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

ABSTRACT: 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.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.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.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.

SUBMITTER: Sengupta N

PROVIDER: S-EPMC3544714 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

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

Sengupta Neel N Yau Christopher C Sakthianandeswaren Anuratha A Mouradov Dmitri D Gibbs Peter P Suraweera Nirosha N Cazier Jean-Baptiste JB Polanco-Echeverry Guadalupe G Ghosh Anil A Thaha Mohamed M Ahmed Shafi S Feakins Roger R Propper David D Dorudi Sina S Sieber Oliver O Silver Andrew A Lai Cecilia C

Molecular cancer 20130103

<h4>Background</h4>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.<h4>Methods</h4>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.<h4>Results</h4>Age of onset of BAN CRC was significantly low ...[more]

PMID: 23286373

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Project description:BackgroundComprehensive mutational profiling data now available on all major cancers have led to proposals of novel molecular tumor classifications that modify or replace the established organ- and tissue-based tumor typing. The rationale behind such molecular reclassifications is that genetic alterations underlying cancer pathology predict response to therapy and may therefore offer a more precise view on cancer than histology. The use of individual actionable mutations to select cancers for treatment across histotypes is already being tested in the so-called basket trials with variable success rates. Here, we present a computational approach that facilitates the systematic analysis of the histological context dependency of mutational effects by integrating genomic and proteomic tumor profiles across cancers.MethodsTo determine effects of oncogenic mutations on protein profiles, we used the energy distance, which compares the Euclidean distances of protein profiles in tumors with an oncogenic mutation (inner distance) to that in tumors without the mutation (outer distance) and performed Monte Carlo simulations for the significance analysis. Finally, the proteins were ranked by their contribution to profile differences to identify proteins characteristic of oncogenic mutation effects across cancers.ResultsWe apply our approach to four current proposals of molecular tumor classifications and major therapeutically relevant actionable genes. All 12 actionable genes evaluated show effects on the protein level in the corresponding tumor type and showed additional mutation-related protein profiles in 21 tumor types. Moreover, our analysis identifies consistent cross-cancer effects for 4 genes (FGFR1, ERRB2, IDH1, KRAS/NRAS) in 14 tumor types. We further use cell line drug response data to validate our findings.ConclusionsThis computational approach can be used to identify mutational signatures that have protein-level effects and can therefore contribute to preclinical in silico tests of the efficacy of molecular classifications as well as the druggability of individual mutations. It thus supports the identification of novel targeted therapies effective across cancers and guides efficient basket trial designs.

Project description:Background and objectivesLow levels of vitamin D among dark-skinned migrants to northern latitudes and increased risks for associated pathologies illustrate an evolutionary mismatch between an environment of high ultraviolet (UV) radiation to which such migrants are adapted and the low UV environment to which they migrate. Recently, low levels of vitamin D have also been associated with higher risks for contracting COVID-19. South Asians in the UK have higher risk for low vitamin D levels. In this study, we assessed vitamin D status of British-Bangladeshi migrants compared with white British residents and Bangladeshis still living in Bangladesh ('sedentees').MethodologyThe cross-sectional study compared serum vitamin D levels among 149 women aged 35-59, comprising British-Bangladeshi migrants (n = 50), white British neighbors (n = 54) and Bangladeshi sedentees (n = 45). Analyses comprised multivariate models to assess serum levels of 25-hydroxyvitamin D (25(OH)D), and associations with anthropometric, lifestyle, health and migration factors.ResultsVitamin D levels in Bangladeshi migrants were very low: mean 25(OH)D = 32.2 nmol/L ± 13.0, with 29% of migrants classified as deficient (<25 nmol/L) and 94% deficient or insufficient (≤50 nmol/L). Mean levels of vitamin D were significantly lower among British-Bangladeshis compared with Bangladeshi sedentees (50.9 nmol/L ± 13.3, P < 0.001) and were also lower than in white British women (55.3 nmol/L ± 20.9). Lower levels of vitamin D were associated with increased body mass index and low iron status.Conclusions and implicationsWe conclude that lower exposure to sunlight in the UK reduces vitamin D levels in Bangladeshi migrants. Recommending supplements could prevent potentially adverse health outcomes associated with vitamin D deficiency.Lay summaryVitamin D deficiency is one example of mismatch between an evolved trait and novel environments. Here we compare vitamin D status of dark-skinned British-Bangladeshi migrants in the UK to Bangladeshis in Bangladesh and white British individuals. Migrants had lower levels of vitamin D and are at risk for associated pathologies.

Dataset Information

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

Publications

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

Similar Datasets

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