Displaying publications 1 - 20 of 62 in total

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  1. Fulltext Whole-Genome Profiles of Malay Colorectal Cancer Patients with Intact MMR Proteins
    Juhari WKW, Ahmad Amin Noordin KB, Zakaria AD, Rahman WFWA, Mokhter WMMWM, Hassan MRA, et al.
    Genes (Basel), 2021 09 20;12(9).
    PMID: 34573430 DOI: 10.3390/genes12091448
    BACKGROUND: This study aimed to identify new genes associated with CRC in patients with normal mismatch repair (MMR) protein expression.

    METHOD: Whole-genome sequencing (WGS) was performed in seven early-age-onset Malay CRC patients. Potential germline genetic variants, including single-nucleotide variations and insertions and deletions (indels), were prioritized using functional and predictive algorithms.

    RESULTS: An average of 3.2 million single-nucleotide variations (SNVs) and over 800 indels were identified. Three potential candidate variants in three genes-IFNE, PTCH2 and SEMA3D-which were predicted to affect protein function, were identified in three Malay CRC patients. In addition, 19 candidate genes-ANKDD1B, CENPM, CLDN5, MAGEB16, MAP3K14, MOB3C, MS4A12, MUC19, OR2L8, OR51Q1, OR51AR1, PDE4DIP, PKD1L3, PRIM2, PRM3, SEC22B, TPTE, USP29 and ZNF117-harbouring nonsense variants were prioritised. These genes are suggested to play a role in cancer predisposition and to be associated with cancer risk. Pathway enrichment analysis indicated significant enrichment in the olfactory signalling pathway.

    CONCLUSION: This study provides a new spectrum of insights into the potential genes, variants and pathways associated with CRC in Malay patients.

    Matched MeSH terms: Colorectal Neoplasms/genetics*
  2. Fulltext Quantitative analysis of the expression of p53 gene in colorectal carcinoma by using real-time PCR
    Bong I, Lim P, Balraj P, Sim Ui Hang E, Zakaria Z
    Trop Biomed, 2006 Jun;23(1):53-9.
    PMID: 17041552 MyJurnal
    Colorectal carcinoma ranks third among ten leading causes of cancer in Malaysia. The colorectal carcinoma tumourigenesis involves the inactivation of tumour suppressor genes, and activation of proto-oncogenes. The p53 is one of the tumour suppressor genes that is involved in the colorectal carcinogenesis. The p53 gene is located on human chromosome 17p13.1 and comprises of 11 exons. Deficiencies in the p53 gene can cause the cancerous cells to spread to distant organs such as liver, lungs, lymph nodes, spine and bone. The most common p53 abnormalities that can lead to the metastasis of colorectal tumours are mutation and deregulation of the gene. In this study, nine colorectal carcinoma samples were used to establish a simple and sensitive strategy in the study on in vivo p53 expression by using realtime LightCycler SYBR Green I technology.
    Matched MeSH terms: Colorectal Neoplasms/genetics*
  3. Fulltext Predominance of G to A codon 12 mutation K-ras gene in Dukes' B colorectal cancer
    Zulhabri O, Rahman J, Ismail S, Isa MR, Wan Zurinah WN
    Singapore Med J, 2012 Jan;53(1):26-31.
    PMID: 22252179
    K-ras gene mutations in codons 12 and 13 are one of the earliest events in colon carcinogenesis.
    Matched MeSH terms: Colorectal Neoplasms/genetics*
  4. Colorectal carcinoma in Malaysians: DNA mismatch repair pattern in a multiethnic population
    Cheah PL, Looi LM, Teoh KH, Rahman NA, Wong LX, Tan SY
    Asian Pac J Cancer Prev, 2014;15(7):3287-91.
