Publications
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Lu Y, Day FR, Gustafsson S, et al., 2016, New loci for body fat percentage reveal link between adiposity and cardiometabolic disease risk, NATURE COMMUNICATIONS, Vol: 7, ISSN: 2041-1723
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- Citations: 199
Lehne B, Drong AW, Loh M, et al., 2015, A coherent approach for analysis of the Illumina HumanMethylation450 BeadChip improves data quality and performance in epigenome-wide association studies, Genome Biology, Vol: 16, ISSN: 1474-760X
DNA methylation plays a fundamental role in the regulation of the genome, but the optimal strategy for analysis ofgenome-wide DNA methylation data remains to be determined. We developed a comprehensive analysis pipelinefor epigenome-wide association studies (EWAS) using the Illumina Infinium HumanMethylation450 BeadChip, basedon 2,687 individuals, with 36 samples measured in duplicate. We propose new approaches to quality control, datanormalisation and batch correction through control-probe adjustment and establish a null hypothesis for EWASusing permutation testing. Our analysis pipeline outperforms existing approaches, enabling accurate identificationof methylation quantitative trait loci for hypothesis driven follow-up experiments.
Sapari NS, Elahi E, Wu M, et al., 2014, Feasibility of Low-Throughput Next Generation Sequencing for Germline DNA Screening, CLINICAL CHEMISTRY, Vol: 60, Pages: 1549-1557, ISSN: 0009-9147
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- Citations: 5
Chambers JC, Abbott J, Zhang W, et al., 2014, The South Asian Genome, PLOS One, Vol: 9, ISSN: 1932-6203
The genetic sequence variation of people from the Indian subcontinent who comprise one-quarter of the world's population, is not well described. We carried out whole genome sequencing of 168 South Asians, along with whole-exome sequencing of 147 South Asians to provide deeper characterisation of coding regions. We identify 12,962,155 autosomal sequence variants, including 2,946,861 new SNPs and 312,738 novel indels. This catalogue of SNPs and indels amongst South Asians provides the first comprehensive map of genetic variation in this major human population, and reveals evidence for selective pressures on genes involved in skin biology, metabolism, infection and immunity. Our results will accelerate the search for the genetic variants underlying susceptibility to disorders such as type-2 diabetes and cardiovascular disease which are highly prevalent amongst South Asians.
Afaq S, Tan ST, Afzal U, et al., 2014, 117 Validation of accelerometers for measurement of physical activity energy expenditure in South asians and europeans., Heart, Vol: 100 Suppl 3, Pages: A66-A67
South Asians are at ~2 fold higher risk of cardiovascular disease (CVD) than Europeans. Physical inactivity is an independent risk factor for CVD, and may be more common in South Asians than Europeans. However, published studies of physical activity in South Asians have all relied on self-report by questionnaire, an approach of limited accuracy, confounded by linguistic, cultural and reporting bias. Accelerometers are validated tools for measurement of physical activity energy expenditure (PAEE) in Europeans, but are influenced by body habitus and device positioning. The accuracy of accelerometers in South Asians is not known.
Tan ST, Mills R, Loh M, et al., 2014, 111 Investigation of the validity of cardiovascular death certification amongst uk Indian asians and europeans., Heart, Vol: 100 Suppl 3
National mortality statistics report that UK Indian Asians are at approxiamately 2 fold higher risk of cardiovascular disease mortality compared with people of European ancestry. However, previous studies in North American and European populations suggest that up to 40% of death certificates are incorrect, leading to an overestimation of cardiovascular disease mortality. The validity of routine death certification amongst Indian Asians is unknown.
