Cancer is a genetic disease. It is caused by DNA mutations that lead to disruption of normal processes in the cell, leading to the uncontrolled growth of that cell. However, the words “genetic” and “hereditary” are often confused, leading people to believe cancer is inheritable.
Most cancers are caused by genetic factors, lifestyle choices and exposure to environmental carcinogens. Some forms of cancer, however, can be inherited. For example, approximately 45-90% of women with a faulty copy of BRCA1 or BRCA2 gene will develop breast cancer. Other cancers that seem to have an inheritable component include breast cancer, ovarian cancer, retinoblastoma, prostate cancer, etc. Find more details here.
But, what happens when you’re predisposed to have multiple cancers throughout your life? What happens when cancer runs in the family?
In 1969, two American physicians, Frederick P. Li and Joseph F. Fraumeni Jr., puzzled by a high incidence of cancer in some families, worked their way through medical records and death certificates of 648 childhood rhabdomyosarcoma patients. Rhabdomyosarcoma is a rare type of cancer that affects the musculoskeletal system.
Li and Fraumeni closely studied families with high incidence of soft tissue sarcomas, trying to establish an inheritable cause for the disease. They published their findings in Annals of Internal Medicine, where they suggested a familial cause for the high incidence of cancer in some families. But they did not know what was causing it.
I will briefly take you through the history of what is now called Li-Fraumeni Syndrome (LFS), which is responsible for an inheritable predisposition to multiple cancers.
In 1979, scientists discovered a gene they named TP53, while studying the oncogenic properties of SV40 viruses. It was later identified as the target of the SV40 virus, during the process of oncogenesis. It took a long time before scientists realised that p53 (another name for TP53) was a gene that contributed to preventing cancer, not causing it.
Ten years later, in 1989, Bert Vogelstein from John Hopkins School of Medicine revealed the true identity of p53 as a tumour suppressor, a protein that suppresses the development of cancer. An oncogene antagonist, if you may. In the following two to three years, studies on p53 increased dramatically, leading to a number of publications.
p53 is the most frequently mutated gene in human cancer, with a mutation present in almost 50% of cases. This has led to p53 being called the “Guardian of the Genome”. It is also the most studied gene in history, with 83,167 hits on PubMed!
Sometimes, a copy of the TP53 gene undergoes a germline mutation (heritable variation in germ cells). Children born from parents with a germline TP53 mutation are known to suffer from Li-Fraumeni Syndrome. Because p53 is responsible for maintaining genome integrity, loss of function of the p53 protein leads to multiple cancers throughout the life of the individual. p53 was pinpointed as being the cause of Li-Fraumeni syndrome in 1990, before which the syndrome was assumed to be caused by a virus.
People suffering from Li-Fraumeni Syndrome usually develop sarcomas, cancers of the breast, brain and adrenal glands. This is true for almost 80% of LFS cases. The risk for developing sarcomas and female breast cancer is almost 100 times greater than the general population.
In the early 1990s, Dr Maria Isabel Achatz studied a population in Brazil that had a high incidence of familial cancers, arising from a similar mutation, leading researchers to believe the population might have shared a common ancestor with the germline TP53 mutation. While this is perhaps the largest known population to have Li-Fraumeni Syndrome, Dr Achatz suggests there might be other populations with high incidence of familial cancers.
Being diagnosed with Li-Fraumeni Syndrome can be scary and depressing. In Sue Armstrong’s book p53: The Gene That Cracked The Cancer Code, Armstrong mentions a man with a family history of LFS, who after having himself tested for the mutation, committed suicide before he got the results. It was later found that he did not have the mutation.Dr Achatz has had patients with as many as 15 different tumours throughout their lives. This can be quite alarming, especially when it affects the patient at a young age. Usually, patients require counselling and emotional support from family and friends.
While Li-Fraumeni Syndrome appears to be rare, with only 400 cases reported since first being described in 1969, the effect it can have on someone suffering from the disease can be devastating. The George Pantziarka TP53 Trust in the UK is dedicated to providing support to people suffering from LFS in the UK. They also provide screening for people with supposed LFS, and help promote research related to the syndrome.
The TP53 Trust estimates that 1 in 10,000 or 1 in 25,000 people in the UK might be carriers of LFS, based upon predicted TP53 mutation rates. I am unsure about the validity of these claims, as I could not find sufficient supporting evidence.
For more information, buy Sue Armstrong’s book “p53: The Gene that Cracked the Cancer Code”. It’s an amazing book that chronicles the discovery of p53 in dizzying detail.
Do you have a question about cancer? Leave it in the comments below!