Serrated polyposis syndrome

A serrated polyposis syndrome (SPS) diagnosis is based on clinical diagnostic criteria. The aetiology is not fully understood, and although there is clearly a familial component – the risk of colorectal cancer and polyps is increased in close relatives – it is rarely due to a monogenic syndrome, with only a very small proportion of cases caused by pathogenic variants in the RNF43 gene. Genomic testing may, however, help differentiate SPS from other heritable polyposis syndromes and when, rarely, a monogenic syndrome is confirmed, the results may inform risk and screening in blood relatives.

• SPS is characterised by the presence of multiple serrated polyps in the colon and rectum.
• Serrated polyps are those with a ‘saw-toothed’ appearance under the microscope.
• Patients with SPS have an overall lifetime risk of colorectal cancer (CRC) of between 7% and 70%, and there is an increased risk in first-degree relatives of patients with SPS.
• Although many patients have serrated polyps, SPS as a diagnosis is defined according to the World Health Organisation’s clinical criteria, outlined below in ‘Diagnosis’.

Constitutional (germline) pathogenic variants in the RNF43 gene have been associated with this phenotype in a small proportion of patients with SPS (about 1 in 300), and RNF43 is included in the ‘R211 Inherited polyposis and early onset colorectal cancer – germline’ gene panel in the NHS England Genomic Test Directory.

Other intestinal polyposis syndromes may present with serrated lesions. As such, the British Society of Gastroenterology guidelines recommend that other polyposis syndromes should be excluded by gene panel testing and before making a definitive diagnosis of SPS if:

• the patient is under 50 years of age;
• there are multiple affected individuals within a family; or
• there is dysplasia within any of the polyps.

Genomic testing is available via R211 if a living affected individual (proband), with or without a family history and with a clinical diagnosis of SPS as per WHO criteria (see ‘Diagnosis’), meets one of the following criteria:

• the patient is younger than 50 years old;
• family history of one or more affected first-degree relative with SPS; or
• evidence of dysplasia within any polyp.

Note that the majority of polyps are histologically confirmed. Genomic testing may occasionally be appropriate outside these criteria following discussion at a specialist multidisciplinary team meeting with a cancer geneticist present.

SPS is a clinically diagnosed condition. A genetic diagnosis of RNF43-associated SPS does not inform clinical management, including surveillance, in the proband. It is, however, relevant for cascade testing in relatives.

As reported by Monahan and others, the 2019 Updated WHO clinical criteria for the diagnosis of serrated polyposis are:

• at least five serrated lesions/polyps proximal to the rectum all being 5mm or greater in size, with two or more 10mm or greater in size; or
• more than 20 serrated lesions/polyps of any size distributed throughout the large bowel, with at least five proximal to the rectum.

RNF43-associated SPS is inherited in an autosomal dominant manner. Each child (son or daughter) and each sibling (brother or sister) of an individual who has an inherited variant in RNF43 has a 50% (1-in-2) chance of inheriting the same variant. They can access genomic testing on a predictive basis, if they so wish, with affected relatives requiring ongoing enhanced bowel surveillance (see ‘Management’).

The penetrance associated with RNF43 variants has not been fully established; recommendations regarding the ongoing management of those with and without familial RNF43 variants requires careful consideration of the age, personal history and family history of the relative, as well as their RNF43 genotype. Decisions regarding management should be informed by discussion at a specialist multidisciplinary team meeting.

For relatives of individuals with SPS where genomic testing did not identify a causative variant, there remains a known increased risk: the condition in such families may be due to the combined impact of multiple genetic traits, shared lifestyle and/or environmental risk factors. If no variant is identified in the proband, genetic testing is not recommended for their unaffected relatives. Enhanced bowel surveillance may be recommended, however (see ‘Management’).

Colonoscopic surveillance in SPS is recommended for patients and their first-degree relatives, as per guidelines published by Monahan and others. Colonoscopic surveillance is highly effective in CRC risk management, and colorectal resection is rarely indicated.

Patients with SPS should have colonoscopic surveillance yearly once the colon has been cleared of all lesions greater than 5mm in size. If no polyps greater or equal to 10mm in size are identified at subsequent surveillance examinations, then the interval can be extended to once every two years.

For first-degree relatives of patients with SPS, they should be offered an index colonoscopic screening examination at the age of 40 years old, or 10 years before the diagnosis of the index case.

Where patients have a molecularly confirmed diagnosis of heritable SPS (such as with a RNF43 pathogenic variant), they should be referred to a regional genetics service and either to St Mark’s Hospital Polyposis Registry or another clinical service within the rare disease collaborative network for polyposis.

For clinicians

• St Mark’s Hospital Polyposis Registry
• St Mark’s Hospital: The St Mark’s Centre for Familial Intestinal Cancer
• UK Cancer Genetics Group: Rare Disease Collaborative Networks

References:

• Monahan KJ, Bradshaw N, Dolwani S and others. ‘Guidelines for the management of hereditary colorectal cancer from the British Society of Gastroenterology (BSG)/Association of Coloproctology of Great Britain and Ireland (ACPGBI)/United Kingdom Cancer Genetics Group (UKCGG)‘. Gut 2020: volume 69, issue 3, pages 411–444. DOI: 10.1136/gutjnl-2019-319915