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Fulltext Author Correction: Delineating colorectal cancer distribution, interaction, and risk prediction by environmental risk factors and serum trace elements

Nawi AM, Chin SF, Mazlan L, Jamal R

Sci Rep, 2021 Feb 23;11(1):4853.
PMID: 33623112 DOI: 10.1038/s41598-021-83219-8
Fulltext Delineating colorectal cancer distribution, interaction, and risk prediction by environmental risk factors and serum trace elements

Nawi AM, Chin SF, Mazlan L, Jamal R

Sci Rep, 2020 10 29;10(1):18670.
PMID: 33122698 DOI: 10.1038/s41598-020-75760-9

The burden of colorectal cancer (CRC) is increasing worldwide especially in developing countries. This phenomenon may be attributable to lifestyle, dietary and environmental risk factors. We aimed to determine the level of 25 trace elements, their interaction with environmental risk factors, and subsequently develop a risk prediction model for CRC (RPM CRC). For the discovery phase, we used a hospital-based case-control study (CRC and non-CRC patients) and in the validation phase we analysed pre-symptomatic samples of CRC patients from The Malaysian Cohort Biobank. Information on the environmental risk factors were obtained and level of 25 trace elements measured using the ICP-MS method. CRC patients had lower Zn and Se levels but higher Li, Be, Al, Co, Cu, As, Cd, Rb, Ba, Hg, Tl, and Pb levels compared to non-CRC patients. The positive interaction between red meat intake ≥ 50 g/day and Co ≥ 4.77 µg/L (AP 0.97; 95% CI 0.91, 1.03) doubled the risk of CRC. A panel of 24 trace elements can predict simultaneously and accurate of high, moderate, and low risk of CRC (accuracy 100%, AUC 1.00). This study provides a new input on possible roles for various trace elements in CRC as well as using a panel of trace elements as a screening approach to CRC.
Profiling of cytokines, chemokines and other soluble proteins as a potential biomarker in colorectal cancer and polyps

Johdi NA, Mazlan L, Sagap I, Jamal R

Cytokine, 2017 11;99:35-42.
PMID: 28689023 DOI: 10.1016/j.cyto.2017.06.015

Soluble proteins including cytokines, chemokines and growth factors are small proteins that mediate and regulate immunity. They involved in the pathogenesis of many diseases including cancers. The concentration of these proteins in biological fluids (serum or plasma) and tissues in diseases may suggest pathway activation that leads to inflammatory response or disease progression. Therefore, these soluble proteins may be useful as a tool for screening, diagnosis classification between stages of disease or surveillance for therapy. Enzyme-linked immunosorbent assays (ELISA) and bioassay have been used as a gold standard in cytokine level measurements in clinical practice. However, these methods allow only single cytokine detection at a time and ineffective for screening purposes. Hence, the innovation of multiplexing technology allows measurement of many these soluble proteins simultaneously, thus allowing rapid, cost effective and better efficiency by using a minute amount of sample. In this study, we explored the profiles of key inflammatory cytokines, chemokines and other soluble proteins from the serum derived from colorectal carcinoma (CRC, n=20), colorectal polyps (P, n=20) and healthy volunteers (N, n=20) using multiplexed bead-based immunoassays. We aimed to evaluate if the levels of these soluble proteins can classify these groups of populations and explore the possible application of the soluble proteins as biomarkers in early stage screening and/or surveillance. We observed significant high IL-4, MIP-1β, FasL and TGF-β1 levels but lower levels for RANTES in P-derived serum as compared to N-derived serum. Significant high IL-8, VEGF, MIP-1β, Eotaxin and G-CSF observed in CRC-derived serum when compared to N-derived serum. Between CRC- and P-derived serum, significantly higher levels of IL-8, Eotaxin and G-CSF but lower levels for TGF-β1 were detected in CRC-derived serum. These preliminary results were obtained from small sample size and could be further validated with larger sample size cohort to produce a panel of biomarkers for CRC and P patients. Our findings might be useful in developing a disease-specific panel for biomarker screening assay. This could be used for early diagnosis and/or treatment surveillance.
Fulltext Identification of Schizosaccharomyces pombe in the guts of healthy individuals and patients with colorectal cancer: preliminary evidence from a gut microbiome secretome study

