Type 1 serrated polyposis represents a predominantly female disease with a high prevalence of dysplastic serrated adenomas, without germline mutation in MUTYH, APC, and PTEN genes

Abstract

Aim: The aim of this article is to clarify the epidemiologic, clinical, endoscopic, biological and genetic characteristics of type 1 serrated polyposis patients. Patients and methods: Consecutive patients responding to the WHO definition of type 1 serrated polyposis in one reference center for polyposis patients accepted genetic counseling. Detailed data on previous endoscopies, histology, and life habits were recorded, after informed consent, germline analysis of MUTYH, APC, and PTEN germline mutations. Molecular biology was tested on available fixed tissue from different lesion types. Results: We included 29 patients (mean age 53.5 years, 21 women (72.4%)), four with a personal history of colorectal cancer (CRC), with a mean of 11.6 SSAs, with associated hyperplastic polyps in 93.1% and adenomas in 82.8%. SSAs showed no dysplasia in 46.9% of lesions (three of 29 patients), LGD in 51.9% (22/29 patients), and HGD in 1.2% (four of 29 patients). Dysplasia was more frequent in proximal SSAs and in women. Colectomy 15 patients (51.7%), upper digestive neoplasms: eight patients (27.5%); smokers: 24 patients (82.8%); family history of CRC: 16 patients (55.2%). Biology: MSI-H phenotype in one SSA, V600E BRAF mutation in 95% of SSAs; MGMT hypermethylation in three of 17 SSAs. No germline mutation was detected in MYH, APC or PTEN genes. Conclusion: Type 1 serrated polyposis corresponds to a majority of women, with a high prevalence of smokers, a high prevalence of dysplastic serrated adenomas, particularly in females, without identified germline mutation in targeted predisposing genes.

Germline variant testing in serrated polyposis syndrome

“…In our study from a single large tertiary referral center, gene panel testing identified pathogenic germline variants in 4% of those tested. This is higher than previously reported 33,34 . The two smaller previous studies found no pathogenic variants in the specific genes tested: PTEN, SMAD4, BMPR1A, MUTYH, GREM1, and APC.…”

“…This is higher than previously reported. 33,34 The two smaller previous studies found no pathogenic variants in the specific genes tested: PTEN, SMAD4, BMPR1A, MUTYH, GREM1, and APC. In one study, 33 the majority (83.1%) of the patients fulfilled WHO 2010 criterion 3 (equivalent to WHO 2019 criterion 2), which differs from our cohort in which 85.5% (n = 148) fulfilled WHO 2019 criterion 1.…”

“…In a study of 64 SPS patients, germline testing for BMPR1A, SMAD4, PTEN, MUTYH, and GREM1 genes found one monoallelic MUTYH and one non‐functional PTEN variant, but no pathogenic variants 33 . Similarly, 29 patients fulfilling WHO criteria 1 for SPS had genetic testing for MUTYH, APC, and PTEN and no germline variants were found 34 . The low yield of pathogenic Mendelian variants intimates a polygenic or alternative pathogenesis for this common polyposis.…”

“… 33 Similarly, 29 patients fulfilling WHO criteria 1 for SPS had genetic testing for MUTYH, APC, and PTEN and no germline variants were found. 34 The low yield of pathogenic Mendelian variants intimates a polygenic or alternative pathogenesis for this common polyposis. This may account for why SPS was not included in the 2019/2020 National Genomic Test Directory, which specifies genomic tests commissioned by the NHS for rare and inherited diseases.…”

Body Mass Index, sex, non-steroidal anti-inflammatory drug medications, smoking and alcohol are differentially associated with World Health Organisation criteria and colorectal cancer risk in people with Serrated Polyposis Syndrome: an Australian case-control study

“…Moreover, these studies only examined limited risk factors including sex, smoking and CRC or polyp-affected first-degree relatives and were limited by study size and specific WHO criteria examined. The 2016 cohort study by Petronio et al found that people with WHO 2010 SPS criterion I were mostly women and there was a high prevalence of smokers, however, only 29 people were examined [ 17 ]. The large 2017 retrospective Dutch and British multicentre study involving 434 people with SPS found that only tobacco smoking had an inverse association with CRC in people with SPS, however, risk factors associated with SPS were not stratified by WHO criteria [ 16 ].…”