Familial adenomatous polyposis (FAP): APC gene, polyps and bowel cancer risk

In most people a polyp in the bowel is an occasional finding. In classic FAP, the NHS Genomics Education Programme describes polyp numbers in the hundreds to thousands, beginning from the late teens. The polyps are adenomas, which are not cancer, but each one has the potential to become cancerous and with so many the chance that at least one does is very high. Cancer Research UK says that people with classic FAP will almost certainly develop bowel cancer by the age of 45 if they do not have treatment.

There is a milder form, called attenuated FAP or AFAP. People with AFAP have fewer polyps, which usually appear later, and Cancer Research UK puts their cancer risk lower than classic FAP at around 7 in 10. The severity varies between families and the NHS Genomics Education Programme warns that genotype alone should not be used to guide an individual's management.

Polyps can also form in the stomach and duodenum, and FAP is linked to other findings: thyroid cancer, a liver tumour of early childhood called hepatoblastoma, brain tumours, adrenal adenomas, desmoid tumours (non-cancerous but locally invasive growths of connective tissue) and, in some people, harmless pigmented spots in the retina, dental changes and bony lumps called osteomas.

Cancer Research UK describes the APC change as one that can cause hundreds of non-cancerous growths, called polyps, to develop in the bowel. The change is present from birth, but polyps are usually picked up in the teens and twenties, which fits with the general principle Cancer Research UK states that further gene changes are needed before problems develop.

FAP is autosomal dominant. Each child or sibling of someone with an inherited APC change has a 50% chance, or 1 in 2, of inheriting it, according to the NHS Genomics Education Programme. The programme notes that 20% to 25% of APC changes arise de novo, meaning neither parent carries it. A person may therefore be the first in the family to have FAP, and may later pass it on in the usual 1 in 2 pattern. Mosaicism, where only some cells carry the change, is not unusual either.

Cancer Research UK distinguishes this from MUTYH-associated polyposis, where a person needs a changed copy of the MUTYH gene from each parent to be affected. FAP needs only one changed copy.

The National Genomic Test Directory sets who is eligible. A polyposis panel that includes APC is offered to people with colorectal, endometrial or small bowel cancer before 40, people with colorectal cancer and five or more adenomas, people with several adenomas at younger ages, and some families with several siblings affected by bowel or womb cancer. A single-gene APC test is available for people with features that can come before polyps, such as multifocal retinal pigment spots, desmoid tumours, hepatoblastoma, multiple osteomas of the skull and jaw, or a specific type of papillary thyroid cancer.

Once a family variant is known, other relatives can be offered a predictive test. Because bowel checks begin in the early teens and liver surveillance in infancy may be considered, the NHS Genomics Education Programme says predictive testing in children may be appropriate after counselling, unlike most adult-onset cancer genes.

The NHS says genetic testing is done on a blood or saliva sample after referral by a hospital specialist, and that a genetic counsellor can help families think through the implications.

Because polyps may be evident from early adolescence, colonoscopy surveillance normally begins at age 12 to 14, repeated every one to three years according to polyp burden. Surgery is considered when polyps exceed 10 mm, when there is high-grade dysplasia in a polyp, or when the number of polyps rises significantly between examinations. How much of the bowel is removed can be guided by the individual pattern of disease.

An upper gut examination (oesophagogastroduodenoscopy) is advised from age 25 to manage stomach and duodenal polyps, with frequency based on polyp burden and a grading system called Spigelman. The usefulness of routine thyroid screening is uncertain and it is not recommended outside research. Hepatoblastoma surveillance is unproven, and risk is highest before five years of age.

Chemoprevention with drugs such as sulindac is still being researched and is not currently recommended. The NHS Genomics Education Programme says care is best provided by an expert centre as part of the Polyposis Rare Disease Collaborative Network, because the lifelong care of FAP is specialised.

Because colonoscopy begins in the early teens and surgery may be needed in early adulthood, the condition shapes adolescence and the years that follow. The NHS Genomics Education Programme says the extent of bowel removal can be guided by the individual pattern of disease, so it is worth asking the specialist team what the options are and how each would affect day-to-day bowel function before agreeing a date.

Adults also need continued checks of the remaining bowel and the upper gut, and attention to non-bowel features such as desmoid tumours. Where a family variant is known, a predictive test can establish which relatives need this programme and which can follow population screening.

The Human Fertilisation and Embryology Authority has approved pre-implantation genetic testing (PGT-M) for couples in whom a parent carries an APC variant. A clinical geneticist or genetic counsellor can explain this and the other routes the NHS Genomics Education Programme lists, which include prenatal testing, gamete donation and adoption.