Chin SF, Megat Mohd Azlan PIH, Mazlan L, Neoh HM

Gut Pathog, 2018;10:29.
PMID: 30008808 DOI: 10.1186/s13099-018-0258-5

Over the years, genetic profiling of the gut microbiome of patients with colorectal cancer (CRC) using genome sequencing has suggested over-representation of several bacterial taxa. However, little is known about the protein or metabolite secretions from the microbiota that could lead to CRC pathology. Proteomic studies on the role of microbial secretome in CRC are relatively rare. Here, we report the identification of proteins from Schizosaccharomyces pombe found in the stool samples of both healthy individuals and patients with CRC. We found that distinctive sets of S. pombe proteins were present exclusively and in high intensities in each group. Our finding may trigger a new interest in the role of gut mycobiota in carcinogenesis.
Fulltext A Case of Large Perianal Mucinous Adenocarcinoma Arising from Recurrent Abscess and Complex Fistulae

Azmi FP, Rahman NAA, Mazlan L, Basiron N, Imran FH

Case Rep Surg, 2020;2020:1798543.
PMID: 33381344 DOI: 10.1155/2020/1798543

Mucinous adenocarcinoma of the perianal region is an oncologic rarity posing a diagnostic and therapeutic dilemma for treating oncologists. This is due to the low number of reported cases, compounded by the lack of definitive therapeutic guidelines. It accounts for 2% to 3% of all gastrointestinal malignancies and is historically known to arise from chronic anal fistulas and ischiorectal or perianal abscesses. We hereby report an interesting case of perianal mucinous adenocarcinoma in a 66-year-old male initially treated for a horseshoe abscess with complex fistulae. He presented with a 6-month history of a discharging growth in perianal region and painful defecation associated with occasional blood mixed stools. An incisional biopsy from the ulcer revealed mucinous adenocarcinoma. Contrast-enhanced computed tomography (CT) scan and magnetic resonance imaging (MRI) scan showed a localized perianal growth which involves the internal and external sphincter as well as suspicious involvement in the posterior aspect of the levator ani/puborectalis sling, which was further confirmed with colonoscopy (see figures). With no preset treatment protocol for this rare entity, he was managed with an abdominoperineal resection (APR) and vertical rectus abdominis myocutaneous flap (VRAM) tissue reconstruction. He had a turbulent postoperative period including intestinal obstruction secondary to internal herniation of bowel resulting in flap failure. The subsequent perineal wound was managed conservatively with advanced wound care and has since completely healed.
Serum Procalcitonin Predicts Anastomotic Leaks in Colorectal Surgery

Hayati F, Mohd Azman ZA, Nasuruddin DN, Mazlan L, Zakaria AD, Sagap I

Asian Pac J Cancer Prev, 2017 07 27;18(7):1821-1825.
PMID: 28749112

Background: Anastomotic leaks in colorectal surgery results in a high morbidity and mortality rate. Serum procalcitonin levels is known as a sensitive and specific marker of sepsis and could be use as a marker for early detection of a leak allowing early intervention. It may help a clinician decide to perform a CT scan even earlier especially when the diagnosis of a leak is uncertain. The aim of this study is to determine whether serum procalcitonin is a good predictor of anastomotic leak in colorectal surgery. Methodology: Between July 2014 until October 2015, 70 patients undergoing colorectal surgery were prospectively analyzed in a single-center tertiary teaching hospital. Demographic and surgical data were obtained. Serum procalcitonin was taken before surgery and at day 3 (72 hours) postoperatively. During the postoperative period, the patients were observed in the ward for features of anastomotic leak and if present, it was managed accordingly. The primary outcome was to prospectively determine an association between serum procalcitonin levels and an anastomotic leak in patients who underwent colorectal surgery with a primary anastomosis. Result: The rate of anastomotic leak was 4.5% (3 patients) with a mortality rate of 4.3% (3 patients). A rise in serum procalcitonin was statistically significant among patients with anastomotic leak. The optimal procalcitonin cut-off level at postoperative day 3 was 5.27 ng/mL, resulting in 100% sensitivity, 85% specificity, 23% positive predictive value and 100% negative predictive value. Nevertheless, none of the variables showed statistical significance with an anastomotic leak. Conclusion: Procalcitonin is a reliable biochemical marker to help diagnose anastomotic leak in colorectal surgery. Our study has shown that a level of 5 times beyond normal is statistically significant and a value of more than 5.27 ng/mL is confirmatory of a leak.
LOC285629 regulates cell proliferation and motility in colorectal cancer cells

Nasir SN, Abu N, Ab Mutalib NS, Ishak M, Sagap I, Mazlan L, et al.