Loh M, Liem N, Vaithilingam A, et al., 2014, DNA methylation subgroups and the CpG island methylator phenotype in gastric cancer: a comprehensive profiling approach., BMC Gastroenterol, Vol: 14
BACKGROUND: Methylation-induced silencing of promoter CpG islands in tumor suppressor genes plays an important role in human carcinogenesis. In colorectal cancer, the CpG island methylator phenotype (CIMP) is defined as widespread and elevated levels of DNA methylation and CIMP+ tumors have distinctive clinicopathological and molecular features. In contrast, the existence of a comparable CIMP subtype in gastric cancer (GC) has not been clearly established. To further investigate this issue, in the present study we performed comprehensive DNA methylation profiling of a well-characterised series of primary GC. METHODS: The methylation status of 1,421 autosomal CpG sites located within 768 cancer-related genes was investigated using the Illumina GoldenGate Methylation Panel I assay on DNA extracted from 60 gastric tumors and matched tumor-adjacent gastric tissue pairs. Methylation data was analysed using a recursively partitioned mixture model and investigated for associations with clinicopathological and molecular features including age, Helicobacter pylori status, tumor site, patient survival, microsatellite instability and BRAF and KRAS mutations. RESULTS: A total of 147 genes were differentially methylated between tumor and matched tumor-adjacent gastric tissue, with HOXA5 and hedgehog signalling being the top-ranked gene and signalling pathway, respectively. Unsupervised clustering of methylation data revealed the existence of 6 subgroups under two main clusters, referred to as L (low methylation; 28% of cases) and H (high methylation; 72%). Female patients were over-represented in the H tumor group compared to L group (36% vs 6%; P = 0.024), however no other significant differences in clinicopathological or molecular features were apparent. CpG sites that were hypermethylated in group H were more frequently located in CpG islands and marked for polycomb occupancy. CONCLUSIONS: High-throughput methylation analysis implicates genes involved in embryonic development
Chong M-L, Loh M, Thakkar B, et al., 2014, Phosphatidylinositol-3-kinase pathway aberrations in gastric and colorectal cancer: meta-analysis, co-occurrence and ethnic variation., Int J Cancer, Vol: 134, Pages: 1232-1238
Inhibition of the phosphatidylinositol-3-kinase (PI3K) signaling pathway is a cancer treatment strategy that has entered into clinical trials. We performed a meta-analysis on the frequency of prominent genetic (PIK3CA mutation, PIK3CA amplification and PTEN deletion) and protein expression (high PI3K, PTEN loss and high pAkt) aberrations in the PI3K pathway in gastric cancer (GC) and colorectal cancer (CRC). We also performed laboratory analysis to investigate the co-occurrence of these aberrations. The meta-analysis indicated that East Asian and Caucasian GC patients differ significantly for the frequencies of PIK3CA Exon 9 and 20 mutations (7% vs. 15%, respectively), PTEN deletion (21% vs. 4%) and PTEN loss (47% vs. 78%), while CRC patients differed for PTEN loss (57% vs. 26%). High study heterogeneity (I(2) > 80) was observed for all aberrations except PIK3CA mutations. Laboratory analysis of tumors from East Asian patients revealed significant differences between GC (n = 79) and CRC (n = 116) for the frequencies of PIK3CA amplification (46% vs. 4%) and PTEN loss (54% vs. 78%). The incidence of GC cases with 0, 1, 2 and 3 concurrent aberrations was 14%, 52%, 27% and 8%, respectively, while for CRC it was 10%, 60%, 25% and 4%, respectively. Our study consolidates knowledge on the frequency, co-occurrence and clinical relevance of PI3K pathway aberrations in GC and CRC. Up to 86% of GC and 90% of CRC have at least one aberration in the PI3K pathway, and there are significant differences in the frequencies of these aberrations according to cancer type and ethnicity.
Collura A, Lagrange A, Svrcek M, et al., 2014, Patients with colorectal tumors with microsatellite instability and large deletions in HSP110 T17 have improved response to 5-fluorouracil–based chemotherapy., Gastroenterology, Vol: 146, Pages: 401-11.e1
BACKGROUND & AIMS: Patients with colorectal tumors with microsatellite instability (MSI) have better prognoses than patients with tumors without MSI, but have a poor response to 5-fluorouracil–based chemotherapy. A dominant-negative form of heat shock protein (HSP)110 (HSP110DE9) expressed by cancer cells with MSI, via exon skipping caused by somatic deletions in the T(17) intron repeat, sensitizes the cells to 5-fluorouracil and oxaliplatin.We investigated whether HSP110 T(17) could be used to identify patients with colorectal cancer who would benefit from adjuvant chemotherapy with 5-fluorouracil and oxaliplatin. METHODS: We characterized the interaction between HSP110 and HSP110DE9 using surface plasmon resonance. By using polymerase chain reaction and fragment analysis, we examined how the size of somatic allelic deletions in HSP110 T(17) affected the HSP110 protein expressed by tumor cells. We screened 329 consecutive patients with stage II–III colorectal tumors with MSI who underwent surgical resection at tertiary medical centers for HSP110 T(17). RESULTS: HSP110 and HSP110DE9 interacted in a1:1 ratio. Tumor cells with large deletions in T(17) had increased ratios of HSP110DE9:HSP110, owing to the loss of expression of full-length HSP110. Deletions in HSP110 T(17) were mostly biallelic in primary tumor samples with MSI. Patients with stage II–III cancer who received chemotherapy and had large HSP110 T(17) deletions (≥5 bp; 18 of 77 patients, 23.4%) had longer times of relapse-free survival than patients with small or no deletions (≤4 bp; 59 of 77 patients, 76.6%) in multivariate analysis (hazard ratio, 0.16; 95% confidence interval, 0.012–0.8; P = .03). We found a significant interaction between chemotherapy and T17 deletion (P =.009). CONCLUSIONS: About 25% of patients with stages II–III colorectal tumors with MSI have an excellent response to chemotherapy, due to large, biallelic deletions in the T(17) intron repeat of