    PMID: 24815484
    BACKGROUND: The interesting preponderance of Chinese with colorectal carcinoma (CRC) amongst the three major ethnic groups in Malaysia prompted a study to determine DNA mismatch repair (MMR) status in our CRC and attempt correlation with patient age, gender and ethnicity as well as location, grade, histological type and stage of tumour. Histologically re-confirmed CRC, diagnosed between 1st January 2005 and 31st December 2007 at the Department of Pathology, University of Malaya Medical Centre, were immunohistochemically stained with monoclonal antibodies to MMR proteins, MLH1, MSH2, MSH6 and PMS2 on the Ventana Benchmark XT autostainer. Of the 142 CRC cases entered into the study, there were 82 males and 60 females (M:F=1.4:1). Ethnically, 81 (57.0%) were Chinese, 32 (22.5%) Malays and 29 (20.4%) Indians. The patient ages ranged between 15-87 years (mean=62.4 years) with 21 cases <50-years and 121 ≥50-years of age. 14 (9.9%) CRC showed deficient MMR (dMMR). Concurrent loss of MLH1 and PMS2 occurred in 10, MSH2 and MSH6 in 2 with isolated loss of MSH6 in 1 and PMS2 in 1. dMMR was noted less frequently amongst the Chinese (6.2%) in comparison with their combined Malay and Indian counterparts (14.8%), and was associated with right sided and poorly differentiated tumours (p<0.05). 3 of the 5 (60.0%) dMMR CRC cases amongst the Chinese and 1 of 9 cases (11.1%) amongst the combined Malay and Indian group were <50-years of age. No significant association of dMMR was noted with patient age and gender, tumour stage or mucinous type.
    Matched MeSH terms: Colorectal Neoplasms/genetics*
  5. Koetjapic acid, a natural triterpenoid, induces apoptosis in colon cancer cells
    Nassar ZD, Aisha AF, Idris N, Khadeer Ahamed MB, Ismail Z, Abu-Salah KM, et al.
    Oncol Rep, 2012 Mar;27(3):727-33.
    PMID: 22134768 DOI: 10.3892/or.2011.1569
    Deregulated cell signaling pathways result in cancer development. More than one signal transduction pathway is involved in colorectal cancer pathogenesis and progression. Koetjapic acid (KA) is a naturally occurring seco-A-ring oleanene triterpene isolated from the Sandoricum koetjape stem bark. We report the cellular and molecular mechanisms of anticancer activity of KA towards human colorectal cancer. The results showed that KA induces apoptosis in HCT 116 colorectal carcinoma cells by inducing the activation of extrinsic and intrinsic caspases. We confirmed that KA-induced apoptosis was mediated by DNA fragmentation, nuclear condensation and disruption in the mitochondrial membrane potential. Further studies on the effect of KA on cancer pathways show that the compound causes down-regulation of Wnt, HIF-1α, MAP/ERK/JNK and Myc/Max signaling pathways and up-regulates the NF-κB signaling pathway. The result of this study highlights the anticancer potential of KA against colorectal cancer.
    Matched MeSH terms: Colorectal Neoplasms/genetics
  6. Molecular alterations of Ras-Raf-mitogen-activated protein kinase and phosphatidylinositol 3-kinase-Akt signaling pathways in colorectal cancers from a tertiary hospital at Kuala Lumpur, Malaysia
    Yip WK, Choo CW, Leong VC, Leong PP, Jabar MF, Seow HF
    APMIS, 2013 Oct;121(10):954-66.
