N12: The Role Of RNF43 In Serrated Polyposis And Colorectal Cancer Predisposition

M. Lorans1, K. Mahmood1, M. Clendenning1, B. Pope1, D. J. Park1, S. Joseland1, V. Vijay2, J. Arnold2, K. Sweet3, K. Semotiuk4, M. Aronson4, S. Holter4, S. Gallinger4, P. Newcomb5, F. Hutchinson5, A. Win1, M. Jenkins1, F. Macrae6, I. M. Winship6, C. Rosty7, S. Parry2, D. D. Buchanan1

1 – University of Melbourne. 2 – Auckland City Hospital. 3 – Ohio State University Medical Center. 4 – Lunenfeld-Tanenbaum Research Institute. 5 – Cancer Research Center. 6 – Royal Melbourne Hospital. 7 – Envoi Pathology.


Aim: Rare germline truncating variants in the RNF43 gene have been implicated in Serrated Polyposis Syndrome (SPS), a condition with an increased risk of colorectal cancer (CRC).  We screened individuals with SPS and a cohort of CRC-affected probands for germline variants in RNF43 to determine prevalence and clinicopathological features of carriers.

Method: 418 probands with SPS and n=1951 CRC-affected probands and n=1208 controls were screened by targeted multiplex-PCR and sequencing (Hi-Plex) for coding variants within RNF43.  Single nucleotide variants and short indels were classified as predicted pathogenic if they were: 1) novel or present in gnomAD at <5.0E-05 minor allele frequency; and 2) were truncating, frameshift or splice site variants or a non-synonymous change predicted to be deleterious on protein function (CADD or REVEL).

Results: Six carriers of predicted pathogenic variants in RNF43 were identified in 418 SPS probands (1.4%); these particular variants were significantly enrichment in the SPS cohort compared with gnomAD (odds ratio=4.4, 95%CI=1.7-9.1, p=0.0003).  A single predicted pathogenic variant in RNF43 was identified in one of the CRC-affected probands tested.  Clinicopathological findings and segregation in the carrier families will be presented.

Conclusion: Rare germline RNF43 predicted pathogenic variants were significantly enriched in individuals with SPS.