Journal ArticleDOI
RNF43 germline and somatic mutation in serrated neoplasia pathway and its association with BRAF mutation
Helen H.N. Yan,Jeffrey C W Lai,Siu Lun Ho,Wai K. Leung,Wai Lun Law,Janet F. Y. Lee,Anthony K W Chan,Wai Yin Tsui,Annie S Y Chan,Bernard C H Lee,Sarah S K Yue,Alice H Y Man,Hans Clevers,Siu Tsan Yuen,Suet Yi Leung +14 more
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TLDR
The importance of RNF43, along with BRAF mutation in the serrated neoplasia pathway is illustrated to inform genetic diagnosis protocol and raise therapeutic opportunities through Wnt inhibition in different stages of evolution of serrated polyps.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 me+ ; APC and CTNNB1 in MLH1 me− ); and identified significant co-occurrence of BRAF and RNF43 mutations in the MSI (p me+ 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.read more
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Integrative Genomics Viewer
James T. Robinson,Helga Thorvaldsdottir,Wendy Winckler,Mitchell Guttman,Eric S. Lander,Eric S. Lander,Gad Getz,Jill P. Mesirov +7 more
TL;DR: The sheer volume and scope of data posed by this flood of data pose a significant challenge to the development of efficient and intuitive visualization tools able to scale to very large data sets and to flexibly integrate multiple data types, including clinical data.
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Organoids in cancer research
Jarno Drost,Hans Clevers +1 more
TL;DR: In this Review, Drost and Clevers discuss the recent advances in organoid models of cancer and how they can be exploited to drive the translation of basic cancer research into novel patient-specific treatment regimens in the clinic.
Journal ArticleDOI
A Comprehensive Human Gastric Cancer Organoid Biobank Captures Tumor Subtype Heterogeneity and Enables Therapeutic Screening.
Helen H.N. Yan,Hoi Cheong Siu,Simon Law,Siu Lun Ho,Sarah S K Yue,Wai Yin Tsui,D Chan,April S. Chan,Stephanie Ma,Ka-On Lam,Sina Bartfeld,Alice H Y Man,Bernard C H Lee,Annie S Y Chan,Jason W. H. Wong,Priscilla S.W. Cheng,Anthony K W Chan,Jiangwen Zhang,Jue Shi,Xiaodan Fan,Dora Lai-Wan Kwong,Tak W. Mak,Siu Tsan Yuen,Siu Tsan Yuen,Hans Clevers,Suet Yi Leung +25 more
TL;DR: A primary gastric cancer organoid biobank that comprises normal, dysplastic, cancer, and lymph node metastases from 34 patients, including detailed whole-exome and transcriptome analysis, provides a useful resource for studying both cancer cell biology and precision cancer therapy.
Journal ArticleDOI
ALK, ROS1, and NTRK Rearrangements in Metastatic Colorectal Cancer.
Filippo Pietrantonio,Federica Di Nicolantonio,Alexa B. Schrock,Jeeyun Lee,Sabine Tejpar,Andrea Sartore-Bianchi,Jaclyn F. Hechtman,Jason Christiansen,Luca Novara,Niall C. Tebbutt,Giovanni Fucà,Carlotta Antoniotti,Seung Tae Kim,Danielle Murphy,Rosa Berenato,Federica Morano,James Sun,Bosun Min,Philip J. Stephens,Marissa Chen,Luca Lazzari,Vincent A. Miller,Robert H. Shoemaker,Alessio Amatu,Massimo Milione,Jeffrey S. Ross,Salvatore Siena,Alberto Bardelli,Siraj M. Ali,A. Falcone,Filippo de Braud,Chiara Cremolini +31 more
TL;DR: ALK, ROS1, and NTRK rearrangements define a new rare subtype of mCRC with extremely poor prognosis, and four evaluable patients with rearranged patients showed primary resistance to anti-epidermal growth factor receptor agents.
Journal ArticleDOI
Guidelines for the management of hereditary colorectal cancer from the British Society of Gastroenterology (BSG)/Association of Coloproctology of Great Britain and Ireland (ACPGBI)/United Kingdom Cancer Genetics Group (UKCGG)
Kevin J. Monahan,Nicola Bradshaw,Sunil Dolwani,Bianca DeSouza,Malcolm G. Dunlop,James E. East,Mohammad Ilyas,Asha Kaur,Fiona Lalloo,Andrew Latchford,Matthew D. Rutter,Ian Tomlinson,Huw Thomas,James Hill +13 more
TL;DR: This guideline is concerned specifically with people who have increased lifetime risk of CRC due to hereditary factors, including those with Lynch syndrome, polyposis or a family history of CRC.
References
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RNF43 is frequently mutated in colorectal and endometrial cancers
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