    PMID: 23992303 DOI: 10.1111/apm.12152
    Molecular alterations in KRAS, BRAF, PIK3CA, and PTEN have been implicated in designing targeted therapy for colorectal cancer (CRC). The present study aimed to determine the status of these molecular alterations in Malaysian CRCs as such data are not available in the literature. We investigated the mutations of KRAS, BRAF, and PTEN, the gene amplification of PIK3CA, and the protein expression of PTEN and phosphatidylinositol 3-kinase (PI3K) catalytic subunit (p110α) by direct DNA sequencing, quantitative real-time PCR, and immunohistochemistry, respectively, in 49 CRC samples. The frequency of KRAS (codons 12, 13, and 61), BRAF (V600E), and PTEN mutations, and PIK3CA amplification was 25.0% (11/44), 2.3% (1/43), 0.0% (0/43), and 76.7% (33/43), respectively. Immunohistochemical staining demonstrated loss of PTEN protein in 54.5% (24/44) of CRCs and no significant difference in PI3K p110α expression between CRCs and the adjacent normal colonic mucosa (p = 0.380). PIK3CA amplification was not associated with PI3K p110α expression level, but associated with male cases (100% of male cases vs 56% of female cases harbored amplified PIK3CA, p = 0.002). PI3K p110α expression was significantly higher (p = 0.041) in poorly/moderately differentiated carcinoma compared with well-differentiated carcinoma. KRAS mutation, PIK3CA amplification, PTEN loss, and PI3K p110α expression did not correlate with Akt phosphorylation or Ki-67 expression. KRAS mutation, PIK3CA amplification, and PTEN loss were not mutually exclusive. This is the first report on CRC in Malaysia showing comparable frequency of KRAS mutation and PTEN loss, lower BRAF mutation rate, higher PIK3CA amplification frequency, and rare PTEN mutation, as compared with published reports.
    Matched MeSH terms: Colorectal Neoplasms/genetics*
  7. PIK3CA gene mutations in breast carcinoma in Malaysian patients
    Ching-Shian Leong V, Jabal MF, Leong PP, Abdullah MA, Gul YA, Seow HF
    Cancer Genet. Cytogenet., 2008 Dec;187(2):74-9.
    PMID: 19027487 DOI: 10.1016/j.cancergencyto.2008.07.005
    Somatic mutations of phosphoinositide-3-kinase, catalytic, alpha; PIK3CA gene have been reported in several types of human cancers. The majority of the PIK3CA mutations map to the three "hot spots" - E542 K and E545 K in the helical (exon 9) and H1047R in the kinase (exon 20) domains of the p110alpha. These hot spot mutations lead to a gain of function in PI3 K signaling. We aimed to determine the frequency of PIK3CA mutations in the three most common Malaysian cancers. In this study, we assessed the genetic alterations in the PIK3CA gene in a series of 20 breast carcinomas, 24 colorectal carcinomas, 27 nasopharyngeal carcinomas (NPC), and 5 NPC cell lines. We performed mutation analysis of the PIK3CA gene by genomic polymerase chain reaction (PCR) and followed by DNA direct sequencing in exons 9 and 20. No mutations were detected in any of the 24 colorectal and 27 NPC samples, but one hot spot mutation located at exon 20 was found in a NPC cell line, SUNE1. Interestingly, PIK3CA somatic mutations were present in 6/20 (30%) breast carcinomas. Two of the six mutations, H1047R, have been reported previously as a hot spot mutation. Only one out of three hot spot mutations were identified in breast tumor samples. The remaining four mutations were novel. Our data showed that a higher incidence rate of PIK3CA mutations was present in Malaysian breast cancers as compared to colorectal and nasopharyngeal tumor tissues. Our findings also indicate that PIK3CA mutations play a pivotal role in activation of the PI3 K signaling pathway in breast cancer, and specific inhibitors of PIK3CA could be useful for breast cancer treatment in Malaysia.
    Matched MeSH terms: Colorectal Neoplasms/genetics
  8. Fulltext Variant Toll-like receptor4 (Asp299Gly and Thr399Ile alleles) and Toll-like receptor2 (Arg753Gln and Arg677Trp alleles) in colorectal cancer
    Davoodi H, Seow HF
    Iran J Allergy Asthma Immunol, 2011 Jun;10(2):91-9.