Clin Transl Oncol, 2018 Jun;20(6):775-784.
PMID: 29098557 DOI: 10.1007/s12094-017-1788-x

PURPOSE: Colorectal cancer (CRC) is one of the most widely diagnosed cancers in men and women worldwide. With the advancement of next-generation sequencing technologies, many studies have highlighted the involvement of long non-coding RNAs (lncRNAs) in cancer development. Growing evidence demonstrates that lncRNAs play crucial roles in regulating gene and protein expression and are involved in various cancers, including CRC. The field of lncRNAs is still relatively new and a lot of novel lncRNAs have been discovered, but their functional roles are yet to be elucidated. This study aims to characterize the expression and functional roles of a novel lncRNA in CRC.
METHOD: Several methods were employed to assess the function of LOC285629 such as gene silencing, qPCR, proliferation assay, BrdU assay, transwell migration assay, ELISA and protein profiler.
RESULTS: Via in silico analyses, we identified significant downregulation of LOC285629, a novel lncRNA, across CRC stages. LOC285629 expression was significantly downregulated in advanced stages (Stage III and IV) compared to Stage I (Kruskal-Wallis Test; p = 0.0093). Further in-house validation showed that the expression of LOC285629 was upregulated in colorectal cancer tissues and cell lines compared to the normal counterparts, but was downregulated in advanced stages. By targeting LOC285629, the viability, proliferative abilities, invasiveness and resistance of colorectal cancer cells towards 5-fluorouracil were reduced. It was also discovered that LOC285629 may regulate cancer progression by targeting several different proteins, namely survivin, BCL-xL, progranulin, PDGF-AA, enolase 2 and p70S6 K.
CONCLUSION: Our findings suggest that LOC285629 may be further developed as a potential therapeutic target for CRC treatment.
Randomised controlled trial to assess and compare the performance and safety of two-piece ostomy appliances

Sagap I, Loo GH, Azman ZAM, Mazlan L, Gan SY, Eng HS, et al.

Br J Nurs, 2022 Dec 15;31(22):S34-S42.
PMID: 36519479 DOI: 10.12968/bjon.2022.31.22.S34

BACKGROUND: Choice of ostomy appliances is based on multiple factors including economic considerations, individual patient requirements and lifestyle. A recently launched two-piece ostomy collection device with an extended tape border is expected to provide a long wear time and increase patients' sense of security.
AIMS AND METHODS: A randomised controlled, non-blinded, cross-over study involving 38 patients (with colostomies and ileostomies) compared the test device to a similar device from the same manufacturer but without the tape border. The main objective was to assess wear time for non-inferiority as a measure of efficacy. Secondary efficacy assessment included peristomal skin condition using the DET (discolouration, erosion and tissue growth) score and patient acceptability, which was assessed through questionnaires using Likert-scale options. Safety was assessed according to the incidence and intensity of device-related adverse events, and the condition of the peristomal skin.
RESULTS AND CONCLUSION: Analysis of results in the per-protocol population showed an average wear time of 4.5 days for both devices and demonstrated non-inferiority. DET scores were similar in both groups, and both had low rates of device-related adverse events, all of which related to peristomal skin. Patients said the devices were user friendly. While the two devices are similar, some patients may find one with an adhesive tape more suited to their needs.
Fulltext Breast carcinoma occurring from chronic granulomatous mastitis

Mazlan L, Suhaimi SN, Jasmin SJ, Latar NH, Adzman S, Muhammad R

Malays J Med Sci, 2012 Apr;19(2):82-5.
PMID: 22973142 MyJurnal

Chronic granulomatous mastitis is known as a benign and relatively rare disorder that is often difficult to differentiate from breast carcinoma. We highlight the case of a 34-year-old woman who had recurrent episodes of right breast swelling and abscess for 8 years. These were proven to be chronic granulomatous mastitis by tissue biopsies on 3 different occasions. Her condition improved on similar courses of antibiotics and high-dose prednisolone. However, she subsequently developed progressive loss of vision due to an orbital tumour. She then underwent a craniotomy and left orbital decompression with excision of the tumour, which proved to be a metastatic carcinoma. A trucut biopsy of the right breast was then done and showed features consistent with an infiltrating ductal carcinoma. This case illustrates the possibility that chronic granulomatous mastitis could be a precursor for malignancy and the difficulty in differentiating one from the other. The possible mechanisms of development and the implications for future management are also discussed.
Extracellular Vesicles Derived From Colorectal Cancer Affects CD8 T Cells: An Analysis Based on Body Mass Index

Abu N, Othman N, Ab Razak NS, Bakarurraini NAAR, Nasir SN, Soh JEC, et al.

