A deleterious RNF43 germline mutation in a severely affected serrated polyposis kindred

We report a germline nonsense mutation within the extracellular domain of the RING finger ubiquitin ligase RNF43, segregating with a severe form of serrated polyposis within a kindred. The finding provides evidence that inherited RNF43 mutations define a familial cancer syndrome. The serrated polyposis syndrome comprises multiple epithelial polyps in the colon and rectum of serrated histology. WHO clinical criteria1 are the presence of >20 serrated polyps throughout the colon, or >5 proximal to the rectum. Serrated polyps, particularly large sessile polyps in the proximal colon, frequently exhibit the oncogenic V600E mutation together with hypermethylation of the mismatch repair protein MLH1 and are responsible for 15–20% of sporadic colorectal cancer (CRC).2\ud \ud The serrated polyposis syndrome is associated with CRC risk. Serrated polyposis shows familial clustering,3 and first and second-degree relatives of index cases with serrated polyposis without CRC are more likely to have been diagnosed with CRC or pancreatic cancer.4 The risk of CRC in relatives is higher in those cases diagnosed below the age of 50 years.4 A small number of serrated polyposis patients harbor dominant germline mutations in mismatch repair proteins or biallelic MUTYH mutations, however, when these patients are excluded the familial risk of CRC remains4 and the genetic basis for familial serrated polyposis has not been established. The appearance of serrated polyposis in consanguineous kindreds and in monozygotic twins5 has led to the hypothesis that serrated polyposis may be due in part to recessive or codominant mutations.5\ud \ud As serrated polyposis is a relatively newly described condition, its natural history is not known and the lifetime risk of CRC in serrated polyposis is also not known. Significantly, it is also not known whether those first and second-degree relatives of serrated polyposis cases, who had a history of CRC or pancreatic cancer, themselves had serrated polyposis.4 If so, then a dominant mode of inheritance in at least a subset of serrated polyposis is likely. If not, however, serrated polyposis could be the result of several codominant alleles.\ud \ud We identified a severely affected kindred with serrated polyposis. The proband developed microsatellite instability (MSI)– CRC age 23 years arising from a serrated polyp, in the setting of multiple (>50) large serrated polyps throughout the colon; one sibling has multiple serrated polyps and another a single large adenoma. Their mother developed pancreatic cancer and died before this study at age 50 years. On the paternal side, an informative pedigree had no history of multiple polyposis or CRC in the father's generation. Full sequencing of the MUTYH gene in the proband did not reveal any abnormality.\ud \ud We performed exon capture and deep sequencing in this kindred to identify strong and potentially interacting cancer alleles