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RNF43 germline and somatic mutation in serrated neoplasia pathway and its association with BRAF mutation
- Source :
- Gut. BMJ Publishing Group
- Publication Year :
- 2016
- Publisher :
- BMJ, 2016.
-
Abstract
- 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 (MLH1(me+)). 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 MLH1(me+) (85%) versus MLH1(me-) (33.3%) group (p
- Subjects :
- Adenoma
Adult
Male
Proto-Oncogene Proteins B-raf
0301 basic medicine
congenital, hereditary, and neonatal diseases and abnormalities
Colorectal cancer
Ubiquitin-Protein Ligases
Colonic Polyps
Biology
MLH1
Germline
Loss of heterozygosity
03 medical and health sciences
Germline mutation
medicine
Humans
Family
Genetic Predisposition to Disease
Genetic Testing
Wnt Signaling Pathway
neoplasms
Exome sequencing
Oncogene Proteins
Genetics
Gastroenterology
Microsatellite instability
Middle Aged
medicine.disease
digestive system diseases
DNA-Binding Proteins
030104 developmental biology
Hyperplastic Polyp
Mutation
Hong Kong
Female
Microsatellite Instability
Colorectal Neoplasms
MutL Protein Homolog 1
Subjects
Details
- ISSN :
- 14683288 and 00175749
- Volume :
- 66
- Database :
- OpenAIRE
- Journal :
- Gut
- Accession number :
- edsair.doi.dedup.....9c66b88971dcf1658a9beec807a24e76