Subramaniam MM, Loh M, Chan JY, et al., 2014, The topography of DNA methylation in the non-neoplastic colonic mucosa surrounding colorectal cancers., Mol Carcinog, Vol: 53, Pages: 98-108
The degree of gene hypermethylation in non-neoplastic colonic mucosa (NNCM) is a potentially important event in the development of colorectal cancer (CRC), particularly for the subgroup with a CpG island methylator phenotype (CIMP). In this study, we aimed to use an unbiased and high-throughput approach to evaluate the topography of DNA methylation in the non-neoplastic colonic mucosa (NNCM) surrounding colorectal cancer (CRC). A total of 61 tissue samples comprising 53 NNCM and 8 tumor samples were obtained from hemicolectomy specimens of two CRC patients (Cases 1 and 2). NNCM was stripped from the underlying colonic wall and samples taken at varying distances from the tumor. The level of DNA methylation in NNCM and tumor tissues was assessed at 1,505 CpG sites in 807 cancer-related genes using Illumina GoldenGate® methylation arrays. Case 1 tumor showed significantly higher levels of methylation compared to surrounding NNCM samples (P < 0.001). The average level of methylation in NNCM decreased with increasing distance from the tumor (r = -0.418; P = 0.017), however this was not continuous and "patches" with higher levels of methylation were observed. Case 2 tumor was less methylated than Case 1 tumor (average β-value 0.181 vs. 0.415) and no significant difference in the level of methylation was observed in comparison to the surrounding NNCM. No evidence was found for a diminishing gradient of methylation in the NNCM surrounding CRC with a high level of methylation. Further work is required to determine whether CIMP+ CRC develop from within "patches" of NCCM that display high levels of methylation.
Wen Y-Y, Pan X-F, Loh M, et al., 2014, Association of the IL-1B +3954 C/T polymorphism with the risk of gastric cancer in a population in Western China., Eur J Cancer Prev, Vol: 23, Pages: 35-42
With an estimate of 380 000 new cases each year, gastric cancer (GC) is one of the most frequently occurring cancers in China. Genes encoding proinflammatory and anti-inflammatory cytokines are good candidates for the study of susceptibility to GC. We tested the hypothesis that the polymorphisms of interleukin 1B (IL-1B) and IL-1RN contribute toward host susceptibility to GC. In a matched case-control design, we enrolled 308 pairs of GC and control participants between October 2010 and August 2011. We sequenced IL-1B +3954 C/T, IL-1RN -9876 G/A, -9739 A/G, and IL-1RN -9091 A/C using MALDI-TOF MS and collected demographic data as well as lifestyle factors using a questionnaire. GC patients reported statistically significantly greater proportions with family history of cancer (29.9 vs. 10.7%, P<0.01) and alcohol drinking (54.5 vs. 43.2%, P<0.01) than the controls. The proportion of irregular eaters was statistically higher among the patients than among the controls (66.7 vs. 24.4%, P<0.01). The IL-1B +3954 CT or the TT variant genotype was statistically significantly associated with a risk of GC [adjusted odds ratio (OR), 2.94; 95% confidence interval (CI), 1.06-8.15], whereas variants of IL-1RN -9876 G/A, IL-1RN -9739 A/G, and IL-1RN -9091 A/C were not associated (adjusted OR, 1.29, 95% CI, 0.77-2.16; adjusted OR, 1.25, 95% CI, 0.75-2.07; adjusted OR, 1.09, 95% CI, 0.71-1.67, respectively). Haplotypes established from the three polymorphisms of IL-1RN were not associated with a risk of GC. The IL-1B +3954 C/T polymorphism is associated with a risk of GC in our study. Lifestyle and environmental factors such as drinking, eating irregularly, and family history of cancer increase the risk.
Pan X-F, Wen Y, Loh M, et al., 2014, Interleukin-4 and-8 Gene Polymorphisms and Risk of Gastric Cancer in a Population in Southwestern China, ASIAN PACIFIC JOURNAL OF CANCER PREVENTION, Vol: 15, Pages: 2951-2957, ISSN: 1513-7368
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- Citations: 22
Loh M, Chua D, Yao Y, et al., 2013, Can population differences in chemotherapy outcomes be inferred from differences in pharmacogenetic frequencies?, Pharmacogenomics J, Vol: 13, Pages: 423-429
Inter-ethnic differences in drug handling and frequencies of pharmacogenetic variants are increasingly being characterized. In this study, we systematically assessed the feasibility of inferring ethnic trends in chemotherapy outcomes from inter-ethnic differences in pharmacogenetic variant frequencies. Frequencies of 51 variants and chemotherapy outcomes of East Asian and Caucasian colorectal cancer patients on standard chemotherapy regimens were summarized by meta-analyses, and variant frequencies were validated by MassARRAY analysis. Inferences of relative chemotherapy outcomes were made by considering minor allele function and population differences in their frequency. Significant population differences in genotype distributions were observed for 13/23 (60%) and 27/35 (77%) variants in the meta-analyses and validation series, respectively. Across chemotherapy regimens, East Asians had lower rates of grade 3/4 toxicity for diarrhea and stomatitis/mucositis than Caucasians, which was correctly inferred from 13/18 (72%, P=0.018) informative genetic variants. With appropriate variant selection, inferring relative population toxicity rates from population genotype differences may be relevant.
