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RNF43 germline and somatic mutation in serrated neoplasia pathway and its association with BRAF mutation
  1. Helen H N Yan1,
  2. Jeffrey C W Lai1,
  3. Siu Lun Ho1,
  4. Wai Keung Leung2,
  5. Wai Lun Law3,
  6. Janet F Y Lee4,
  7. Anthony K W Chan1,
  8. Wai Yin Tsui1,
  9. Annie S Y Chan1,
  10. Bernard C H Lee1,
  11. Sarah S K Yue1,
  12. Alice H Y Man1,
  13. Hans Clevers5,
  14. Siu Tsan Yuen1,
  15. Suet Yi Leung1
  1. 1Hereditary Gastrointestinal Cancer Genetic Diagnosis Laboratory, Department of Pathology, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong
  2. 2Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong
  3. 3Department of Surgery, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong
  4. 4Department of Surgery, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong
  5. 5Hubrecht Institute for Developmental Biology and Stem Cell Research, University Medical Centre Utrecht, Utrecht, The Netherlands
  1. Correspondence to Dr Suet Yi Leung, Department of Pathology, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong; suetyi{at} and Dr Siu Tsan Yuen, Department of Pathology, St Paul's Hospital, Causeway Bay, Hong Kong; styuen{at}


Objective Serrated polyps (hyperplastic polyps, sessile or traditional serrated adenomas), which can arise in a sporadic or polyposis setting, predispose to colorectal cancer (CRC), especially those with microsatellite instability (MSI) due to MLH1 promoter methylation (MLH1me+). We investigate genetic alterations in the serrated polyposis pathway.

Design We used a combination of exome sequencing and target gene Sanger sequencing to study serrated polyposis families, sporadic serrated polyps and CRCs, with validation by analysis of The Cancer Genome Atlas (TCGA) cohort, followed by organoid-based functional studies.

Results In one out of four serrated polyposis families, we identified a germline RNF43 mutation that displayed autosomal dominant cosegregation with the serrated polyposis phenotype, along with second-hit inactivation through loss of heterozygosity or somatic mutations in all serrated polyps (16), adenomas (5) and cancer (1) examined, as well as coincidental BRAF mutation in 62.5% of the serrated polyps. Concurrently, somatic RNF43 mutations were identified in 34% of sporadic sessile/traditional serrated adenomas, but 0% of hyperplastic polyps (p=0.013). Lastly, in MSI CRCs, we found significantly more frequent RNF43 mutations in the MLH1me+ (85%) versus MLH1me− (33.3%) group (p<0.001). These findings were validated in the TCGA MSI CRCs (p=0.005), which further delineated a significant differential involvement of three Wnt pathway genes between these two groups (RNF43 in MLH1me+; APC and CTNNB1 in MLH1me−); and identified significant co-occurrence of BRAF and RNF43 mutations in the MSI (p<0.001), microsatellite stable (MSS) (p=0.002) and MLH1me+ MSI CRCs (p=0.042). Functionally, organoid culture of serrated adenoma or mouse colon with CRISPR-induced RNF43 mutations had reduced dependency on R-spondin1.

Conclusions These results illustrate the importance of RNF43, along with BRAF mutation in the serrated neoplasia pathway (both the sporadic and familial forms), inform genetic diagnosis protocol and raise therapeutic opportunities through Wnt inhibition in different stages of evolution of serrated polyps.


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