Front Cell Dev Biol, 2020;8:564648.
PMID: 33324632 DOI: 10.3389/fcell.2020.564648

Colorectal cancer (CRC) is one of the most widely diagnosed cancers worldwide. It has been shown that the body-mass index (BMI) of the patients could influence the tumor microenvironment, treatment response, and overall survival rates. Nevertheless, the mechanism on how BMI affects the tumorigenesis process, particularly the tumor microenvironment is still elusive. Herein, we postulate that extracellular vesicles (EVs) from CRC patients and non-CRC volunteers with different BMI could affect immune cells differently, in CD8 T cells particularly. We isolated the EVs from the archived serum of CRC patients with high and low BMI, as well as healthy controls with similar BMI status. The EVs were further characterized via electron microscopy, western blot and dynamic light scattering. Then, functional analysis was performed on CD8 T cells including apoptosis, cell proliferation, gene expression profiling and cytokine release upon co-incubation with the different EVs. Our results suggest that CRC-derived EVs were able to regulate the CD8 T cells. In some assays, low BMI EVs were functionally different than high BMI EVs. This study highlights the possible difference in the regulatory mechanism of cancer patients-derived EVs, especially on CD8 T cells.
Colorectal screening using the immunochemical faecal occult blood test kit among the Malaysian cohort participants

Abdullah N, Abd Jalal N, Ismail N, Kamaruddin MA, Abd Mutalib NS, Alias MR, et al.

Cancer Epidemiol, 2020 04;65:101656.
PMID: 31923638 DOI: 10.1016/j.canep.2019.101656

BACKGROUND: There has been a rapid increase in colorectal cancer (CRC) cases in Asian countries, including Malaysia. CRC is usually diagnosed at a late stage, and early detection of CRC is vital in improving survival. This study was conducted to determine the uptake rate of the immunochemical faecal occult blood test (iFOBT), the response rate to colonoscopy, and the CRC detection rate. We also wanted to identify the association between colorectal neoplasia and the Asia Pacific Colorectal Cancer Screening (APCS) scoring system.
METHODS: We recruited 2264 individuals from The Malaysian Cohort participants aged 35-65 years who consented to colorectal screening using the iFOBT kit from July 2017 until January 2019.
RESULTS: The response rate and positive iFOBT test rate of this study were 79.6% and 13.1% respectively. Among those with positive results, 125 individuals (52.7%) underwent colonoscopy; CRC was detected in six of them while 45 others (36.0%) had polyps. The overall CRC detection rate was 0.3% while the colorectal neoplasia detection rate (both colorectal cancer and colorectal polyps) was 2.3%. The APCS scoring indicated a significant association with colorectal neoplasia risk, with increasing trend by severity from moderate to high risk (3.46-11.14) compared to low risk. Most of the participants who were positive for iFOBT were those at high risk.
CONCLUSIONS: The awareness of CRC risk and iFOBT screening are important strategies for early detection of CRC. We showed a CRC detection rate of 0.3 % among those who volunteered to have the iFOBT screening.
Validation of immunogenic PASD1 peptides against HLA-A*24:02 colorectal cancer

Soh JE, Abu N, Sagap I, Mazlan L, Yahaya A, Mustangin M, et al.

Immunotherapy, 2019 10;11(14):1205-1219.
PMID: 31478431 DOI: 10.2217/imt-2019-0073

Colorectal cancer is the third commonest malignancy in Asia including Malaysia. The immunogenic cancer-testis antigens, which are expressed in a variety of cancers but with limited expression in normal tissues except the testis, represent an attractive approach to improve treatment options for colorectal cancer. We aimed to validate four PASD1 peptides as the immunotherapeutic targets in colorectal cancer. First, PASD1 mRNA and protein expression were determined via real-time polymerase chain reaction (RT-PCR) and immunohistochemistry. The PASD1 peptides specific to HLA-A*24:02 were investigated using IFN-y-ELISpot assay, followed by the cytolytic and granzyme-B-ELISpot assays to analyze the cytolytic effects of CD8+ T cells. Gene and protein expressions of PASD1 were detected in 20% and 17.3% of colorectal cancer samples, respectively. PASD1(4) peptide was shown to be immunogenic in colorectal cancer samples. CD8+ T cells raised against PASD1(4) peptide were able to lyze HLA-A*24:02+ PASD1+ cells. Our results reveal that PASD1(4) peptide represents a potential target for colorectal cancer.
Fulltext Parvimonas micra, Peptostreptococcus stomatis, Fusobacterium nucleatum and Akkermansia muciniphila as a four-bacteria biomarker panel of colorectal cancer

Osman MA, Neoh HM, Ab Mutalib NS, Chin SF, Mazlan L, Raja Ali RA, et al.

