Dysregulated Wnt signalling and recurrent mutations of the tumour suppressor RNF43 in early gastric carcinogenesis

Abstract

Several recurrent mutations and epigenetic changes have been identified in advanced gastric cancer, but the genetic alterations associated with early gastric carcinogenesis and malignant transformation remain unclear. We investigated the genomic and transcriptomic landscape of adenomas with low-grade dysplasia (LGD) and high-grade dysplasia (HGD), and intestinal-type early gastric cancer (EGC). The results were validated in an independent cohort that included EGCs directly adjacent to adenoma (EGC-adenomas) that were in the process of malignant transformation, and de novo EGCs that do not seem to have been derived from adenoma. The expression patterns clearly divided into normal, LGD, and EGC, whereas those of HGD overlapped with LGD or EGC. These results suggest that HGD is the critical stage determining malignant transformation. We found that genes related to focal adhesion and extracellular matrix receptor interaction pathways were upregulated as LGD progressed to EGC, whereas canonical Wnt signalling and peroxisome proliferator-activated receptor (PPAR) signalling pathway genes were downregulated in EGC. Genomic alterations such as somatic mutation, gene fusion and copy number variation increased gradually from LGD to EGC. APC mutations were present in 67% of LGDs, 58% of HGDs, and 18% of EGCs. RNF43 mutations were present only in HGD and EGC, and TP53 mutations were present only in EGC. In a validation cohort, RNF43 mutations were present in 35.2% of EGC-adenomas, but in only 8.6% of de novo EGCs. This is the first study to investigate the genomic and transcriptomic landscape of multistep gastric carcinogenesis. We investigated important alterations and their related pathways in each step as tumours progressed from LGD to HGD and eventually to EGC. We suggest that mutations and downregulation of RNF43 may play a critical role in the transition from adenoma to carcinoma. Given these findings and Wnt dependency in tumours with RNF43 mutation, intestinal-type gastric cancer or adenoma with RNF43 mutation might represent a promising indication for Wnt-targeted agents. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Initial and crucial genetic events in intestinal‐type gastric intramucosal neoplasia

“…We presented a mutational landscape of 25 gastric D/IENs. Prominent involvement of APC mutations was verified in our series, as reported previously . We also revealed several findings that are novel and meaningful.…”

“…Mining their mutation data revealed that the majority of the APC mutations in their gastric D/IEN (5/6 and 6/12 ) also clustered to the same region (codons 1400–1600). When the APC ‐mutated D/IENs in our ( n = 19) and other ( n = 13 ) studies were analyzed together, the accumulation of mutations at the hotspots became more apparent (Figure ); both p.R1450* and p.E1554 (fs/*) was found in 25% (8/32) of APC ‐mutated D/IENs. The distribution pattern of mutations in the APC protein did not differ between LG‐D/IEN and HG‐D/IEN.…”

Winding back Wnt signalling: potential therapeutic targets for treating gastric cancers

“…Recent large‐scale genomic data have identified frequent RNF43 LOF mutations, predominantly truncating or missense alterations, in >50 and 4.8% of MSI and microsatellite stable gastric tumours respectively (Cancer Genome Atlas Research, ; Wang et al , ). A recent examination of the progressive genomic and transcriptomic alterations from early‐stage gastric adenomas through to later‐stage disease validate the recurrent mutations to RNF43 previously described (Min et al , ). Furthermore, the frequency of RNF43 mutations in early‐mid stage gastric tumours identifies deregulated Wnt signalling as a critical driver and potential biomarker of early gastric tumourigenesis.…”

“…Furthermore, the frequency of RNF43 mutations in early‐mid stage gastric tumours identifies deregulated Wnt signalling as a critical driver and potential biomarker of early gastric tumourigenesis. Thus, determining if a gastric tumour has RNF43 mutations will help stratify which patients are more likely to benefit from therapies targeted to the Wnt receptor complex or the production of Wnts (Min et al , ). To date, the efficacy of antibodies that block FZD receptors and/or inhibitors of Wnt secretion has not been thoroughly tested in preclinical models of GC.…”

Rnf43

“…Isoform 1 has two variants: variant 1 represents the longest transcript and encodes the longer isoform; variant 2 uses an alternate splice site in its 5′ UTR compared with variant 1. Both variants 1 and 2 encode the same protein 5. Isoform 2, variant 3, has multiple differences, compared with variant 1.…”