution of protein from DNA mutations Missense m ...

in the DNA-binding domain. These missense mutations cause a decrease in the ability of p53 to bind to DNA, thus inhibiting the normal ''TP53'' mechanism. * Unique Brazilian mutation: Although other mutations leading to Li–Fraumeni syndrome have been found outside the DNA-binding domain, a mutation at codon 337 of the tetramerization domain of ''TP53'' has shown a particularly high frequency. The tetramerization domain plays a major role in the oligomerization of the p53 protein, which exists as a

tetramer A tetramer () ('' tetra-'', "four" + '' -mer'', "parts") is an oligomer formed from four monomers or subunits. The associated property is called ''tetramery''. An example from inorganic chemistry is titanium methoxide with the empirical formula ...

. This mutation has only been found in Brazilian families, and is located in exon 10 of the ''TP53'' gene. The mutation causes an amino acid change from arginine to histidine at codon 337. With pH in the low to normal physiological range (up to 7.5), the mutant protein forms normal oligomers and retains its suppressor function. However, at a high physiological pH, p53 is unable to assemble into a tetramer. This unique feature may contribute to why families with this particular mutation often show

incomplete penetrance Penetrance in genetics is the proportion of individuals carrying a particular variant (or allele) of a gene (the genotype) that also express an associated trait (the phenotype). In medical genetics, the penetrance of a disease-causing mutation is t ...

. * Dominant negative mutations: Most individuals with Li–Fraumeni syndrome are heterozygous for a mutant ''TP53'' gene, and some p53 mutants can inhibit the function of the wild-type p53 in a

dominant negative In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...

manner. Mutated p53 proteins are typically more stable than wild-type, and can inhibit the activity of the wild-type protein in suppressing cell proliferation and in inducing cell cycle arrest. Due to the mutant p53 being able to inhibit some wild-type p53, damaged cells are at an even greater susceptibility to proliferate and become transformed, resulting in cancer. LFS2: mutations in ''CHEK2'' Another variant of Li–Fraumeni that remains somewhat controversial, is a mutation of the ''

CHEK2 CHEK2 (Checkpoint kinase 2) is a tumor suppressor gene that encodes the protein CHK2, a serine-threonine kinase. CHK2 is involved in DNA repair, cell cycle arrest or apoptosis in response to DNA damage. Mutations to the CHEK2 gene have been linke ...

'' (or ''CHK2'') gene. ''CHK2'' is also a

; it regulates the action of p53 and is activated by ATM, which detects DNA damage, and in this way, DNA damage information can be conveyed to p53 to indirectly arrest the cell cycle at that point for DNA repair to be able to take place or to cause apoptosis (programmed cell death). LFS-L: Families who do not conform to the criteria of classical Li–Fraumeni syndrome have been termed "LFS-like". LFS-like individuals generally do not have any detectable p53 mutations, and tend to be diagnosed on either the Birch or Eeles criteria. A third locus has been mapped to the long arm of

chromosome 1 Chromosome 1 is the designation for the largest human chromosome. Humans have two copies of chromosome 1, as they do with all of the autosomes, which are the non- sex chromosomes. Chromosome 1 spans about 249 million nucleotide base pairs, which ...

(1q23), but no gene has yet been identified. Another locus that has been linked to this syndrome is ''

CDKN2A CDKN2A, also known as cyclin-dependent kinase inhibitor 2A, is a gene which in humans is located at chromosome 9, band p21.3. It is ubiquitously expressed in many tissues and cell types. The gene codes for two proteins, including the INK4 family ...

CDKN2B Cyclin-dependent kinase 4 inhibitor B also known as multiple tumor suppressor 2 (MTS-2) or p15INK4b is a protein that is encoded by the ''CDKN2B'' gene in humans. Function This gene lies adjacent to the tumor suppressor gene CDKN2A in a regi ...

''.

Clinical

The classical LFS malignancies—sarcoma, cancers of the breast, brain, and adrenal glands—comprise about 80% of all cancers that occur in this syndrome. The risk of developing any invasive cancer (excluding skin cancer) is about 50% by age 30 (1% in the general population) and is 90% by age 70. Early-onset breast cancer accounts for 25% of all the cancers in this syndrome. This is followed by soft-tissue sarcomas (20%), bone sarcoma (15%), and brain tumors—especially

glioblastoma Glioblastoma, previously known as glioblastoma multiforme (GBM), is one of the most aggressive types of cancer that begin within the brain. Initially, signs and symptoms of glioblastoma are nonspecific. They may include headaches, personality ...

s—(13%). Other tumours seen in this syndrome include

leukemia Leukemia ( also spelled leukaemia and pronounced ) is a group of blood cancers that usually begin in the bone marrow and result in high numbers of abnormal blood cells. These blood cells are not fully developed and are called ''blasts'' or ...

lymphoma Lymphoma is a group of blood and lymph tumors that develop from lymphocytes (a type of white blood cell). In current usage the name usually refers to just the cancerous versions rather than all such tumours. Signs and symptoms may include en ...

