Familial Adenomatous Polyposis (FAP) and Lynch Syndrome are the two most common forms of inherited colorectal cancer predisposition, both carrying a significantly elevated lifetime cancer risk. Both conditions are passed down through families and require specialized medical management, yet they arise from distinct genetic malfunctions. FAP is characterized by a high burden of precancerous growths in the colon and rectum. In contrast, Lynch Syndrome involves a broader spectrum of malignancies with a lower polyp count. Understanding the specific differences between these two inherited disorders is necessary for proper diagnosis, surveillance, and treatment planning.
Genetic Foundations and Inheritance
Both FAP and Lynch Syndrome are inherited in an autosomal dominant pattern. This means a person needs to inherit only one copy of the altered gene, resulting in a 50% chance of passing the condition to each child. However, the specific genes involved and their biological functions differ fundamentally.
Familial Adenomatous Polyposis is caused by a germline mutation in the Adenomatous Polyposis Coli (APC) gene. Located on chromosome five, APC normally acts as a tumor suppressor, producing a protein that controls how cells grow and divide. When mutated, the resulting non-functional protein fails to regulate cell growth, leading to the uncontrolled proliferation of cells that form polyps. While most cases are inherited, approximately one-quarter of FAP diagnoses result from a spontaneous de novo mutation.
Lynch Syndrome is caused by mutations in one of several DNA Mismatch Repair (MMR) genes: MLH1, MSH2, MSH6, or PMS2. These MMR genes produce proteins that act as “spellcheckers” to correct errors that occur during DNA copying. When one of these genes is mutated, the DNA repair system fails, allowing replication errors to accumulate throughout the genome, a state known as microsatellite instability (MSI). A mutation in the EPCAM gene, which functionally silences MSH2, also causes Lynch Syndrome.
Clinical Presentation and Cancer Risk Profile
The clinical manifestation of FAP and Lynch Syndrome differs significantly regarding polyp burden and cancer location. The hallmark of classic FAP is the development of hundreds to thousands of adenomatous polyps throughout the colon and rectum, often starting in early adolescence. Without intervention, the lifetime risk of developing colorectal cancer is nearly 100%, typically diagnosed around age 39.
FAP also increases the risk for several extra-colonic cancers and non-cancerous growths. Individuals have an elevated risk for duodenal and gastric polyps, particularly cancer in the duodenum near the ampulla of Vater. Other manifestations include:
- Papillary thyroid cancer
- Medulloblastoma and hepatoblastoma (the latter primarily in young children)
- Desmoid tumors and osteomas of the jaw
- Congenital hypertrophy of the retinal pigment epithelium (CHRPE)
Lynch Syndrome is characterized by few, if any, polyps in the colon. When polyps do form, they tend to progress much more rapidly to cancer compared to those in the general population. The lifetime colorectal cancer risk for Lynch carriers is high, approaching 80% for some gene mutations. However, the defining feature of Lynch Syndrome is its association with a wide spectrum of extra-colonic cancers.
The most significant non-colorectal risk is endometrial cancer, with a lifetime risk up to 60%. Other associated cancers include:
- Ovarian cancer
- Stomach cancer
- Urinary tract cancer (renal pelvis and ureter)
- Small intestine cancer
- Pancreatic cancer
- Brain cancer
The specific MMR gene mutation influences the precise cancer risks. Mutations in MLH1 and MSH2 generally carry the highest overall risks, while MSH6 and PMS2 mutations are often associated with a later age of onset.
Diagnostic Screening and Surveillance
The differences in clinical presentation necessitate distinct strategies for diagnosis and monitoring. For FAP, diagnosis is often confirmed by identifying a pathogenic APC gene mutation through genetic testing in a patient or a family member. Predictive genetic testing is recommended for at-risk family members in childhood, as surveillance must begin early.
Endoscopic surveillance for FAP typically starts between ages 10 and 12, using annual sigmoidoscopy or colonoscopy to monitor the colon and rectum. This intense surveillance is necessary due to the rapid accumulation of polyps in classic FAP. To monitor for extra-colonic manifestations, upper gastrointestinal endoscopy is initiated around ages 20 to 25 to check for polyps in the stomach and duodenum.
For Lynch Syndrome, diagnosis often begins with tumor screening. All newly diagnosed colorectal or endometrial cancers are tested for features consistent with a faulty MMR system. This involves immunohistochemistry (IHC) to look for the absence of MMR proteins or microsatellite instability (MSI) testing. If the tumor shows evidence of MMR deficiency, germline genetic testing confirms the pathogenic mutation in an MMR gene.
The surveillance protocol for Lynch Syndrome is comprehensive and multi-organ. Colonoscopy is recommended every one to two years, starting between ages 20 and 25, or earlier based on the youngest age of cancer diagnosis in the family. Women require annual screening for endometrial cancer, which may involve transvaginal ultrasound and endometrial biopsy. Screening for urinary tract cancers may also be performed using urine cytology.
Management and Treatment Protocols
The long-term management of FAP and Lynch Syndrome differs significantly, particularly regarding the necessity and scope of prophylactic surgery. Due to the nearly inevitable progression to colorectal cancer, the primary treatment for classic FAP is prophylactic surgery to remove the entire colon, typically performed between ages 16 and 20. This procedure is either a total colectomy with ileorectal anastomosis or a total proctocolectomy with ileal pouch-anal anastomosis.
The goal of this extensive surgery is to drastically reduce the lifetime colorectal cancer risk, which is unmanageable due to the hundreds of polyps. Patients who retain a portion of their rectum or an ileal pouch require continued endoscopic surveillance every six to twelve months, as the remaining tissue still carries a cancer risk. Chemoprevention agents, such as nonsteroidal anti-inflammatory drugs (NSAIDs), may be used as an adjunct to suppress polyp growth, but they do not replace surgical intervention.
For Lynch Syndrome, management focuses on targeted risk reduction and cancer treatment rather than removing the entire large intestine. Prophylactic removal of the colon is generally not mandated because the polyp burden is low. Surgery is typically reserved for confirmed cancers or for risk reduction in highly affected organs.
For women with Lynch Syndrome, risk-reducing gynecologic surgery is common, often involving a prophylactic hysterectomy and bilateral salpingo-oophorectomy after childbearing is complete, usually around age 40. If colorectal cancer is diagnosed, a subtotal colectomy is often performed instead of a segmental resection. This removes a larger portion of the colon, reducing the high risk of a new cancer developing. Chemoprevention with daily low-dose aspirin is also recommended for many Lynch carriers to help lower the risk of associated cancers.