Genome Institute of Singapore

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Intratumoral heterogeneity is a major obstacle to cancer treatment and a significant confounding factor in bulk-tumor profiling. We performed an unbiased analysis of transcriptional heterogeneity in colorectal tumors and their microenvironments using single-cell RNA–seq from 11 primary colorectal tumors and matched normal mucosa. To robustly cluster single-cell transcriptomes, we developed reference component analysis (RCA), an algorithm that substantially improves clustering accuracy. Using RCA, we identified two distinct subtypes of cancer-associated fibroblasts (CAFs). Additionally, epithelial–mesenchymal transition (EMT)-related genes were found to be upregulated only in the CAF subpopulation of tumor samples. Notably, colorectal tumors previously assigned to a single subtype on the basis of bulk transcriptomics could be divided into subgroups with divergent survival probability by using single-cell signatures, thus underscoring the prognostic value of our approach. Overall, our results demonstrate that unbiased single-cell RNA–seq profiling of tumor and matched normal samples provides a unique opportunity to characterize aberrant cell states within a tumor. © 2017 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.


News Article | April 19, 2017
Site: www.eurekalert.org

A team of scientists from Singapore has discovered new ways in which cancers can escape the body's immune system. Focusing on gastric cancer (GC), the third leading cause of cancer death worldwide, the team's findings may also prove applicable to other major cancers with potential implications for how cancers might be better treated with immunotherapy, one of the most promising classes of anti-cancer drugs today. Promoters are regions in the genome that regulate the expression of genes, similar to the switch of a light bulb. Using an ultra-sensitive technique called NanoChIP-seq, the team surveyed the promoter landscape for GC to better understand the epigenetic mechanisms contributing to GC development. The team found that in GCs, gene promoters are dysregulated in a way that alters a tumour's antigenic profile to evade the body's immune system. The study, published in the leading journal Cancer Discovery, involved scientists and clinicians from Duke-NUS Medical School, Genome Institute of Singapore, Cancer Science Institute of Singapore (CSI Singapore) at the National University of Singapore (NUS), and National Cancer Centre Singapore (NCCS). "Using the NanoChIP-seq platform invented in Singapore, we created comprehensive epigenetic profiles for both GC and normal tissues," explained team leader Professor Patrick Tan. "Epigenetics is a process by which a cell's DNA is chemically modified by the environment, to change gene expression. By comparing the epigenetic profiles of gastric tumours to normal tissues from the same patient, we were able to identify those promoters specifically altered in GC tissues." Professor Tan is a Faculty Member of Duke-NUS Medical School, Deputy Executive Director of the Biomedical Research Council at the Agency for Science, Technology and Research (A*STAR), and also Senior Principal Investigator at CSI Singapore and Principal Investigator at NCCS. Just like how a light can be controlled by multiple switches to influence its intensity and colour, the team identified hundreds of genes controlled by multiple promoters, causing alternate versions of that gene to be produced. The team demonstrated that some of these gene variants are capable of stimulating cancer growth. Strikingly, the team also found that many of these alternate gene variants produced in gastric tumours were also less likely to stimulate the immune system compared with their normal counterparts. "Our data, combining computational, experimental assays, and analyses of human gastric cancers, indicates that the use of these less immunogenic variants may enhance the ability of a tumour to bypass the host's immune system. This process is referred to as tumour immunoediting," added Ms Aditi Qamra, graduate student at the Genome Institute of Singapore and first author of this study. She is also a graduate student with the Department of Physiology at the NUS Yong Loo Lin School of Medicine. The findings provide important insights into mechanisms used in cancer development and may have implications for cancer immunotherapy. While striking clinical responses have been seen in some patients treated with immunotherapy, these drugs are expensive, associated with side effects, and not all patients respond to the treatment. The team's results suggest that studying the promoter profiles of tumours may possibly identify those patients who would be responsive to immunotherapy. Moreover, the team also identified cellular pathways required by the tumour cell to maintain expression of the less immunogenic gene variants. The team is now exploring if targeting these pathways, combined with immunotherapy, can increase the proportion of patients that might respond to such drugs.