Shah N, Thakkar B, Shen E, et al., 2013, Lymphocytic follicles and aggregates are a determinant of mucosal damage and duration of diarrhea., Arch Pathol Lab Med, Vol: 137, Pages: 83-89
CONTEXT: Nonspecific changes (nonspecific chronic inflammation) in patients with chronic diarrhea represent the commonest diagnosis in colorectal biopsy interpretation, but these changes are of little clinical significance. OBJECTIVE: To find, within this group, histologic and immunohistologic diagnostic criteria to predict the duration and resolution of diarrhea. DESIGN: Detailed clinical features and histologic findings were analyzed in a cohort of 47 patients with chronic diarrhea, with near-normal histology and no clear-cut known etiologic agent. Immunohistochemistry to mast cells (CD117) and Treg cells (FOXP3) was also assessed in 39 patients. RESULTS: Increased number of lymphoid follicles and aggregates, increased number of mast cells, and paucity of Treg were the statistically significant key findings (P = .003, P = .008, and P = .04, respectively). The duration of diarrhea was correlated with the number of large lymphoid follicles and aggregates (P = .001, r = .48), number of total lymphoid follicles and aggregates (P = .003, r = .43), density of lymphoid follicles and aggregates (P = .009, r = .38), and total lymphoid follicles and aggregates per biopsy (P = .004, r = .42) and the number of mast cells (P = .001, r = .52). The number of mast cells and Treg cells showed significant difference between resolved and unresolved cases (P = .001 and P = .01 respectively). CONCLUSIONS: Lymphocytic follicles and aggregates colitis, previously regarded as of negligible diagnostic significance, allows the prediction of the behavior of chronic diarrhea in a subset of patients with nonspecific changes on colonic biopsy. The increased number of mast cells and paucity of Treg cells further helps to identify such unresolved cases.
Pan X-F, Yang S-J, Loh M, et al., 2013, Interleukin-10 gene promoter polymorphisms and risk of gastric cancer in a Chinese population: single nucleotide and haplotype analyses., Asian Pac J Cancer Prev, Vol: 14, Pages: 2577-2582
OBJECTIVES: Interleukin (IL) -10 is a potent cytokine with a dual ability to immunosuppress or immunostimulate. We aimed to explore the association of IL10 promoter polymorphisms with risk of gastric cancer (GC) in a Han population in Southwestern China. METHODS: We enrolled 308 pairs of GC and control subjects from four hospitals and a community between October 2010 and August 2011 in a 1:1 matched case-control design. Demographic information was collected using a designed questionnaire. IL10-592 A>C and IL10-1082 A>G polymorphisms were determined by Sequenom MassARRAY analysis. RESULTS: Patients with GC reported statistically higher proportions of family history of cancer (29.9% versus 10.7%, P<0.01) and alcohol drinking (54.6% versus 43.2%, P<0.01) than did controls. Similar results were observed in comparison between non-cardia GC patients and controls (P<0.01 and P=0.03). Variant genotypes of IL10-592 A>C and IL10-1082 A>G were not associated with overall GC risk (adjusted OR, 0.94, 95% CI, 0.66-1.33; adjusted OR, 1.00, 95% CI, 0.62-1.60). Sub-analysis showed that the IL10-592 AC/CC variant genotype was associated with decreased non-cardia GC risk (adjusted OR, 0.58; 95% CI, 0.36-0.95). No association was found between any of the IL10 haplotypes established from two polymorphisms and risk of non-cardia GC. CONCLUSIONS: In conclusion, our data do not link the two SNPs of IL10-592 and IL10-1082 with overall GC risk. We demonstrate that IL10-592 polymorphism is associated with protective effect against non-cardia GC. Our findings may offer insight into risk associated with the development of GC in this region.