    PMID: 21625017 DOI: 010.02/ijaai.9199
    The innate immune system recognizes the presence of bacterial products through the expression of a family of membrane receptors known as Toll-like receptors (TLRs). Polymorphisms in TLRs have been shown to be associated with increased susceptibility to diseases such as inflammatory bowel disease. The aim of this study was to determine whether there was a correlation between polymorphisms of TLR4 (Asp299Gly; Thr399Ile) and TLR2 (Arg677Trp; Arg753Gln) genes and risk of colorectal cancer. DNA from 60 colorectal carcinoma patients from 3 major races in Malaysia (22 Malays, 20 Chinese and 18 Indians) and blood from 50 apparently healthy individuals were evaluated. Control group were matched to study group by race and age. The polymorphisms were determined by Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP). Genotyping results showed two out of sixty tumour specimens (3.3%) harbored both variant TLR4 Asp299Gly and Thr399Ile alleles. In contrast, DNA isolated from blood cells of 50 apparently healthy individuals harbored wild type TLR4. In the case of TLR2 Arg753Gln genotyping, all of the fifty normal and 60 tumours were of the wild type genotype. TLR2 Arg677Trp genotyping showed a heterozygous pattern in all samples. However, this may not be a true polymorphism of the TLR2 gene as it is likely due to a variation of a duplicated ( pseudogene) region. There was only a low incidence (2/60; 3.3%) of TLR4 polymorphism at the Asp299Gly and Thr399Ile alleles in colorectal cancer patients. All normal and tumour samples harbored the wild type TLR2 Arg753 allele. Our study suggests that variant TLR4 (Asp299Gly and Thr399Ile alleles) as well as TLR2 (Arg753Gln allele) are not associated with risk of colorectal cancer.
    Matched MeSH terms: Colorectal Neoplasms/genetics*
  9. Positive correlation between overexpression of phospho-BAD with phosphorylated Akt at serine 473 but not threonine 308 in colorectal carcinoma
    Khor TO, Gul YA, Ithnin H, Seow HF
    Cancer Lett, 2004 Jul 16;210(2):139-50.
    PMID: 15183529
    The enhancement of cell proliferation and promotion of cell survival via the inhibition of apoptosis is thought to be the key to the initiation and progression of cancers. The phosphatidylinositol-3 kinase (PI3K)/Akt is an important survival signal pathway that has been shown to be crucial in the regulation of balance between pro-apoptotic and survival (anti-apoptotic) signal. In this study, the expression of phosphorylated Akt at Thr308 and Ser473, BCL-2-antagonist of cell death (BAD) at Ser136 and glycogen synthase kinase-3beta (GSK-3beta) at Ser9 in 47 paraffin-embedded human colorectal carcinoma (CRC) tissues were determined by immunohistochemical staining in order to dissect the alterations in the signal transduction pathways in CRC. Our results showed that there was a significant increase in the expression of these biomolecules in CRC tissues compared to the apparently normal adjacent tissues. The frequency of increased expression in tumor colonic mucosa were as follows: p-Akt1/2/3 (Thr308) = 16/47 (34%); p-Akt1 (Ser473) = 21/47 (44.7%); phospho-BAD (p-BAD) Ser136 = 27/47 (57.4%) and phospho-GSK-3beta (p-GSK-3beta) = 21/47 (44.7%). Analysis of the total p-Akt1 (Ser473), p-Akt1/2/3 (Thr308), p-GSK-3beta (Ser9) and p-BAD (Ser136) score found that there was a statistically significant relationship with each other. A statistically significant positive linear relationship was found between total p-Akt (Ser473) score and total p-GSK-3beta (Ser9) score as well as with total p-BAD (Ser136) score. On the other hand, total p-Akt1/2/3 (Thr308) scores had a statistically significant positive linear relationship with p-GSK-3beta (Ser9) only. The Akt targets, p-GSK-3beta (Ser9) and p-BAD (Ser136) were positively correlated to each other. There was no significant correlation between clinico-pathological data with total p-Akt1 (Ser473), p-Akt1/2/3 (Thr308), p-GSK-3beta (Ser9) and p-BAD (Ser136) score except for age. The total scores of p-GSK-3beta were found to be higher in patients in the age group of greater than 60. This is the first report of p-Akt1/2/3 (Thr308) and p-BAD (Ser136) expression in primary colorectal tumor tissue. Our data further supports the role of PI3K/Akt signaling pathways in the pathogenesis of CRC and contributes to the identification of target molecules in the signal transduction pathway for cancer therapy.
