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.

OBJECTIVE: The unknown aetiology of Serrated Polyposis Syndrome (SPS) impedes risk prediction and prevention. We investigated risk factors for SPS, overall and stratified by World Health Organization (WHO)2010 clinical criteria and by colorectal cancer (CRC). METHOD: A retrospective case-control study involving a cross-sectional analysis from 350 unrelated individuals with SPS from the Genetics of Colonic Polyposis Study and 714 controls from the Australasian Colorectal Cancer Family Registry. Univariate and multivariate logistic regression modelling was used to determine the association between risk factors and SPS and risk factors associated with CRC in SPS. RESULTS: Female biological sex (odds ratio (OR) = 4.54; 95%Confidence interval (CI) = 2.77-7.45), increasing body mass index (BMI) at age 20 years (OR = 1.09; 95%CI = 1.04-1.13), hormone replacement therapy (OR = 0.44; 95%CI = 0.20.98), and increasing weekly folate intake (OR = 0.82; 95%CI = 0.75-0.90) were associated with SPS by multivariate analysis. Increasing weekly calcium intake (OR = 0.79; 95%CI = 0.64-0.97) and smoking > 10 cigarettes daily (OR = 0.45; 95%CI = 0.23-0.86) were associated with WHO criterion I only. The consumption of 1-100 g of alcohol per week (OR = 0.39; 95%CI = 0.18-0.83) was associated with WHO criterion III only. Smoking 1-5 cigarettes daily (OR = 2.35; 95%CI = 1.09-5.05), weekly non-steroidal anti-inflammatory drug (NSAIDs) intake (OR = 0.88; 95%CI = 0.78-0.99), and increased height (OR = 1.09; 95% = 1.05-1.13), were associated with SPS fulfilling both WHO criteria I and III. Moreover, weekly NSAIDs intake (OR = 0.81; 95%CI = 0.67-0.98) was associated with a reduced likelihood of CRC in SPS. CONCLUSION: We identified novel risk and potential protective factors associated with SPS, some specific for certain WHO2010 criteria. Weekly use of NSAIDs may reduce the risk of CRC in people with SPS.

Rare germline variants in the AXIN2 gene in families with colonic polyposis and colorectal cancer.

Germline loss-of-function variants in AXIN2 are associated with oligodontia and ectodermal dysplasia. The association between colorectal cancer (CRC) and colonic polyposis is less clear despite this gene now being included in multi-gene panels for CRC. Study participants were people with genetically unexplained colonic polyposis recruited to the Genetics of Colonic Polyposis Study who had a rare germline AXIN2 gene variant identified from either clinical multi-gene panel testing (n=2) or from whole genome/exome sequencing (n=2). Variant segregation in relatives and characterisation of tumour tissue were performed where possible. Four different germline pathogenic variants in AXIN2 were identified in four families. Five of the seven carriers of the c.1049delC, p.Pro350Leufs*13 variant, two of the six carriers of the c.1994dupG, p.Asn666Glnfs*41 variant, all three carriers of c.1972delA, p.Ser658Alafs*31 variant and the single proband carrier of the c.2405G>C, p.Arg802Thr variant, which creates an alternate splice form resulting in a frameshift mutation (p.Glu763Ilefs*42), were affected by CRC and/or polyposis. Carriers had a mean age at diagnosis of CRC/polyposis of 52.5 ± 9.2 years. Colonic polyps were typically pan colonic with counts ranging from 5 to >100 (median 12.5) comprising predominantly adenomatous polyps but also serrated polyps. Two CRCs from carriers displayed evidence of a second hit via loss of heterozygosity. Oligodontia was observed in carriers from two families. Germline AXIN2 pathogenic variants from four families were associated with CRC and/or polyposis in multiple family members. These findings support the inclusion of AXIN2 in CRC and polyposis multigene panels for clinical testing.