Cancer Predisposition Syndromes: Diagnosis and Management

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Ryan Ripsman

         For most people, developing cancer is the result of bad luck. For people with cancer predisposition syndromes cancer can be an almost guaranteed part of life. Cancer predisposition syndromes encompass a wide variety of disorders that all increase a person’s likelihood of developing cancer. There are many different types of cancer predisposition syndromes. Some syndromes affect only specific organ systems like Neurofibromatosis type II which causes brain tumors. Other syndromes affect many different organ systems like Li-Fraumeni syndrome which increases the incidence of brain tumors, leukemia, breast tumors and adrenal gland tumors. Some syndromes which are not conventionally thought of as cancer predisposition syndromes come with an increased rate of cancer. For instance, down syndrome can be thought of as a cancer predisposition syndrome as it is associated with a higher incidence rate of leukemia.

Cancer is a disease of DNA mutations (changes in the set of instructions for producing and regulating the production of proteins). When cells acquire certain combinations of mutations in important genes, called driver mutations, cancer develops. Mutations can be classified depending on the cells they affect. The first type of mutations are somatic mutations, mutations which are only present in a small subset of cells and are not found in one’s reproductive cells. These mutations develop over the course of one’s lifetime either randomly or through exposure to mutagens, substances which cause mutations like X-ray radiation. The second type of mutations are called germline mutations. These mutations are present in every cell in a person’s body. Germlines mutations can arise spontaneously due to a random mutation in a person’s parents’ reproductive cells, or they can be passed along from parent to child. When a person has a germline mutation, this mutation has the potential to be passed on to any potential children that they may have. In general, cancer predisposition syndromes are caused by germline mutations. When a person has a germline mutation in a driver gene or in a gene that prevents cancer, this can make it more likely they will develop cancer.

         Identifying cancer predisposition syndromes can be difficult. To aid healthcare providers in this task, a set of five criteria for when one should suspect that a child has a cancer predisposition syndrome have been developed. These criteria include family history; children with cancer who have a parent or sibling who also developed cancer below the age of 45 or multiple other relatives who developed cancer at a young age should be screened for cancer predisposition syndromes. Furthermore, certain types of cancer are strongly associated with cancer predisposition syndromes. Children with these cancers should be screened for cancer predisposition syndromes. Children who have specific genetic signatures that are commonly associated with cancer predisposition syndromes should be screened as well. For example, the presence of many mutations in a small, localized area of the genome (the full set of all one’s DNA), called chromothripsis, can be a sign of Li-Fraumeni syndrome. Suspected cancer predisposition syndromes can be confirmed using genetic sequencing, the transcribing of a person’s DNA, to identify germline mutations in driver genes. Once a healthcare provider has identified a cancer predisposition syndrome, they can refer the patient to a genetic counselor who can discuss possible management options.

         Cancer predisposition syndromes are managed with a wide variety of approaches. The most common approach is continuous surveillance for the appearance of tumors. Patients with cancer predisposition syndromes may undergo routine scans to find any tumors as early as possible, so they can be treated before they become deadly. In general, MRIs are used rather than scans that use radiation like CT scans since even a bit of radiation could be dangerous to people with cancer predisposition syndromes due to its mutagenic effects. Surveillance methods will vary depending on the type of cancer associated with the syndrome. For instance, cancers predisposition syndromes that are associated with colon cancers can be surveilled using colonoscopies. If the cancers are identified early, they can be surgically removed before they have the chance to grow and become life-threatening. Even if the cancer is not found at an early stage, knowing a cancer patient has a cancer predisposition syndrome can be important as certain syndromes are associated with specific molecular targets, genetic features that can be exploited during the treatment of the tumor. For instance, children with constitutional mismatch repair deficiency disorder, a type of cancer predisposition syndrome which prevents cells from correctly fixing errors in the DNA tend to have high levels of mutations. Because of the high level of mutations, people with this disorder may be likely to respond to immune checkpoint inhibitors, a type of therapy that works best on tumors with many mutations.

For certain cancer predisposition syndromes approaches can be taken to reduce the risk of developing cancer. For instance, women with a mutation in the BRCA1 or 2 genes, who are more likely to develop breast and ovary cancer can opt to have their breasts and ovaries removed surgically. This approach has become more popular over the years after celebrity Angelina Jolie publicly announced her decision to undergo these surgeries due to her high cancer risk. 

         The future holds many possible routes for the prevention and improved treatment of cancer predisposition syndromes. In the future cancer predisposition syndromes could potentially be prevented using CRISPR-cas technology. CRISPR-cas is a technology for editing the genome. Currently, CRISPR-cas is not used on people as it has not undergone rigorous safety testing on humans yet. However, in the future, CRISPR-cas technology could be used to edit sperm or egg DNA to avoid the passing on of harmful mutations from parents to children. In addition to prevention, better methods for the surveillance of people with cancer predisposition syndromes are being developed. One such method takes advantage of small DNA fragments present in a person’s plasma, the liquid part of one’s blood, called cell-free DNA. This DNA comes from cells in multiples areas of the body. In some cancer patients, tumor DNA can be identified amidst these fragments based on their mutations. This potentially opens the door for the early identification of cancer using blood in patients with a cancer predisposition syndromes like Li-Fraumeni Syndrome. This could improve the quality of life in people with these syndromes, as getting a blood test is much easier than getting routine MRIs.

Edited by Manisit Das

Image credits: Shutterstock

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