Open Access Research

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

Neel Sengupta1, Christopher Yau2, Anuratha Sakthianandeswaren3, Dmitri Mouradov3, Peter Gibbs3, Nirosha Suraweera1, Jean-Baptiste Cazier4, Guadalupe Polanco-Echeverry15, Anil Ghosh1, Mohamed Thaha16, Shafi Ahmed6, Roger Feakins7, David Propper8, Sina Dorudi1, Oliver Sieber39, Andrew Silver1* and Cecilia Lai1*

Author Affiliations

1 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, Whitechapel, London, E1 2AT, UK

2 Department of Mathematics, South Kensington Campus, Imperial College London, London, SW7 2AZ, UK

3 Ludwig Colon Cancer Initiative Laboratory, Ludwig Institute for Cancer Research, Parkville, VIC, 3050, Australia

4 Bioinformatics and Statistical Genetics, Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford, OX3 7BN, UK

5 Present address: Genomic Services, Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford, OX3 7BN, UK

6 Academic Surgical Unit, The Royal London Hospital, 80 Newark St, Whitechapel, London, E1 2ES, UK

7 Department of Pathology, The Royal London Hospital, 80 Newark St, Whitechapel, London, E1 2ES, UK

8 St Bartholomew’s Hospital, Gloucester House, Little Britain, London, UK

9 Faculty of Medicine, Dentistry and Health Sciences, Department of Surgery, University of Melbourne, Parkville, VIC, 3050, Australia

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Molecular Cancer 2013, 12:1  doi:10.1186/1476-4598-12-1

Published: 3 January 2013

Abstract

Background

Prevalence 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.

Methods

We 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.

Results

Age 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.

Conclusions

KRAS mutations were rare in BAN MSS CRC and a mucinous histotype common. Loss of RBFOX1 may explain the anomalous splicing activity associated with CRC.

Keywords:
Colorectal cancer; Genome analysis; British Bangladeshi; RBFOX1; KRAS; BRAF