    Matched MeSH terms: Colorectal Neoplasms/genetics
  10. Potential of dihydropyrimidine dehydrogenase genotypes in personalizing 5-fluorouracil therapy among colorectal cancer patients
    Teh LK, Hamzah S, Hashim H, Bannur Z, Zakaria ZA, Hasbullani Z, et al.
    Ther Drug Monit, 2013 Oct;35(5):624-30.
    PMID: 23942539 DOI: 10.1097/FTD.0b013e318290acd2
    Dihydropyrimidine dehydrogenase (DPD) is a pyrimidine catabolic enzyme involved in the initial and rate-limiting step of the catabolic pathway of toxic metabolites of 5-fluorouracil (5-FU). Several studies have reported that deficiency of DPD and polymorphisms of its gene are related to 5-FU toxicities and death. Association between serum concentration of 5-FU and its related toxicity has also been previously demonstrated. Hence, this study aims to understand the role of DPYD variants in serum level of 5-FU and the risk of developing toxicity to prevent adverse reactions and maximize therapy outcome for personalized medicine.
    Matched MeSH terms: Colorectal Neoplasms/genetics*
  11. Fulltext Overexpression of WNT2 and TSG101 genes in colorectal carcinoma
    Ma XR, Edmund Sim UH, Pauline B, Patricia L, Rahman J
    Trop Biomed, 2008 Apr;25(1):46-57.
    PMID: 18600204 MyJurnal
    Colorectal carcinoma (CRC) arises as a result of mutational activation of oncogenes coupled with inactivation of tumour suppressor genes. Mutations in APC, K-ras and p53 have been commonly reported. In a previous study by our group, the tumour susceptibility gene 101 (TSG101) were found to be persistently upregulated in CRC cases. TSG101 was reported to be closely related to cancers of the breast, brain and colon, and its overexpression in human papillary thyroid carcinomas and ovarian carcinomas had previously been reported. The wingless-type MMTV integration site family member 2 (WNT2) is potentially important in the Wnt/beta-catenin pathway and upregulation of WNT2 is not uncommon in human cancers. In this study, we report the investigation for mutation(s) and expression pattern(s) of WNT2 and TSG101, in an effort to further understand their role(s) in CRC tumourigenesis. Our results revealed no mutation in these genes, despite their persistent upregulation in CRC cases studied.
    Matched MeSH terms: Colorectal Neoplasms/genetics*
  12. Mutations in mitochondrial NADH dehydrogenase subunit 1 (mtND1) gene in colorectal carcinoma
    Yusnita Y, Norsiah MD, Rahman AJ
    Malays J Pathol, 2010 Dec;32(2):103-10.
    PMID: 21329181 MyJurnal
    Mitochondrial Subunit ND1 (mtND1) gene is involved in the first step of the electron transport chain of oxidative phosphorylation (OXPHOS). Alteration of the electron transport components by mutations in mtDNA may compromise the normal electron flow. This could lead to an increase of bifurcation and generation of superoxidase radicals and increase oxidative stress in various types of cancer cells. Genomic DNA was extracted from thirty matched primary colorectal tumour tissues and matching non-tumour tissues. Blood samples were obtained from twenty-five normal people. The mtNDI coding region was amplified by step-down PCR. The purified products were then subjected to direct sequencing and subsequently, the DNA sequences obtained were compared with the revised Cambridge Reference Sequence (rCRS) and MITOMAP. From the analysis, the mtND1 gene showed 11 (45.8%) different mutations and also 13 (54.2%) polymorphisms. The heteroplasmic mutation A4123A/G (I273I/V) might have a pathogenic significance as it fulfills various pathogenic criteria. Three mutations, T3394C (Y30H), A3434G (Y43C) and C3497T (A64V) which occur in a highly conserved region were likely to alter the structure and function of the ND1 protein. We suggest that these mutations, and in combination with the polymorphic variance in mtDNA, may cause slight changes that generate subtly higher levels of toxic reactive oxygen species (ROS).
