Syndrome

A syndrome is a medical term that describes a collection of signs, symptoms, or characteristics that tend to occur together and are associated with a particular condition or disease. Some syndromes are inherited and caused by genetic changes passed from parents to children, while others may result from environmental factors, infections, or a combination of different influences.

What causes a syndrome?

The causes of a syndrome depend on the specific condition. In the case of familial cancer syndromes, the primary cause is a genetic mutation that affects the normal function of particular genes. These mutations may disrupt how cells grow, divide, or repair DNA damage, increasing the risk of developing cancer. Familial cancer syndromes are often inherited in families through autosomal dominant or autosomal recessive patterns.

What is the risk of inheriting a familial cancer syndrome?

The risk of inheriting a familial cancer syndrome depends on how the syndrome is transmitted through families. Most familial cancer syndromes are inherited in an autosomal dominant or autosomal recessive pattern. These patterns refer to how the gene associated with the syndrome is passed from parents to children.

Autosomal dominant inheritance

In autosomal dominant syndromes, a person only needs to inherit one copy of the altered gene from one parent to be at risk of developing the syndrome.

• Risk of inheritance: If one parent carries the gene mutation, there is a 50% chance that each child will inherit the mutation and the syndrome. This risk is the same for each pregnancy, regardless of whether other siblings have inherited the mutation.
• Examples: Lynch syndrome, hereditary breast and ovarian cancer syndrome (BRCA1/BRCA2), and Li-Fraumeni syndrome are all inherited in an autosomal dominant pattern.

Autosomal recessive inheritance

In autosomal recessive syndromes, a person must inherit two copies of the altered gene, one from each parent, to develop the syndrome. If a person inherits only one altered copy, they are considered carriers but typically do not develop the syndrome themselves.

• Risk of inheritance:
  • If both parents are carriers (each has one altered copy of the gene):
    • There is a 25% chance that a child will inherit two altered copies and develop the syndrome.
    • There is a 50% chance that a child will inherit one altered copy and be a carrier.
    • There is a 25% chance that a child will inherit no altered copies and neither develop the syndrome nor be a carrier.
  • If one parent is a carrier and the other parent does not carry the gene mutation, there is no risk of the child developing the syndrome, but there is a 50% chance the child will be a carrier.
• Examples: Syndromes inherited in an autosomal recessive pattern include MUTYH-associated polyposis (MAP).

Understanding the inheritance pattern helps families assess risk and informs decisions about genetic testing and counseling. Genetic counseling can provide detailed information about inheritance risks and help individuals make informed choices about screening and preventive measures.

What are the most common types of familial cancer syndrome?

Lynch syndrome (hereditary nonpolyposis colorectal cancer)

• Genes involved: MLH1, MSH2, MSH6, PMS2, and EPCAM
• Transmission: Autosomal dominant
• Associated cancers: Colorectal, endometrial, ovarian, stomach, small intestine, urinary tract, and others.
• Cancer risk: Up to 70% lifetime risk of colorectal cancer and up to 50% risk for endometrial cancer, depending on the gene mutation.

BRCA1 and BRCA2-related hereditary breast and ovarian cancer syndrome

• Genes involved: BRCA1 and BRCA2
• Transmission: Autosomal dominant
• Associated cancers: Breast, ovarian, prostate, and pancreatic cancers.
• Cancer risk: The lifetime risk of breast cancer is 50–85%, and ovarian cancer risk is 20–40%, depending on the gene mutation.

Familial adenomatous polyposis (FAP)

• Genes involved: APC
• Transmission: Autosomal dominant
• Associated cancers: Colorectal, duodenal, thyroid, and others.
• Cancer risk: Nearly 100% risk of colorectal cancer without preventive measures.

Li-Fraumeni syndrome

• Genes involved: TP53
• Transmission: Autosomal dominant
• Associated cancers: Breast, brain, soft tissue sarcoma, osteosarcoma, and others
• Cancer risk: Over 90% lifetime risk of developing any cancer.

Peutz-Jeghers syndrome

• Genes involved: STK11 (LKB1)
• Transmission: Autosomal dominant
• Associated cancers: Gastrointestinal (stomach, colon, pancreas), breast, ovarian, and testicular cancers.
• Cancer risk: The lifetime risk of cancer ranges from 37% to 93%, depending on the type of cancer.

Cowden syndrome

• Genes involved: PTEN
• Transmission: Autosomal dominant
• Associated cancers: Breast, thyroid, endometrial, and kidney cancers.
• Cancer risk: Up to 85% lifetime risk of breast cancer and 35% risk of thyroid cancer.

Von Hippel-Lindau syndrome

• Genes involved: VHL
• Transmission: Autosomal dominant
• Associated cancers: Kidney cancer, pheochromocytoma, and hemangioblastoma.
• Cancer risk: Up to 70% lifetime risk of kidney cancer.

Retinoblastoma syndrome

• Genes involved: RB1
• Transmission: Autosomal dominant
• Associated cancers: Retinoblastoma (eye cancer), osteosarcoma, and soft tissue sarcomas.
• Cancer risk: Nearly 90% risk of retinoblastoma in early childhood if the gene mutation is inherited.

Multiple endocrine neoplasia type 1 (MEN1)

• Genes involved: MEN1
• Transmission: Autosomal dominant
• Associated cancers: Parathyroid, pancreatic, and pituitary tumours.
• Cancer risk: The lifetime risk of cancer varies but is significant for endocrine organs.

Multiple endocrine neoplasia type 2 (MEN2)

• Genes involved: RET
• Transmission: Autosomal dominant
• Associated cancers: Medullary thyroid cancer, pheochromocytoma, and parathyroid tumours.
• Cancer risk: Nearly 100% risk of medullary thyroid cancer if untreated.

How do doctors test for familial cancer syndromes?

Doctors use genetic testing to diagnose familial cancer syndromes. This process involves analyzing a person’s DNA for specific genetic mutations associated with known syndromes. Testing is often recommended if there is a strong family history of cancer or if a patient develops cancer at a young age.

The testing process typically includes:

1. Detailed family history: Doctors collect information about the types of cancer in the family, the ages at diagnosis, and whether there are patterns that suggest a genetic cause.
2. Genetic counseling: Genetic counselors explain the potential benefits, risks, and implications of genetic testing before testing.
3. DNA testing: A blood or tissue tests for mutations in genes linked to familial cancer syndromes.
4. Result interpretation: A positive result indicates the presence of a genetic mutation, while a negative result may suggest no known mutations but does not entirely rule out inherited risk.

Testing helps patients understand their cancer risk and allows doctors to recommend tailored screening and preventive measures to reduce the likelihood of developing cancer.