Nagarajan N.,Genome Institute of Singapore | Pop M.,University of Maryland University College
Nature Reviews Genetics | Year: 2013

Advances in sequencing technologies and increased access to sequencing services have led to renewed interest in sequence and genome assembly. Concurrently, new applications for sequencing have emerged, including gene expression analysis, discovery of genomic variants and metagenomics, and each of these has different needs and challenges in terms of assembly. We survey the theoretical foundations that underlie modern assembly and highlight the options and practical trade-offs that need to be considered, focusing on how individual features address the needs of specific applications. We also review key software and the interplay between experimental design and efficacy of assembly. © 2013 Macmillan Publishers Limited. All rights reserved.


Despite the central role of estrogen exposure in breast and endometrial cancer development and numerous studies of genes in the estrogen metabolic pathway, polymorphisms within the pathway have not been consistently associated with these cancers. We posit that this is due to the complexity of multiple weak genetic effects within the metabolic pathway that can only be effectively detected through multi-variant analysis. We conducted a comprehensive association analysis of the estrogen metabolic pathway by interrogating 239 tagSNPs within 35 genes of the pathway in three tumor samples. The discovery sample consisted of 1,596 breast cancer cases, 719 endometrial cancer cases, and 1,730 controls from Sweden; and the validation sample included 2,245 breast cancer cases and 1,287 controls from Finland. We performed admixture maximum likelihood (AML)-based global tests to evaluate the cumulative effect from multiple SNPs within the whole metabolic pathway and three sub-pathways for androgen synthesis, androgen-to-estrogen conversion, and estrogen removal. In the discovery sample, although no single polymorphism was significant after correction for multiple testing, the pathway-based AML global test suggested association with both breast (p(global) = 0.034) and endometrial (p(global) = 0.052) cancers. Further testing revealed the association to be focused on polymorphisms within the androgen-to-estrogen conversion sub-pathway, for both breast (p(global) = 0.008) and endometrial cancer (p(global) = 0.014). The sub-pathway association was validated in the Finnish sample of breast cancer (p(global) = 0.015). Further tumor subtype analysis demonstrated that the association of the androgen-to-estrogen conversion sub-pathway was confined to postmenopausal women with sporadic estrogen receptor positive tumors (p(global) = 0.0003). Gene-based AML analysis suggested CYP19A1 and UGT2B4 to be the major players within the sub-pathway. Our study indicates that the composite genetic determinants related to the androgen-estrogen conversion are important for the induction of two hormone-associated cancers, particularly for the hormone-driven breast tumour subtypes.


Clarke N.D.,Genome Institute of Singapore
Current Opinion in Structural Biology | Year: 2010

The conversion of biomass to fuels and chemicals faces substantial challenges if it is to be done on a large scale, in a sustainable manner, and at reasonable cost. Some of these challenges can be addressed through protein engineering technologies, for example by improving biomass-processing enzymes or by manipulating the activities and substrate specificity of enzymes in metabolic pathways. Recent highlights include structure-guided chimera design to improve the properties of cellulases, the engineering of synthetic scaffold proteins to enhance metabolic flux, and the broadening of substrate specificity to co-opt metabolic pathways to the production of long-chain branched alcohols. © 2010 Elsevier Ltd.


Huss M.,Genome Institute of Singapore
Briefings in Bioinformatics | Year: 2010

Sequencing-based approaches now allow high-resolution, genome-scale investigation of cellular epigenetic landscapes. For example, mapping of open chromatin regions, post-translational histone modifications and DNA methylation across a whole genome is now feasible, and new non-coding regulatory RNAs can be sensitively identified via RNA sequencing. The resulting large-scale data sets promise to contribute towards a more precise and complete understanding of gene regulation and to yield insights into the interplay between genomes and the environment. In this article, I review some of the conceptual issues and currently available software tools for the analysis of sequencing-based whole-genome epigenetics data. © The Author 2010. Published by Oxford University Press.