    Matched MeSH terms: Colorectal Neoplasms/genetics*
  13. Fulltext Genetic variation in the ADIPOQ gene, adiponectin concentrations and risk of colorectal cancer: a Mendelian Randomization analysis using data from three large cohort studies
    Nimptsch K, Song M, Aleksandrova K, Katsoulis M, Freisling H, Jenab M, et al.
    Eur J Epidemiol, 2017 May;32(5):419-430.
    PMID: 28550647 DOI: 10.1007/s10654-017-0262-y
    Higher levels of circulating adiponectin have been related to lower risk of colorectal cancer in several prospective cohort studies, but it remains unclear whether this association may be causal. We aimed to improve causal inference in a Mendelian Randomization meta-analysis using nested case-control studies of the European Prospective Investigation into Cancer and Nutrition (EPIC, 623 cases, 623 matched controls), the Health Professionals Follow-up Study (HPFS, 231 cases, 230 controls) and the Nurses' Health Study (NHS, 399 cases, 774 controls) with available data on pre-diagnostic adiponectin concentrations and selected single nucleotide polymorphisms in the ADIPOQ gene. We created an ADIPOQ allele score that explained approximately 3% of the interindividual variation in adiponectin concentrations. The ADIPOQ allele score was not associated with risk of colorectal cancer in logistic regression analyses (pooled OR per score-unit unit 0.97, 95% CI 0.91, 1.04). Genetically determined twofold higher adiponectin was not significantly associated with risk of colorectal cancer using the ADIPOQ allele score as instrumental variable (pooled OR 0.73, 95% CI 0.40, 1.34). In a summary instrumental variable analysis (based on previously published data) with higher statistical power, no association between genetically determined twofold higher adiponectin and risk of colorectal cancer was observed (0.99, 95% CI 0.93, 1.06 in women and 0.94, 95% CI 0.88, 1.01 in men). Thus, our study does not support a causal effect of circulating adiponectin on colorectal cancer risk. Due to the limited genetic determination of adiponectin, larger Mendelian Randomization studies are necessary to clarify whether adiponectin is causally related to lower risk of colorectal cancer.
    Matched MeSH terms: Colorectal Neoplasms/genetics*
  14. Gene symbol: APC. Disease: colorectal cancer
    Tan LP, Ng BK, Balraj P, Poh BH, Lim PK, Peh SC
    Hum Genet, 2005 Dec;118(3-4):539-40.
    PMID: 16521263
    Matched MeSH terms: Colorectal Neoplasms/genetics*
  15. No difference in the occurrence of mismatch repair defects and APC and CTNNB1 genes mutation in a multi-racial colorectal carcinoma patient cohort
    Tan LP, Ng BK, Balraj P, Lim PK, Peh SC
    Pathology, 2007 Apr;39(2):228-34.
    PMID: 17454753
    BACKGROUND AND AIMS: Colorectal cancers of different subtypes involve different pathogenic pathways like the Wnt and the mutator pathways. In this study, we screened 73 colorectal cancer cases from a multi-racial group for genetic and expression profile defects with the aim of correlating these with patients' clinicopathological characteristics.
    METHODS: Mutation screening of the entire coding region of APC and exon 3 of CTNNB1, loss of heterozygosity (LOH) of APC, and microsatellite instability (MSI) status were assessed for 44 patients with available paired frozen normal and tumour tissues. In addition, 29 cases with available paraffin embedded tumour blocks were screened for mutation in exon 3 of CTNNB1, the APC mutation cluster region (codon 1286-1513), and hMLH1, hMSH2, hMSH6 protein expressions by immunohistochemistry method.
    RESULTS: In our study, 15/73 cases showed APC mutations (20.5%), 1/73 cases had CTNNB1 mutation (1.4%), 5/32 cases had APC LOH (15.6%), and 16/70 (22.9%) cases revealed at least some form of mismatch repair (MMR) defect. Tumour grade (poor differentiation) was found to correlate significantly with right-sided tumour and mucinous histology (p = 0.01879 and 0.00320, respectively). Patients of younger age (below 45 years) more often had tumours of mucinous histology (p = 0.00014), while patients of older age (above 75 years) more often had tumours on the right side of the colon (p = 0.02448). Tumours of the mucinous histology subtype often had MMR defects (p = 0.02686). There was no difference in the occurrence of APC and CTNNB1 mutations and MMR defects found within our multi-racial colorectal cancer patient cohort.
