Li-Fraumeni Syndrome and Cancer
Li-Fraumeni syndrome (LFS) is a familial genetic disease with an incidence in the general population as high as 1 in 20,000. It is inherited in an autosomal dominant manner, and the mutated gene is TP53, located at chromosome 17p13.
Li-Fraumeni syndrome is one of the genetic diseases with the highest cancer risk. The risk of related cancers in LFS patients is about 50% before age 30 and about 90% before age 60. Female LFS patients have a higher cancer risk than males: the female risk is at least 90%, while the male LFS cancer risk is less than 70%. Moreover, LFS patients may develop more than one cancer in a lifetime; about 57% of LFS patients develop a second cancer, and about 38% develop a third cancer.
Therefore, if LFS is diagnosed before childbearing, it is best not to have offspring. Most members of LFS families will develop cancer; although the types of cancer they develop may differ, the root cause is all related to the TP53 mutation.
The most common malignancies associated with LFS patients include bone and soft tissue sarcomas, breast cancer, brain tumors, and adrenocortical carcinoma. In addition, LFS and LFS-like (LFL) family members also have a risk of colorectal cancer, endometrial cancer, esophageal cancer, gonadal germ cell tumors, leukemia, lymphoma, lung cancer, skin cancer (non-melanoma), neuroblastoma (NB), ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, thyroid cancer, Wilms tumor (WT), and other kidney cancers. To date, essentially only Ewing sarcoma has not appeared in LFS families; all other tumors have been reported in LFS families.
The reason the cancer risk is so high in LFS patients is that they carry mutations in TP53, a key human tumor suppressor gene. TP53 mutations have been found in about 70% of LFS families. The TP53 gene is located on chromosome 17 and is an important tumor suppressor gene in the human genome; more than half of all malignant tumors show mutations in this gene.
The human genome contains both oncogenes and tumor suppressor genes; oncogenes are the chief culprits causing carcinogenesis. But over the long course of life, we have also evolved tumor suppressor genes to counter the oncogenes, and wild-type TP53 is the most important of them all. The reason elephants, which have huge bodies, do not easily get cancer is that the elephant genome has 20 copies of TP53, whereas normal humans have only 2 copies. In LFS patients, even these 2 TP53 genes are mutated. Therefore LFS patients have lost the mechanism that suppresses oncogenes, and carcinogenesis becomes inevitable.
The diagnostic criteria for LFS syndrome are: 1. The proband (the first person in the family diagnosed with a certain genetic disease) has a sarcoma before age 45; 2. A first-degree relative has any cancer before age 45; 3. A first- or second-degree relative has any cancer before age 45, or a sarcoma at any age.
The diagnostic criteria for Li-Fraumeni-like (LFL) syndrome are: 1. The proband has any childhood cancer or sarcoma, a brain tumor, or an adrenocortical tumor before age 45; 2. A first- or second-degree relative has a typical LFS cancer at any age; 3. A first- or second-degree relative has any cancer before age 60.
The offspring of LFS patients have a high proportion of cancer, and it tends to occur at a young age. We often find "cancer families," in which most members develop cancer at some age. Children in families with congenital 17p deletion also have medical problems such as developmental delay. Genetic testing can determine whether a person has a TP53 gene mutation, and there are now some targeted treatment options for patients with TP53 mutations.
If LFS patients also have other high-risk carcinogenic factors, such as smoking, alcohol consumption, and long-term exposure to carcinogens (such as radiation), their cancer risk will rise substantially and the age of onset will be earlier. If a family is identified as an LFS family, members should begin regular early cancer screening from age 30; early detection and early treatment are the key to prolonging life. But even if carcinogenesis is detected during the in situ cancer stage and radical treatment is performed, regular early cancer screening is still needed thereafter, because there remains a high possibility of developing a second and third cancer.