Meningococcal disease is an infection caused by Neisseria meningitidis. Genetic factors contribute to host susceptibility and progression to disease, but the genes responsible for disease development are largely unknown. We report here a genome-wide association study for host susceptibility to meningococcal disease using 475 individuals with meningococcal disease (cases) and 4,703 population controls from the UK. We performed, in Western European and South European cohorts (consisting of 968 cases and 1,376 controls), two replication studies for the most significant SNPs. A cluster of complement factor SNPs replicated independently in both cohorts, including SNPs within complement factor H (CFH) (rs1065489 (p.936D


Lee C.W.,Genome Institute of Singapore
Nucleic acids research | Year: 2010

In April 2009, a new influenza A (H1N1 2009) virus emerged that rapidly spread around the world. While current variants of this virus have caused widespread disease, particularly in vulnerable groups, there remains the possibility that future variants may cause increased virulence, drug resistance or vaccine escape. Early detection of these virus variants may offer the chance for increased containment and potentially prevention of the virus spread. We have developed and field-tested a resequencing kit that is capable of interrogating all eight segments of the 2009 influenza A(H1N1) virus genome and its variants, with added focus on critical regions such as drug-binding sites, structural components and mutation hotspots. The accompanying base-calling software (EvolSTAR) introduces novel methods that utilize neighbourhood hybridization intensity profiles and substitution bias of probes on the microarray for mutation confirmation and recovery of ambiguous base queries. Our results demonstrate that EvolSTAR is highly accurate and has a much improved call rate. The high throughput and short turn-around time from sample to sequence and analysis results (30 h for 24 samples) makes this kit an efficient large-scale evolutionary biosurveillance tool.


Li J.,Genome Institute of Singapore
Journal of clinical oncology : official journal of the American Society of Clinical Oncology | Year: 2013

Tamoxifen treatment is associated with a reduction in mammographic density and an improved survival. However, the extent to which change in mammographic density during adjuvant tamoxifen therapy can be used to measure response to treatment is unknown. Overall, 974 postmenopausal patients with breast cancer who had both a baseline and a follow-up mammogram were eligible for analysis. On the basis of treatment information abstracted from medical records, 474 patients received tamoxifen treatment and 500 did not. Mammographic density was measured by using an automated thresholding method and expressed as absolute dense area. Change in mammographic density was calculated as percentage change from baseline. Survival analysis was performed by using delayed-entry Cox proportional hazards regression models, with death as a result of breast cancer as the end point. Analyses were adjusted for a range of patient and tumor characteristics. During a 15-year follow-up, 121 patients (12.4%) died from breast cancer. Women treated with tamoxifen who experienced a relative density reduction of more than 20% between baseline and first follow-up mammogram had a reduced risk of death as a result of breast cancer of 50% (hazard ratio, 0.50; 95% CI, 0.27 to 0.93) compared with women with stable mammographic density. In the no-tamoxifen group, there was no statistically significant association between mammographic density change and survival. The survival advantage was not observed when absolute dense areas at baseline or follow-up were evaluated separately. A decrease in mammographic density after breast cancer diagnosis appears to serve as a prognostic marker for improved long-term survival in patients receiving adjuvant tamoxifen, and these data should be externally validated.


Hu J.,Franklin And Marshall College | Ng P.C.,Genome Institute of Singapore
Genome Biology | Year: 2012

Each human has approximately 50 to 280 frameshifting indels, yet their implications are unknown. We created SIFT Indel, a prediction method for frameshifting indels that has 84% accuracy. The percentage of human frameshifting indels predicted to be gene-damaging is negatively correlated with allele frequency. We also show that although the first frameshifting indel in a gene causes loss of function, there is a tendency for the second frameshifting indel to compensate and restore protein function. SIFT Indel is available at http://sift-dna.org/www/SIFT_indels2.html. © 2012 Hu and Ng; licensee BioMed Central Ltd.

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