Soo RA, Kawaguchi T, Loh M, et al., 2012, Differences in outcome and toxicity between Asian and caucasian patients with lung cancer treated with systemic therapy., Future Oncol, Vol: 8, Pages: 451-462
It is increasingly recognized that differences in overall survival and toxicity exist between Asian and caucasian patients with small-cell and non-small-cell lung cancer, with a longer survival, higher response rates and greater toxicity to chemotherapy and targeted therapy reported in Asian patients. Two global studies are used to illustrate how the proportions of Asian patients can influence survival outcome. Ethnicity is an important and complex characteristic that should considered in the design and conduct of a global clinical study, as the safety, tolerability and response may vary between Asian and caucasian patients. Whether ethnic differences in lung cancer survival are attributed to genetic differences among races or are simply a surrogate marker of differences in access to healthcare because of socioeconomic differences is unclear. Carefully designed prospective studies investigating ethnic-specific determinants of sensitivity and toxicity to systemic therapy are warranted.
Wen Y-Y, Pan X-F, Loh M, et al., 2012, ADPRT Val762Ala and XRCC1 Arg194Trp polymorphisms and risk of gastric cancer in Sichuan of China., Asian Pac J Cancer Prev, Vol: 13, Pages: 2139-2144
OBJECTIVE: Gastric cancer remains a major health problem in China. We hypothesized that XRCC1 Arg194Trp and ADPRT Val762Ala may be associated with risk. METHODS: We designed a multicenter 1:1 matched case- control study of 307 pairs of gastric cancers and controls between October 2010 and August 2011. XRCC1 Arg194Trp and ADPRT Val762Ala were sequenced, and demographic data as well as lifestyle factors were collected using a self-designed questionnaire. RESULTS: Individuals carrying XRCC1 Trp/Trp or Arg/Trp variant genotype had a significantly increased risk of gastric cancer (OR, 1.718; 95% CI, 1.190-2.479), while the OR for ADPRT Val762Ala variant genotype (Ala/Ala or Val/Ala) was 1.175 (95% CI, 0.796-1.737). No gene-gene or gene-environment interactions were found. In addition, family history of cancer and drinkers proportion were higher among cases than among controls (P<0.05). CONCLUSIONS: XRCC1 194 Arg/Trp or Trp/Trp genotype, family history of cancer, and drinking are suspected risk factors of gastric cancer from our study. Our findings may offer insight into further similar large gene-environment and gene-gene studies in this region.
Pan X-F, Xie Y, Loh M, et al., 2012, Polymorphisms of XRCC1 and ADPRT genes and risk of noncardia gastric cancer in a Chinese population: a case-control study., Asian Pac J Cancer Prev, Vol: 13, Pages: 5637-5642
OBJECTIVE: Gastric cancer (GC) is one of the most common malignancies and its mortality ranks third among all cancers in China. We previously noted that XRCC1 Arg194Trp was associated with GC risk in Western China in a study on XRCC1 Arg194Trp and ADPRT Val762Ala. We aimed to further explore the association of these polymorphisms with risk of the noncardia subtype. METHODS: We enrolled 176 noncardia GC patients and 308 controls from four hospitals and a community between October 2010 and August 2011. Genotyping was performed in a 384-well plate format on the Sequenom MassARRAY platform. A self-designed questionnaire was utilized to collect epidemiological data from the subjects regarding demographic factors and potential risk factors. RESULTS: Subjects were aged 56.8±11.8 (mean±standard deviation) and 57.6±11.1 years in the case and control groups, respectively. Individuals carrying the XRCC1 Trp/Trp or Arg/Trp variant genotype were at significantly increased risk of noncardia GC (adjusted OR, 1.48; 95% CI, 1.00-2.17), after adjustment for family history of cancer, drinking, and smoking. The increased risk of XRCC1 Arg194Trp variant genotype was more pronounced among subjects below 60 years old (adjusted OR, 1.78; 95% CI, 1.07-2.96), compared to older individuals. ADPRT Val762Ala variants (Ala/Ala or Val/Ala) were not associated with noncardia GC (adjusted OR, 1.03; 95% CI, 0.69-1.54). CONCLUSIONS: Our study suggests that XRCC1 Arg194Trp is a genetic susceptibility factor for developing noncardia GC in Han Chinese in Western China. In particular, individuals with the XRCC1 Arg194Trp variant genotype are at increased risk for GC below 60 years old.
