Adenomatous polyposis syndromes

Familial adenomatous polyposis, due to mutation in the APC gene, was the first adenomatous polyposis syndrome described. However, adenomatous polyposis may also be due to recessive MUTYH-associated polyposis (MAP) or an increasing number of other conditions, such as polymerase proofreading-associated polyposis (PPAP).

Familial adenomatous polyposis (FAP)

FAP is caused by constitutional mutations in the APC gene, which encodes APC, a key component of the wnt signalling pathway, has a prevalence of about 1/8,500. It is a multi-system disorder characterised by the development of usually hundreds to thousands of colorectal adenomatous polyps, a very high risk of colorectal cancer, as well as upper GI polyps and cancer.  It has many extra-colonic manifestations, such as desmoid tumour, and a number of established genotype-phenotype correlations.  Management is directed at surveillance and prophylactic surgery.

Attenuated FAP (AFAP), when patients develop anywhere from 0 to 100+ adenomas, can also be due to particular mutations in APC. A similar phenotype can be due to mutations in other genes, including MUTYH and POLD1/POLE.

Genetics

FAP is caused by dominantly inherited mutations in APC.  At least 10% of cases arise de novo, and mosaicism is not uncommon.

Patients with mutations in the ‘Mutation Cluster Region’ develop the highest number of polyps and have the highest risk of colorectal cancer at a younger age. Patients with mutations in the 5’ or 3’ regions or exon 9 may develop attenuated FAP (AFAP), where the number of adenomas is reduced compared to FAP.  Indeed, some patients may develop no adenomas and yet still be at risk of colorectal cancer.

Mutations causative of FAP and AFAP are essentially all truncating or nulling.  True missense mutations may confer a small increased risk of polyps, but two mutations (APC p.I1307K and E1317Q) confer a modest degree of risk due to special mechanisms.

Risks

FAP-related tumours include:

  • Colon and rectum: adenomas and cancer
  • Gastric fundal polyps (benign)
  • Duodenal adenomas and cancer
  • Thyroid cancer
  • Desmoid tumours
  • Hepatoblastoma
  • Adrenal adenoma
  • CNS tumours

Other features include:

  • Osteomas
  • Epidermoids cysts
  • Abnormal dentition
  • Congenital hypertrophy of the retinal pigment epithelium (CHRPE)

 

Laboratory testing

APC mutations causing FAP vary from single-nucleotide changes to large chromosomal changes. As well as de novo mosaicism, laboratories should be aware that some APC mutations may occur deep within introns.

Management

Predictive genetic testing can be offered when the underlying mutation has been defined in a family member. Prophylactic colectomy or proctocolectomy is the mainstay, with the main issues surrounding timing and type of surgery. Upper GI surveillance is usually recommended.

A number of guidelines covering clinical management are available, covering the management of FAP overall, as well as specific aspects such as desmoids and adrenal masses.

MUTYH-associated adenomatous polyposis (MAP)

MAP predisposes to colorectal adenomas and carcinoma, the numbers of adenomatous polyps being in the tens to hundreds, rather than hundreds to thousands as seen in FAP, so it overlaps clinically with FAP and attenuated FAP (AFAP) due to APC mutation. It is caused by the recessive inheritance of biallelic mutations in MUTYH, which encodes mutY-homologue, a component of the oxidative DNA damage repair pathway.

Carrier frequency in most populations is between 1/100 and 1/200, so pseudodominant inheritance is quite possible and has been observed. Note should be taken of consanguinity.

Notably, tumours due to MAP may loose MMR protein expression due to somatic hits in such tumours, and thus exhibit MSI, and appear to be due to LS when they are not (Lynch-like syndrome). In addition, as gene panel testing becomes more available, patients are being found who,intriguingly, have a single mutation in MUTYH and  a variant in another colorectal adenoma/carcinoma predisposition gene.

Laboratory testing

There are two common MUTYH point mutations in Northern Europeans, p.Tyr179Cys and p.Gly396Asp, that together account for approximately 85% of mutant alleles. The remaining 15% are other point mutations of all classes.

In other population groups p.Glu480X is the prevalent Indian mutation, whereas p.Tyr104* is prevalent in Pakistanis. Larger-scale mutations involving whole exons are uncommon.

Note that the current reference sequence in use for MUTYH is NM_001128425.1 6 .  However due to two other reference sequences used historically, mutations may appear in reports and the literature under one of three different numbering systems.

Risks

Colorectal adenomas and carcinomas are the main feature, with a lifetime risk of cancer in excess of 90%. Some patients may have very low numbers of adenomas, if any, but are still at risk of cancer. Duodenal and ambulatory adenomas and cancers occur, but are less common than in FAP.

Management

Predictive testing is possible with identified mutations, and testing of unaffected partners is warranted to define the risks to offspring.

Surveillance and clinical management is very similar to FAP. but more conservative management is often possible due to later onset and lower numbers of adenomas.

Other causes of adenomatous polyposis

NTHL1-associated polyposis (NAP)

NTHL1 is a counterpart of MUTYH in oxidative DNA damage repair, and mutations in NTHL1 can also cause a recessive form of adenomatous polyposis.

Consitutional mismatch repair disorder (CMMR-D)

Individuals with CMMR-D can develop multiple colorectal adenomas, and so in this way resemble MAP and NAP patients.  However, CMMR-D patients also develop a host of other malignancies and clinical abnormalities, often at a much younger age.

Polymerase proofreading-associated polyposis (PPAP)

Individuals with dominantly inherited mutations in the DNA polymerases POLD1 and POLE can also develop adenomatous polyposis, but they are also at risk of endometrial and possibly other LS-related cancers.

MSH3-associated polyposis

Most recently, recessive inheritance of mutations in MSH3 has been found in patients with adenomatous polyposis. Interestingly, tumours in such patients exhibit instability at microsatellites with tetranucleotide but not mono- or di-nucleotide repeats, and thus this sort of instability will not be detected in standard tests for MSI, as used to diagnose LS.

Support groups

There are now a number of support groups or other sources of informationfor patients and families with adenomatous polyposis syndromes:

Content updated 18 Oct 2016