RNF43 germline and somatic mutation in serrated neoplasia pathway and its association with BRAF mutation

Yan, Helen H.N.; Lai, Jeffrey C W; Ho, Simon S. M.; Leung, Wai Keung; Law, Wai Lun; Lee, Janet F. Y.; Chan, Anthony K W; Tsui, Wai Yin; Chan, Alan K. L.; Lee, Bernard C H; Yue, Sarah S K; Man, Alice H Y; Clevers, Hans; Yuen, Siu Tsan; Leung, Suet Yi

doi:10.1136/gutjnl-2016-311849

Cited by 168 publications

(193 citation statements)

References 79 publications

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“…This adds to two previous reports of germline mutations within RNF43 in individuals with SPS or who developed multiple serrated polyps 2 3. The current study by Yan et al 1 also importantly showed loss of second wildtype allele in 16 serrated polyps, five adenomatous polyps, and in the rectal adenocarcinoma from carriers through somatic single nucleotide variants or loss of heterozygosity, adding further weight to a potential role of RNF43 in the development of colonic serrated neoplasia.…”

supporting

confidence: 78%

“…The study by Yan et al 1 adds to the reported number of SPS families with germline mutations in RNF43 , now totalling four. The paucity of RNF43 germline LoF variants in 295 patients with SPS from the GCPS suggests that mutations in RNF43 may account for only a small proportion of SPS suggesting that additional genetic risk factors for SPS are yet to be identified.…”

mentioning

confidence: 97%

“…Defined clinically by the 2010 revised WHO, SPS is associated with an increased risk of colorectal cancer (CRC) for affected individuals and their first-degree relatives. Yan et al 1 recently reported their findings from whole-exome sequencing (WES) of six individuals with SPS from four families, identifying a single family carrying a germline likely pathogenic variant in RNF43 (c.953-1 G>A, c.953_954delAG, p.E318fs). In this family, six carriers were identified, five of whom met the WHO criteria for SPS.…”

mentioning

confidence: 99%

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Lack of evidence for germline RNF43 mutations in patients with serrated polyposis syndrome from a large multinational study

Buchanan

Clendenning

et al. 2016

Gut

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supporting

confidence: 78%

mentioning

confidence: 97%

mentioning

confidence: 99%

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Lack of evidence for germline RNF43 mutations in patients with serrated polyposis syndrome from a large multinational study

Buchanan

Clendenning

et al. 2016

Gut

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“…The high mutation rate suggests this mutations confers a positive selective advantage [13]. This was confirmed by Yan et al where biallelic RNF43 X659fs mutation, along with targeting of ZNRF3 , in a murine colon organoid model conferred R-spondin independence [27]. …”

Section: Discussionmentioning

confidence: 86%

RNF43 and ZNRF3 are commonly altered in serrated pathway colorectal tumorigenesis

et al. 2016

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Serrated pathway colorectal cancers (CRCs) are characterised by a BRAF mutation and half display microsatellite instability (MSI). The Wnt pathway is commonly upregulated in conventional CRC through APC mutation. By contrast, serrated cancers do not mutate APC. We investigated mutation of the ubiquitin ligases RNF43 and ZNRF3 as alternate mechanism of altering the Wnt signal in serrated colorectal neoplasia. RNF43 was mutated in 47/54(87%) BRAF mutant/MSI and 8/33(24%) BRAF mutant/microsatellite stable cancers compared to only 3/79(4%) BRAF wildtype cancers (p<0.0001). ZNRF3 was mutated in 16/54(30%) BRAF mutant/MSI and 5/33(15%) BRAF mutant/microsatellite stable compared to 0/27 BRAF wild type cancers (p=0.004). An RNF43 frameshift mutation (X659fs) occurred in 80% BRAF mutant/MSI cancers. This high rate was verified in a second series of 25/35(71%) BRAF mutant/MSI cancers. RNF43 and ZNRF3 had lower transcript expression in BRAF mutant compared to BRAF wildtype cancers and less cytoplasmic protein expression in BRAF mutant/MSI compared to other subtypes. Treatment with a porcupine inhibitor reduced RNF43/ZNRF3 mutant colony growth by 50% and synergised with a MEK inhibitor to dramatically reduce growth. This study suggests inactivation of RNF43 and ZNRF3 is important in serrated tumorigenesis and has identified a potential therapeutic strategy for this cancer subtype.

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“…For the top-down approach, additional alterations are added in the context of an established tumor. Many of these studies have analyzed the effects of particular genetic alterations observed in human tumors, such mutation of RNF43 or overexpression of miR-483 [81, 66]. Others have investigated particular genes of interest, such as PROX1 and BIM in the context of tumor cell survival and apoptosis resistance [82, 83].…”

Section: Modeling Cancer Biologymentioning

confidence: 99%

Using 3D Organoid Cultures to Model Intestinal Physiology and Colorectal Cancer

Short

Costacurta

Williams

2017

Curr Colorectal Cancer Rep

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The three-dimensional (3D) structure of the intestine is a key determinant of differentiation and function; thus, preserving this architecture is an important consideration for studies of intestinal homeostasis and disease. Over the past decade, a number of systems for 3D intestinal organoid cultures have been developed and adapted to model a wide variety of biological phenomenon. Purpose of this review We discuss the current state of intestinal and colorectal cancer (CRC) 3D modeling, the most common methods for generating organoid cultures, and how these have yielded insights into intestinal physiology and tumor biology. Recent findings Organoids have been used to model numerous aspects of intestinal physiology and disease. Recent adaptations have further improved disease modeling and high-throughput therapeutic screening. Summary These studies show intestinal organoid models are a robust, highly tractable system which maintains many vital features of intestinal tissue, making them a pivotal step forward in the field of gastroenterology.

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RNF43 germline and somatic mutation in serrated neoplasia pathway and its association with BRAF mutation

Cited by 168 publications

References 79 publications

Lack of evidence for germline RNF43 mutations in patients with serrated polyposis syndrome from a large multinational study

Lack of evidence for germline RNF43 mutations in patients with serrated polyposis syndrome from a large multinational study

RNF43 and ZNRF3 are commonly altered in serrated pathway colorectal tumorigenesis

Using 3D Organoid Cultures to Model Intestinal Physiology and Colorectal Cancer

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