Sci Rep, 2021 02 03;11(1):2925.
PMID: 33536501 DOI: 10.1038/s41598-021-82465-0

Dysbiosis of the gut microbiome has been associated with the pathogenesis of colorectal cancer (CRC). We profiled the microbiome of gut mucosal tissues from 18 CRC patients and 18 non-CRC controls of the UKM Medical Centre (UKMMC), Kuala Lumpur, Malaysia. The results were then validated using a species-specific quantitative PCR in 40 CRC and 20 non-CRC tissues samples from the UMBI-UKMMC Biobank. Parvimonas micra, Fusobacterium nucleatum, Peptostreptococcus stomatis and Akkermansia muciniphila were found to be over-represented in our CRC patients compared to non-CRC controls. These four bacteria markers distinguished CRC from controls (AUROC = 0.925) in our validation cohort. We identified bacteria species significantly associated (cut-off value of > 5 fold abundance) with various CRC demographics such as ethnicity, gender and CRC staging; however, due to small sample size of the discovery cohort, these results could not be further verified in our validation cohort. In summary, Parvimonas micra, Fusobacterium nucleatum, Peptostreptococcus stomatis and Akkermansia muciniphila were enriched in our local CRC patients. Nevertheless, the roles of these bacteria in CRC initiation and progression remains to be investigated.
Fulltext Molecular Characterization of Somatic Alterations in Dukes' B and C Colorectal Cancers by Targeted Sequencing

Abdul SN, Ab Mutalib NS, Sean KS, Syafruddin SE, Ishak M, Sagap I, et al.

Front Pharmacol, 2017;8:465.
PMID: 28769798 DOI: 10.3389/fphar.2017.00465

Despite global progress in research, improved screening and refined treatment strategies, colorectal cancer (CRC) remains as the third most common malignancy. As each type of cancer is different and exhibits unique alteration patterns, identifying and characterizing gene alterations in CRC that may serve as biomarkers might help to improve diagnosis, prognosis and predict potential response to therapy. With the emergence of next generation sequencing technologies (NGS), it is now possible to extensively and rapidly identify the gene profile of individual tumors. In this study, we aimed to identify actionable somatic alterations in Dukes' B and C in CRC via NGS. Targeted sequencing of 409 cancer-related genes using the Ion Ampliseq(TM) Comprehensive Cancer Panel was performed on genomic DNA obtained from paired fresh frozen tissues, cancer and normal, of Dukes' B (n = 10) and Dukes' C (n = 9) CRC. The sequencing results were analyzed using Torrent Suite, annotated using ANNOVAR and validated using Sanger sequencing. A total of 141 somatic non-synonymous sequence variations were identified in 86 genes. Among these, 64 variants (45%) were predicted to be deleterious, 38 variants (27%) possibly deleterious while the other 39 variants (28%) have low or neutral protein impact. Seventeen genes have alterations with frequencies of ≥10% in the patient cohort and with 14 overlapped genes in both Dukes' B and C. The adenomatous polyposis coli gene (APC) was the most frequently altered gene in both groups (n = 6 in Dukes' B and C). In addition, TP53 was more frequently altered in Dukes' C (n = 7) compared to Dukes' B (n = 4). Ten variants in APC, namely p.R283(∗), p.N778fs, p.R805(∗), p.Y935fs, p.E941fs, p.E1057(∗), p.I1401fs, p.Q1378(∗), p.E1379(∗), and p.A1485fs were predicted to be driver variants. APC remains as the most frequently altered gene in the intermediate stages of CRC. Wnt signaling pathway is the major affected pathway followed by P53, RAS, TGF-β, and PI3K signaling. We reported the alteration profiles in each of the patient which has the potential to affect the clinical decision. We believe that this study will add further to the understanding of CRC molecular landscape.
Fulltext A four-decade analysis of the incidence trends, sociodemographic and clinical characteristics of inflammatory bowel disease patients at single tertiary centre, Kuala Lumpur, Malaysia

Mokhtar NM, Nawawi KNM, Verasingam J, Zhiqin W, Sagap I, Azman ZAM, et al.