    CONCLUSION: Our findings support the notion that racial factor may not be related to the occurrence of MMR defects and APC and CTNNB1 mutations in our multi-racial patient cohort.
    Matched MeSH terms: Colorectal Neoplasms/genetics*
  16. Novel 2-Benzoyl-6-(2,3-Dimethoxybenzylidene)-Cyclohexenol Confers Selectivity toward Human MLH1 Defective Cancer Cells through Synthetic Lethality
    Song DSS, Leong SW, Ng KW, Abas F, Shaari K, Leong CO, et al.
    SLAS Discov, 2019 06;24(5):548-562.
    PMID: 30897027 DOI: 10.1177/2472555219831405
    DNA mismatch repair (MMR) deficiency has been associated with a higher risk of developing colorectal, endometrial, and ovarian cancer, and confers resistance in conventional chemotherapy. In addition to the lack of treatment options that work efficaciously on these MMR-deficient cancer patients, there is a great need to discover new drug leads for this purpose. In this study, we screened through a library of commercial and semisynthetic natural compounds to identify potential synthetic lethal drugs that may selectively target MLH1 mutants using MLH1 isogenic colorectal cancer cell lines and various cancer cell lines with known MLH1 status. We identified a novel diarylpentanoid analogue, 2-benzoyl-6-(2,3-dimethoxybenzylidene)-cyclohexenol, coded as AS13, that demonstrated selective toxicity toward MLH1-deficient cancer cells. Subsequent analysis suggested AS13 induced elevated levels of oxidative stress, resulting in DNA damage where only the proficient MLH1 cells were able to be repaired and hence escaping cellular death. While AS13 is modest in potency and selectivity, this discovery has the potential to lead to further drug development that may offer better treatment options for cancer patients with MLH1 deficiency.
    Matched MeSH terms: Colorectal Neoplasms/genetics
  17. Fulltext Mechanism of Apoptosis Induced by Curcumin in Colorectal Cancer
    Ismail NI, Othman I, Abas F, H Lajis N, Naidu R
    Int J Mol Sci, 2019 May 17;20(10).
    PMID: 31108984 DOI: 10.3390/ijms20102454
    Colorectal cancer (CRC) is among the top three cancer with higher incident and mortality rate worldwide. It is estimated that about over than 1.1 million of death and 2.2 million new cases by the year 2030. The current treatment modalities with the usage of chemo drugs such as FOLFOX and FOLFIRI, surgery and radiotherapy, which are usually accompanied with major side effects, are rarely cured along with poor survival rate and at higher recurrence outcome. This trigger the needs of exploring new natural compounds with anti-cancer properties which possess fewer side effects. Curcumin, a common spice used in ancient medicine was found to induce apoptosis by targeting various molecules and signaling pathways involved in CRC. Disruption of the homeostatic balance between cell proliferation and apoptosis could be one of the promoting factors in colorectal cancer progression. In this review, we describe the current knowledge of apoptosis regulation by curcumin in CRC with regard to molecular targets and associated signaling pathways.
    Matched MeSH terms: Colorectal Neoplasms/genetics*
  18. Fulltext P53 expression in colorectal carcinoma: the University of Malaya Medical Centre's experience
    Goh KSK, Ong TA, Peh SC, Yuen HL, Naicker M
    Med J Malaysia, 2004 Oct;59(4):515-21.
    PMID: 15779585
    Loss of P53 function is regarded as one of the critical steps in colorectal carcinogenesis. This study determines the P53 expression pattern of colorectal carcinoma in a cohort of 116 local patients. There was no significant relationship between overexpression of P53 with tumour stage (p=-0.209, chi square test) and grade (p=0.877, chi square test). Survival analysis using Kaplan-Meier procedure did not show significant relationship between P53 positivity with overall recurrence-free and survival outcome (p=0.3322 and 0.921 respectively; log rank test). Long-term follow-up may give a better evaluation on the prognostic value of P53 overexpression in colorectal carcinoma.