Sapari NS, Loh M, Vaithilingam A, et al., 2012, Clinical potential of DNA methylation in gastric cancer: a meta-analysis., PLoS One, Vol: 7
BACKGROUND: Accumulating evidence indicates aberrant DNA methylation is involved in gastric tumourigenesis, suggesting it may be a useful clinical biomarker for the disease. The aim of this study was to consolidate and summarize published data on the potential of methylation in gastric cancer (GC) risk prediction, prognostication and prediction of treatment response. METHODS: Relevant studies were identified from PubMed using a systematic search approach. Results were summarized by meta-analysis. Mantel-Haenszel odds ratios were computed for each methylation event assuming the random-effects model. RESULTS: A review of 589 retrieved publications identified 415 relevant articles, including 143 case-control studies on gene methylation of 142 individual genes in GC clinical samples. A total of 77 genes were significantly differentially methylated between tumour and normal gastric tissue from GC subjects, of which data on 62 was derived from single studies. Methylation of 15, 4 and 7 genes in normal gastric tissue, plasma and serum respectively was significantly different in frequency between GC and non-cancer subjects. A prognostic significance was reported for 18 genes and predictive significance was reported for p16 methylation, although many inconsistent findings were also observed. No bias due to assay, use of fixed tissue or CpG sites analysed was detected, however a slight bias towards publication of positive findings was observed. CONCLUSIONS: DNA methylation is a promising biomarker for GC risk prediction and prognostication. Further focused validation of candidate methylation markers in independent cohorts is required to develop its clinical potential.
Loh M, Soong R, 2011, Challenges and pitfalls in the introduction of pharmacogenetics for cancer., Ann Acad Med Singap, Vol: 40, Pages: 369-374
There have been several success stories in the field of pharmacogenetics in recent years, including the analysis of HER2 amplification for trastuzumab selection in breast cancer and VKORC1 genotyping for warfarin dosing in thrombosis. Encouraging results from these studies suggest that genetic factors may indeed be important determinants of drug response and toxicity for at least some drugs. However, to apply pharmacogenetics appropriately, a thorough understanding of the scope and limitations of this field is required. The challenges include an appreciation of biological variability, logistical issues pertaining to the proper management of information, the need for robust methods and adequate sample quality with well-designed workflows. At the same time, the economics of pharmacogenetic testing from the perspective of clinicians, patients, governments, insurance companies and pharmaceutical companies will play an important role in determining its future use. Ethical considerations such as informed consent and patient privacy, as well as the role of regulatory bodies in addressing these issues, must be fully understood. Only once these issues are properly dealt with can the full benefits of pharmacogenetics begin to be realised.
Soo RA, Loh M, Mok TS, et al., 2011, Ethnic differences in survival outcome in patients with advanced stage non-small cell lung cancer: results of a meta-analysis of randomized controlled trials., J Thorac Oncol, Vol: 6, Pages: 1030-1038
INTRODUCTION: Although interethnic differences in survival to cytotoxic chemotherapy in patients with non-small cell lung cancer exist, an analysis of survival outcomes based on ethnicity has not yet been fully evaluated systematically using large patient cohorts. Furthermore, recent trial results may be confounded by the use of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). METHODS: A meta-analysis was performed using trials identified through MEDLINE. Summary data on median overall survival (OS), time to progression, progression-free survival, and overall response rate (ORR) were collected from randomized controlled trials. Outcomes were compared between Asian and Caucasian studies. RESULTS: Of the 1182 citations identified, 391 treatment arms (Asian 90 and Caucasian 301) were analyzed. The median OS and ORR in Asian and Caucasian studies for all chemotherapy regimens was 10.1 and 8.0 months (p < 0.001) and 32.2 and 25.9% (p < 0.001), respectively. The median OS in Asian and Caucasian studies for monotherapy, platinum doublets, and three drugs or more combination was 9.9 and 6.8 months, 10.4 and 8.6 months, and 9.4 and 8.0 months, respectively (all p < 0.001). In studies published pre-EGFR TKI, the median OS and ORR in Asian and Caucasian studies for all chemotherapy regimens was 9.1 versus 7.3 months (p < 0.001), respectively, and 29.0 and 23.0% (p < 0.006), respectively. The median OS in Asian and Caucasian studies for monotherapy, platinum doublets, and three drugs or more combination pre-EGFR TKI was 8.9 and 6.5 months (p < 0.005), 9.1 and 7.5 months (p < 0.001), and 9.3 and 7.6 months (p < 0.003), respectively. In third-generation platinum doublets, the median OS in Asian and Caucasian studies was 11.3 and 9.5 months (p < 0.001), respectively, and ORR was 35.0 and 29.8% (p < 0.001), respectively. CONCLUSION: Ethnic differences in survival and response rate to chemotherapy exist and should be consider
Tan WL, Bhattacharya B, Loh M, et al., 2011, Low cytosine triphosphate synthase 2 expression renders resistance to 5-fluorouracil in colorectal cancer., Cancer Biol Ther, Vol: 11, Pages: 599-608
Understanding the determinants of resistance of 5-fluorouracil (5FU) is of significant value to optimising administration of the drug, and introducing novel agents and treatment strategies. Here, the expression of 92 genes involved in 5FU transport, metabolism, co-factor (folate) metabolism and downstream effects was measured by real-time PCR low density arrays in 14 patient-derived colorectal cancer xenografts characterised for 5FU resistance. Candidate gene function was tested by siRNA and uridine modulation, and immunoblotting, apoptosis and cell cycle analysis. Predictive significance was tested by immunohistochemistry of tumours from 125 stage III colorectal cancer patients treated with and without 5FU. Of 8 genes significantly differentially expressed between 5FU sensitive and resistant xenograft tumours, CTPS2 was the gene with the highest probability of differential expression (p=0.008). Reduction of CTPS2 expression by siRNA increased the resistance of colorectal cancer cell lines DLD1 and LS174T to 5FU and its analogue, FUDR. CTPS2 siRNA significantly reduced cell S-phase accumulation and apoptosis following 5FU treatment. Exposure of cells to uridine, a precursor to the CTPS2 substrate uridine triphosphate, also increased 5FU resistance. Patients with low CTPS2 did not gain a survival benefit from 5FU treatment (p=0.072), while those with high expression did (p=0.003). Low CTPS2 expression may be a rationally-based determinant of 5FU resistance.
