RNF43 germline and somatic mutation in serrated neoplasia pathway and its association with BRAF mutation
| Autor: | Jeffrey C W Lai, Suet Yi Leung, Helen H.N. Yan, Siu Lun Ho, Janet F. Y. Lee, Alice H Y Man, Wai Yin Tsui, Annie S Y Chan, Siu Tsan Yuen, Bernard C H Lee, Wai K. Leung, Wai Lun Law, Hans Clevers, Sarah S K Yue, Anthony K W Chan |
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| Přispěvatelé: | Hubrecht Institute for Developmental Biology and Stem Cell Research |
| Rok vydání: | 2016 |
| Předmět: |
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 |
| Zdroj: | Gut. BMJ Publishing Group |
| ISSN: | 1468-3288 0017-5749 |
| Popis: | 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 |
| Databáze: | OpenAIRE |
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