    Matched MeSH terms: Colorectal Neoplasms/genetics*
  19. Fulltext Gene Therapy Targeting p53 and KRAS for Colorectal Cancer Treatment: A Myth or the Way Forward?
    Hasbullah HH, Musa M
    Int J Mol Sci, 2021 Nov 03;22(21).
    PMID: 34769370 DOI: 10.3390/ijms222111941
    Colorectal cancer (CRC) is the third most commonly diagnosed malignancy worldwide and is responsible as one of the main causes of mortality in both men and women. Despite massive efforts to raise public awareness on early screening and significant advancements in the treatment for CRC, the majority of cases are still being diagnosed at the advanced stage. This contributes to low survivability due to this cancer. CRC patients present various genetic changes and epigenetic modifications. The most common genetic alterations associated with CRC are p53 and KRAS mutations. Gene therapy targeting defect genes such as TP53 (tumor suppressor gene encodes for p53) and KRAS (oncogene) in CRC potentially serves as an alternative treatment avenue for the disease in addition to the standard therapy. For the last decade, significant developments have been seen in gene therapy for translational purposes in treating various cancers. This includes the development of vectors as delivery vehicles. Despite the optimism revolving around targeted gene therapy for cancer treatment, it also has various limitations, such as a lack of availability of related technology, high cost of the involved procedures, and ethical issues. This article will provide a review on the potentials and challenges of gene therapy targeting p53 and KRAS for the treatment of CRC.
    Matched MeSH terms: Colorectal Neoplasms/genetics
  20. Fulltext Contribution of Genetic Polymorphisms of Inflammation Response Genes on Sporadic Colorectal Cancer Predisposition Risk in Malaysian Patients - A Case Control Study
    Ankathil R, Mustapha MA, Abdul Aziz AA, Mohd Shahpudin SN, Zakaria AD, Abu Hassan MR, et al.
    Asian Pac J Cancer Prev, 2019 06 01;20(6):1621-1632.
    PMID: 31244280 DOI: 10.31557/APJCP.2019.20.6.1621
    AIM: To investigate the frequencies and association of polymorphic genotypes of IL-8 -251 T>A, TNF-α -308
    G>A, ICAM-1 K469E, ICAM-1 R241G, IL-6 -174 G>C, and PPAR-γ 34 C>G in modulating susceptibility risk in
    Malaysian colorectal cancer (CRC) patients. Methods: In this case-control study, peripheral blood samples of 560
    study subjects (280 CRC patients and 280 controls) were collected, DNA extracted and genotyped using PCR-RFLP
    and Allele Specific PCR. The association between polymorphic genotype and CRC susceptibility risk was determined
    using Logistic Regression analysis deriving Odds ratio (OR) and 95% CI. Results: On comparing the frequencies of
    genotypes of all single nucleotide polymorphisms ( SNPs ) in patients and controls, the homozygous variant genotypes
    IL-8 -251 AA and TNF-α -308 AA and variant A alleles were significantly higher in CRC patients. Investigation on
    the association of the variant alleles and genotypes singly, with susceptibility risk showed the homozygous variant A
    alleles and genotypes IL-8 -251 AA and TNF-α -308 AA to be at higher risk for CRC predisposition. Analysis based
    on age, gender and smoking habits showed that the polymorphisms IL8 -251 T>A and TNF – α 308 G>A contribute
    to a significantly higher risk among male and female who are more than 50 years and for smokers in this population.
    Conclusion: We observed an association between variant allele and genotypes of IL-8-251 T>A and TNF-α-308
    G>A polymorphisms and CRC susceptibility risk in Malaysian patients. These two SNPs in inflammatory response
    genes which undoubtedly contribute to individual risks to CRC susceptibility may be considered as potential genetic
    predisposition factors for CRC in Malaysian population.
    Matched MeSH terms: Colorectal Neoplasms/genetics*
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