Loh M, Liem N, Lim PL, et al., 2010, Impact of sample heterogeneity on methylation analysis., Diagn Mol Pathol, Vol: 19, Pages: 243-247
The recent emergence of high-throughput arrays for methylation analysis has made the influence of tumor content on the interpretation of methylation levels increasingly pertinent. However, to what degree does tumor content have an influence, and what degree of tumor content makes a specimen acceptable for accurate analysis remains unclear. Taking a systematic approach, we analyzed 98 unselected formalin-fixed and paraffin-embedded gastric tumors and matched normal tissue samples using the Illumina GoldenGate methylation assay. Unsupervised hierarchical clustering showed 2 separate clusters with a significant difference in average tumor content levels. The probes identified to be significantly differentially methylated between the tumors and normals also differed according to the tumor content of the samples included, with the sensitivity of identifying the "top" candidate probes significantly reduced when including samples below 70% tumor content. We also tested whether the removal of the probes featuring single nucleotide polymorphisms and/or DNA repetitive elements, reportedly present in GoldenGate arrays, would significantly affect the study's findings, and found little change in the results with their omission. Our findings suggest that tumor content significantly influences the interpretation of methylation levels and candidate gene identification, and that 70% tumor content may be a suitable threshold for selecting samples for methylation studies.
Chong P, Lee H, Loh MCS, et al., 2010, Upregulation of plasma C9 protein in gastric cancer patients, PROTEOMICS, Vol: 10, Pages: 3210-3221, ISSN: 1615-9853
<jats:title>Abstract</jats:title><jats:p>Gastric cancer is one of the leading causes of cancer‐related deaths worldwide. Current biomarkers used in the clinic do not have sufficient sensitivity for gastric cancer detection. To discover new and better biomarkers, protein profiling on plasma samples from 25 normal, 15 early‐stage and 21 late‐stage cancer was performed using an iTRAQ‐LC‐MS/MS approach. The level of C9 protein was found to be significantly higher in gastric cancer compared with normal subjects. Immunoblotting data revealed a congruent trend with iTRAQ results. The discriminatory power of C9 between normal and cancer states was not due to inter‐patient variations and was independent from gastritis and <jats:italic>Helicobacter pylori</jats:italic> status of the patients. C9 overexpression could also be detected in a panel of gastric cancer cell lines and their conditioned media compared with normal cells, implying that higher C9 levels in plasma of cancer patients could be attributed to the presence of gastric tumor. A subsequent blind test study on a total of 119 plasma samples showed that the sensitivity of C9 could be as high as 90% at a specificity of 74%. Hence, C9 is a potentially useful biomarker for gastric cancer detection.</jats:p>
Chong PK, Lee H, Zhou J, et al., 2010, ITIH3 Is a Potential Biomarker for Early Detection of Gastric Cancer, Journal of Proteome Research, Vol: 9, Pages: 3671-3679, ISSN: 1535-3893
Chong P-K, Lee H, Zhou J, et al., 2010, Reduced plasma APOA1 level is associated with Gastric Tumor Growth in MKN45 mouse xenograft model, Journal of Proteomics, Vol: 73, Pages: 1632-1640, ISSN: 1874-3919
Ang PW, Loh M, Liem N, et al., 2010, Comprehensive profiling of DNA methylation in colorectal cancer reveals subgroups with distinct clinicopathological and molecular features, BMC Cancer, Vol: 10, ISSN: 1471-2407
BACKGROUND: Most previous studies of the CpG island methylator phenotype (CIMP) in colorectal cancer (CRC) have been conducted on a relatively small numbers of CpG sites. In the present study we performed comprehensive DNA methylation profiling of CRC with the aim of characterizing CIMP subgroups. METHODS: DNA methylation at 1,505 CpG sites in 807 cancer-related genes was evaluated using the Illumina GoldenGate methylation array in 28 normal colonic mucosa and 91 consecutive CRC samples. Methylation data was analyzed using unsupervised hierarchical clustering. CIMP subgroups were compared for various clinicopathological and molecular features including patient age, tumor site, microsatellite instability (MSI), methylation at a consensus panel of CpG islands and mutations in BRAF and KRAS. RESULTS: A total of 202 CpG sites were differentially methylated between tumor and normal tissue. Unsupervised hierarchical clustering of methylation data from these sites revealed the existence of three CRC subgroups referred to as CIMP-low (CIMP-L, 21% of cases), CIMP-mid (CIMP-M, 14%) and CIMP-high (CIMP-H, 65%). In comparison to CIMP-L tumors, CIMP-H tumors were more often located in the proximal colon and showed more frequent mutation of KRAS and BRAF (P<0.001). CONCLUSIONS: Comprehensive DNA methylation profiling identified three CRC subgroups with distinctive clinicopathological and molecular features. This study suggests that both KRAS and BRAF mutations are involved with the CIMP-H pathway of CRC rather than with distinct CIMP subgroups.
