Introduction

Familial adenomatous polyposis (FAP) is an autosomal dominant hereditary disorder characterized by the development of hundreds to thousands of adenomatous polyps throughout the colon. Without treatment, virtually all individuals with FAP develop colorectal cancer by 35–40 years of age, and the condition is also associated with an increased risk of several extracolonic malignancies (1). Syndromes associated with APC gene mutations include classic FAP, Gardner syndrome, less commonly Turcot syndrome, and attenuated familial adenomatous polyposis (AFAP). Gardner syndrome is characterized by the presence of typical colorectal adenomatous polyps together with osteomas, dental abnormalities, and soft tissue tumors. Turcot syndrome is characterized by colorectal polyps typical of FAP in combination with central nervous system tumors, most commonly medulloblastoma. Attenuated familial adenomatous polyposis is characterized by fewer colorectal polyps (an average of approximately 30–35) than classic FAP. These polyps also tend to undergo malignant transformation at a later age, with the average age of cancer development being approximately 36 years. They are most commonly located in the proximal colon (2). Within the spectrum of hereditary adenomatous polyposis syndromes, patients presenting with multiple adenomatous polyps most commonly have classic FAP (or one of its variants), attenuated familial adenomatous polyposis, or MUTYH-associated polyposis (MAP). When a hereditary polyposis syndrome is suspected, genetic testing is recommended. If no pathogenic APC variant is identified, targeted MUTYH gene testing should be performed because up to 20% of patients without an APC mutation carry biallelic MUTYH pathogenic variants. MAP most commonly develops in individuals older than 45 years and is frequently associated with colorectal cancer. Duodenal polyps are present in approximately one-fifth of affected individuals. Unlike FAP, MAP is generally not associated with an increased risk of other malignancies (3).

Pathophysiology

The APC gene is a tumor suppressor gene located on chromosome 5. It was identified in 1991. The normal product of the APC gene, the APC protein, protects the intestinal epithelium from excessive polyp formation and malignant transformation. When a pathogenic inherited mutation is present, this protective mechanism is lost, substantially increasing the risk of colorectal cancer. Approximately 30% of APC mutations arise de novo, meaning that neither parent carries the mutation. Loss of APC function impairs regulation of β-catenin, allowing it to accumulate within cells and stimulate abnormal cellular proliferation and adenoma formation. These molecular alterations affect the expression of multiple genes involved in cell proliferation, differentiation, migration, and apoptosis. Over time, the accumulation of additional genetic alterations promotes the progression of adenomatous polyps to colorectal carcinoma. APC inactivation is considered one of the earliest molecular events in colorectal carcinogenesis associated with FAP (1, 4). A retrospective study involving 492 patients with hereditary polyposis demonstrated that individuals carrying APC mutations at codons 0–178 or 312–412 developed polyps later in life and had longer survival than patients with mutations at codons 1249–1549, who experienced earlier disease onset and shorter survival. Approximately 1% of all colorectal cancers are attributable to FAP. The estimated prevalence is approximately 1 in 8,000 individuals. In Lithuania, 4–5 children with FAP are born each year. The prevalence of the disease is relatively constant worldwide. FAP affects individuals of all ethnic backgrounds, with men and women affected equally. The average age at the onset of colorectal polyps in classic FAP is 16 years, while the average age at colorectal cancer diagnosis is 39 years. In attenuated familial adenomatous polyposis, the average age of polyp development is approximately 36 years, and the average age of colorectal cancer diagnosis is 54 years. Patients with AFAP typically develop substantially fewer polyps, averaging approximately 30, compared with individuals with classic FAP.

Prognosis

The average life expectancy of individuals with untreated FAP is approximately 42 years. Survival improves significantly following colectomy. However, upper gastrointestinal malignancies and desmoid tumors (locally aggressive fibrous connective tissue tumors) remain the leading causes of death after colectomy. Consequently, lifelong surveillance is essential following surgical treatment. Although colectomy effectively prevents colorectal cancer, it does not eliminate the risk of extracolonic malignancies. The cumulative risk of developing any malignancy other than colorectal cancer is estimated to be approximately 11% by 50 years of age and 52% by 75 years of age. Non-specific clinical features that may raise suspicion of FAP include unexplained rectal bleeding (hematochezia), diarrhea, and abdominal pain. Dr. Vilius Kontenis Continuation in the "Internistas" magazine, Issue No.1, 2019.