, and adrenocortical carcinoma. About 90% of females with LFS develop breast cancer by age 60 years; the majority of these occur before age 45 years. Females with this syndrome have almost a 100% lifetime risk of developing cancer. This compares with 73% for affected males. The difference may be due to much smaller breast tissue in males and increased estrogen levels in females. The risks of sarcoma, female breast cancer, and haematopoietic malignancies in mutation carriers are more than 100 times greater than those seen in the general population. Other tumours reported in this syndrome, but not yet proved to be linked with it, include melanoma, Wilms' and other kidney tumors, hepatocellular carcinoma, gonadal germ cell, pancreatic, gastric, choroid plexus, colorectal, and prostate cancers. Around 80% of children with

adrenocortical carcinoma Adrenocortical carcinoma (ACC) is an aggressive cancer originating in the cortex (steroid hormone-producing tissue) of the adrenal gland. Adrenocortical carcinoma is remarkable for the many hormonal syndromes that can occur in patients with ste ...

and 2–10% of childhood

brain tumor A brain tumor occurs when abnormal cells form within the brain. There are two main types of tumors: malignant tumors and benign (non-cancerous) tumors. These can be further classified as primary tumors, which start within the brain, and seco ...

s have p53 mutations. About 2–3% of

osteosarcoma An osteosarcoma (OS) or osteogenic sarcoma (OGS) (or simply bone cancer) is a cancerous tumor in a bone. Specifically, it is an aggressive malignant neoplasm that arises from primitive transformed cells of mesenchymal origin (and thus a sarcoma ...

s, 9% of

s, and 7–20% of patients with multiple primary tumours have p53 mutations. Although most cases of this syndrome have early onset of cancer, cases have also been reported later in life.

Diagnosis

Li–Fraumeni syndrome is diagnosed if these three criteria are met: * The patient has been diagnosed with a sarcoma at a young age (below 45). * A first-degree relative has been diagnosed with any cancer at a young age (below 45). * Another first- or a second-degree relative has been diagnosed with any cancer at a young age (below 45) or with a sarcoma at any age. Other criteria have also been proposed: * A proband with any childhood cancer or sarcoma, brain tumor or adrenal cortical carcinoma diagnosed before age 45 * A first- or second-degree relative with a typical LFS malignancy (sarcoma, leukaemia, or cancers of the breast, brain or adrenal cortex) regardless of age at diagnosis * A first- or second-degree relative with any cancer diagnosed before age 60 A third criterion has been proposed: * Two first- or second-degree relatives with LFS-related malignancies at any age.

Management

Genetic counseling Genetic counseling is the process of investigating individuals and families affected by or at risk of genetic disorders to help them understand and adapt to the medical, psychological and familial implications of genetic contributions to disease; t ...

and

genetic testing Genetic testing, also known as DNA testing, is used to identify changes in DNA sequence or chromosome structure. Genetic testing can also include measuring the results of genetic changes, such as RNA analysis as an output of gene expression, or ...

are used to confirm that somebody has this gene mutation. Once such a person is identified, early and regular screenings for cancer are recommended for them as people with Li–Fraumeni are likely to develop another primary malignancy at a future time (57% within 30 years of diagnosis).

Chompret criteria

A 2015 revision of the traditional Chompret criteria for screening has been proposed—a

proband In medical genetics and other medical fields, a proband, proposito (male proband), or proposita (female proband)Bennett, RL. The Language of the Pedigree. In: ''The Practical Guide to the Genetic Family History''. Wiley-Liss. is a particular subjec ...

who has: * A tumor belonging to LFS tumor spectrum (e.g., premenopausal breast cancer, soft tissue sarcoma, osteosarcoma, CNS tumor, adrenocortical carcinoma) before age 46 years, and at least one first- or second-degree relative with LFS tumor (except breast cancer if the proband has breast cancer) before age 56 years or with multiple tumors at any age * Multiple tumors (except multiple breast tumors), two of which belong to LFS spectrum with the initial cancer occurring before the age of 46 years * An adrenocortical carcinoma, choroid plexus tumor, or rhabdomyosarcoma of embryonal anaplastic subtype, at any age of onset, irrespective of family history * Breast cancer before age 31

Recommendations

Recommendations for individuals from families affected by the syndrome include: * Avoidance of radiation therapy to reduce risk of secondary radiation-induced malignancies * Children and adults undergo comprehensive annual physical examination * Women undergo age-specific breast cancer monitoring beginning at age 25 years * All patients consult a physician promptly for evaluation of lingering symptoms and illnesses

Suggestions

* Adults should undergo routine screening for

colorectal cancer Colorectal cancer (CRC), also known as bowel cancer, colon cancer, or rectal cancer, is the development of cancer from the colon or rectum (parts of the large intestine). Signs and symptoms may include blood in the stool, a change in bowel ...

beginning no later than age 25 years. * Individuals should undergo organ-targeted surveillance based on the pattern of cancer observed in their families. * Prophylactic

mastectomy Mastectomy is the medical term for the surgical removal of one or both breasts, partially or completely. A mastectomy is usually carried out to treat breast cancer. In some cases, women believed to be at high risk of breast cancer have the operat ...

to reduce the risk of breast cancer is an option.

Epidemiology

Li–Fraumeni syndrome (LFS) is rare; as of 2011, cases had been reported in more than 500 families. The syndrome was discovered using an epidemiological approach. Li and Fraumeni identified four families in which siblings or cousins of rhabdomyosarcoma patients had a childhood sarcoma, which suggested a familial cancer syndrome. Identification of ''TP53''s the gene affected by mutation was suggested by the same approach. Over half of the cancers in LFS families had been previously associated with inactivating mutations of the p53 gene and in one primary research study, DNA sequencing in samples taken from five Li–Fraumeni syndrome families showed autosomal dominant inheritance of a mutated ''TP53'' gene.