Lai KW, Koh KX, Loh M, et al., 2010, MicroRNA-130b regulates the tumour suppressor RUNX3 in gastric cancer., Eur J Cancer, Vol: 46, Pages: 1456-1463
AIM: Accumulating evidence indicates that RUNX3 is an important tumour suppressor that is inactivated in many cancer types. This study aimed to assess the role of microRNA (miRNA) in the regulation of RUNX3. METHODS: Four bioinformatic algorithms were used to predict miRNA binding to RUNX3. The correlation between candidate miRNAs and RUNX3 expression in cell lines was determined by real-time reverse transcriptase quantitative PCR (RT-qPCR) and Western blot. Candidate miRNAs were tested for functional effects through transfection of miRNA precursors and inhibitors, and monitoring cell viability, apoptosis and Bim expression. miRNA and RUNX3 expression, RUNX3 methylation and RUNX3 protein levels were assessed in gastric tissue by RT-qPCR, Methylight analysis and immunohistochemistry, respectively. RESULTS: Bioinformatics, gene and protein expression analysis in eight gastric cell lines identified miR-130b as the top candidate miRNA for RUNX3 binding. Overexpression of miR-130b increased cell viability, reduced cell death and decreased expression of Bim in TGF-beta mediated apoptosis, subsequent to the downregulation of RUNX3 protein expression. In 15 gastric tumours, miR-130b expression was significantly higher compared to matched normal tissue, and was inversely associated with RUNX3 hypermethylation. CONCLUSION: Attenuation of RUNX3 protein levels by miRNA may reduce the growth suppressive potential of RUNX3 and contribute to tumourigenesis.
Toy W, Lim SK, Loh MCS, et al., 2010, EGF-induced tyrosine phosphorylation of Endofin is dependent on PI3K activity and proper localization to endosomes, Cellular Signalling, Vol: 22, Pages: 437-446, ISSN: 0898-6568
Chew V, Tow C, Teo M, et al., 2010, Inflammatory tumour microenvironment is associated with superior survival in hepatocellular carcinoma patients., J Hepatol, Vol: 52, Pages: 370-379
BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) is an aggressive malignancy with few treatment options. As the status of the tumour immune microenvironment can affect progression of established tumours, we evaluated potential immune mechanisms associated with survival in HCC. METHODS: Immune gene expression profiles were analyzed in tumour and non-tumour liver tissues from resected HCC patients using quantitative PCR and immunohistochemistry. Tumour-infiltrating leukocytes (TILs) were isolated to verify the expression of immune genes and to identify proliferating TILs. These parameters were analyzed statistically in relation with patient survival and tumour phenotype (apoptosis and proliferation). RESULTS: The immune microenvironment within tumours was found to be heterogeneous, although globally more inert compared to the adjacent non-tumour liver tissue. Univariate analysis in 61 patients identified a group of innate immune genes whose expression within tumours is positively associated with patient survival. TNF, IL6 and CCL2 are the most significant genes, with TNF being an independent predictor of survival in multivariate analysis. The gene set includes macrophage and NK-associated molecules such as TLR4, TLR3, CCR2, NCR3. Most of these molecules are expressed by TILs. Importantly, proliferating immune cells, predominantly NK and T cells, are present in tumours of patients with longer survival, and exclusively in areas devoid of proliferating tumour cells. NK and CD8(+) T cell densities are correlated positively with tumour apoptosis, and negatively with tumour proliferation. CONCLUSIONS: Hence, an inflammatory immune microenvironment within HCC tumours could be an important means to control tumour progression via TIL activation and proliferation.
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