BMC Public Health, 2019 Jun 13;19(Suppl 4):550.
PMID: 31196184 DOI: 10.1186/s12889-019-6858-2

BACKGROUND: Inflammatory bowel disease (IBD) was once considered as a Western disease. However, recent epidemiological data showed an emerging trend of IBD cases in the Eastern Asia countries. Clinico-epidemiological data of IBD in Malaysia is scarce. This study aimed to address this issue.
METHODS: Retrospective analysis of ulcerative colitis (UC) and Crohn's disease (CD), diagnosed from January 1980 till June 2018 was conducted at our centre.
RESULTS: A total of 413 IBD patients (281 UC, 132 CD) were identified. Mean crude incidence of IBD has increased steadily over the first three decades: 0.36 (1980-1989), 0.48 (1990-1999) and 0.63 per 100,000 person-years (2000-2009). In the 2010 to 2018 period, the mean crude incidence has doubled to 1.46 per 100,000 person-years. There was a significant rise in the incidence of CD, as depicted by reducing UC:CD ratio: 5:1 (1980-1989), 5:1 (1990-1999), 1.9:1 (2000-2009) and 1.7:1 (2010-2018). The prevalence rate of IBD, UC and CD, respectively were 23.0, 15.67 and 7.36 per 100,000 persons. Of all IBD patients, 61.5% (n = 254) were males. When stratified according to ethnic group, the highest prevalence of IBD was among the Indians: 73.4 per 100,000 persons, followed by Malays: 24.8 per 100,000 persons and Chinese: 14.6 per 100,000 persons. The mean age of diagnosis was 41.2 years for UC and 27.4 years for CD. Majority were non-smokers (UC: 76.9%, CD: 70.5%). The diseases were classified as follows: UC; proctitis (9.2%), left-sided colitis (50.2%) and extensive colitis (40.6%), CD; isolated ileal (22.7%), colonic (28.8%), ileocolonic (47.7%) and upper gastrointestinal (0.8%). 12.9% of CD patients had concurrent perianal disease. Extra intestinal manifestations were observed more in CD (53.8%) as compared to UC (12%). Dysplasia and malignancy, on the other hand, occurred more in UC (4.3%, n = 12) than in CD (0.8%, n = 1). Over one quarter (27.3%) of CD patients and 3.6% of UC patients received biologic therapy.
CONCLUSION: The incidence of IBD is rising in Malaysia, especially in the last one decade. This might be associated with the urbanization and changing diets. Public and clinicians' awareness of this emerging disease in Malaysia is important for the timely detection and management.
Whole genome sequencing of Malaysian colorectal cancer patients reveals specific druggable somatic mutations

Mohd Yunos RI, Ab Mutalib NS, Khoo JS, Saidin S, Ishak M, Syafruddin SE, et al.

Front Mol Biosci, 2022;9:997747.
PMID: 36866106 DOI: 10.3389/fmolb.2022.997747

The incidences of colorectal cancer (CRC) are continuously increasing in some areas of the world, including Malaysia. In this study, we aimed to characterize the landscape of somatic mutations using the whole-genome sequencing approach and identify druggable somatic mutations specific to Malaysian patients. Whole-genome sequencing was performed on the genomic DNA obtained from 50 Malaysian CRC patients' tissues. We discovered the top significantly mutated genes were APC, TP53, KRAS, TCF7L2 and ACVR2A. Four novel, non-synonymous variants were identified in three genes, which were KDM4E, MUC16 and POTED. At least one druggable somatic alteration was identified in 88% of our patients. Among them were two frameshift mutations in RNF43 (G156fs and P192fs) predicted to have responsive effects against the Wnt pathway inhibitor. We found that the exogenous expression of this RNF43 mutation in CRC cells resulted in increased cell proliferation and sensitivity against LGK974 drug treatment and G1 cell cycle arrest. In conclusion, this study uncovered our local CRC patients' genomic landscape and druggable alterations. It also highlighted the role of specific RNF43 frameshift mutations, which unveil the potential of an alternative treatment targeting the Wnt/β-Catenin signalling pathway and could be beneficial, especially to Malaysian CRC patients.

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