Analysis of colorectal cancers in British Bangladeshi identifies early onset, frequent mucinous histotype and a high prevalence of RBFOX1 deletion

Molecular Cancer

Research

Shafi Ahmed¹  Jean-Baptiste Cazier²  Sina Dorudi³  Neel Sengupta³  Anil Ghosh³  Nirosha Suraweera³  Andrew Silver³  Cecilia Lai³  Mohamed Thaha⁴  Guadalupe Polanco-Echeverry⁵  Christopher Yau⁶  Roger Feakins⁷  Dmitri Mouradov⁸  Peter Gibbs⁸  Anuratha Sakthianandeswaren⁸  Oliver Sieber⁹  David Propper^1,10 

[1] Academic Surgical Unit, The Royal London Hospital, 80 Newark St, E1 2ES, London, Whitechapel, UK;Bioinformatics and Statistical Genetics, Wellcome Trust Centre for Human Genetics, Roosevelt Drive, OX3 7BN, Oxford, UK;Centre for Digestive Diseases, Blizard Institute of Cell and Molecular Science, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, 4 Newark St, E1 2AT, London, Whitechapel, UK;Centre for Digestive Diseases, Blizard Institute of Cell and Molecular Science, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, 4 Newark St, E1 2AT, London, Whitechapel, UK;Academic Surgical Unit, The Royal London Hospital, 80 Newark St, E1 2ES, London, Whitechapel, UK;Centre for Digestive Diseases, Blizard Institute of Cell and Molecular Science, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, 4 Newark St, E1 2AT, London, Whitechapel, UK;Genomic Services, Wellcome Trust Centre for Human Genetics, Roosevelt Drive, OX3 7BN, Oxford, UK;Department of Mathematics, South Kensington Campus, Imperial College London, SW7 2AZ, London, UK;Department of Pathology, The Royal London Hospital, 80 Newark St, E1 2ES, London, Whitechapel, UK;Ludwig Colon Cancer Initiative Laboratory, Ludwig Institute for Cancer Research, 3050, Parkville, VIC, Australia;Ludwig Colon Cancer Initiative Laboratory, Ludwig Institute for Cancer Research, 3050, Parkville, VIC, Australia;Dentistry and Health Sciences, Department of Surgery, Faculty of Medicine, University of Melbourne, 3050, Parkville, VIC, Australia;St Bartholomew’s Hospital, Gloucester House, Little Britain, London, UK;

关键词: Colorectal cancer;    Genome analysis;    British Bangladeshi;    RBFOX1;    KRAS;    BRAF;   

DOI  :  10.1186/1476-4598-12-1

 received in 2012-10-24, accepted in 2012-12-26,  发布年份 2013

来源: Springer

【 摘 要 】

BackgroundPrevalence of colorectal cancer (CRC) in the British Bangladeshi population (BAN) is low compared to British Caucasians (CAU). Genetic background may influence mutations and disease features.MethodsWe characterized the clinicopathological features of BAN CRCs and interrogated their genomes using mutation profiling and high-density single nucleotide polymorphism (SNP) arrays and compared findings to CAU CRCs.ResultsAge of onset of BAN CRC was significantly lower than for CAU patients (p=3.0 x 10-5) and this difference was not due to Lynch syndrome or the polyposis syndromes. KRAS mutations in BAN microsatellite stable (MSS) CRCs were comparatively rare (5.4%) compared to CAU MSS CRCs (25%; p=0.04), which correlates with the high percentage of mucinous histotype observed (31%) in the BAN samples. No BRAF mutations was seen in our BAN MSS CRCs (CAU CRCs, 12%; p=0.08). Array data revealed similar patterns of gains (chromosome 7 and 8q), losses (8p, 17p and 18q) and LOH (4q, 17p and 18q) in BAN and CAU CRCs. A small deletion on chromosome 16p13.2 involving the alternative splicing factor RBFOX1 only was found in significantly more BAN (50%) than CAU CRCs (15%) cases (p=0.04). Focal deletions targeting the 5’ end of the gene were also identified. Novel RBFOX1 mutations were found in CRC cell lines and tumours; mRNA and protein expression was reduced in tumours.ConclusionsKRAS mutations were rare in BAN MSS CRC and a mucinous histotype common. Loss of RBFOX1 may explain the anomalous splicing activity associated with CRC.

【 授权许可】

Unknown   
© Sengupta et al.; licensee BioMed Central Ltd. 2013. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.