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Fulltext Differential Analysis of Genetic, Epigenetic, and Cytogenetic Abnormalities in AML

Islam M, Mohamed Z, Assenov Y

Int J Genomics, 2017;2017:2913648.
PMID: 28713819 DOI: 10.1155/2017/2913648

Acute myeloid leukemia (AML) is a haematological malignancy characterized by the excessive proliferation of immature myeloid cells coupled with impaired differentiation. Many AML cases have been reported without any known cytogenetic abnormalities and carry no mutation in known AML-associated driver genes. In this study, 200 AML cases were selected from a publicly available cohort and differentially analyzed for genetic, epigenetic, and cytogenetic abnormalities. Three genes (FLT3, DNMT3A, and NPMc) are found to be predominantly mutated. We identified several aberrations to be associated with genome-wide methylation changes. These include Del (5q), T (15; 17), and NPMc mutations. Four aberrations-Del (5q), T (15; 17), T (9; 22), and T (9; 11)-are significantly associated with patient survival. Del (5q)-positive patients have an average survival of less than 1 year, whereas T (15; 17)-positive patients have a significantly better prognosis. Combining the methylation and mutation data reveals three distinct patient groups and four clusters of genes. We speculate that combined signatures have the better potential to be used for subclassification of AML, complementing cytogenetic signatures. A larger sample cohort and further investigation of the effects observed in this study are required to enable the clinical application of our patient classification aided by DNA methylation.

Matched MeSH terms: Mutation
Fulltext Genetic Spectrum of Familial Hypercholesterolaemia in the Malaysian Community: Identification of Pathogenic Gene Variants Using Targeted Next-Generation Sequencing

Razman AZ, Chua YA, Mohd Kasim NA, Al-Khateeb A, Sheikh Abdul Kadir SH, Jusoh SA, et al.

Int J Mol Sci, 2022 Nov 29;23(23).
PMID: 36499307 DOI: 10.3390/ijms232314971

Familial hypercholesterolaemia (FH) is caused by mutations in lipid metabolism genes, predominantly in low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB), proprotein convertase subtilisin/kexin-type 9 (PCSK9) and LDL receptor adaptor protein 1 (LDLRAP1). The prevalence of genetically confirmed FH and the detection rate of pathogenic variants (PV) amongst clinically diagnosed patients is not well established. Targeted next-generation sequencing of LDLR, APOB, PCSK9 and LDLRAP1 was performed on 372 clinically diagnosed Malaysian FH subjects. Out of 361 variants identified, 40 of them were PV (18 = LDLR, 15 = APOB, 5 = PCSK9 and 2 = LDLRAP1). The majority of the PV were LDLR and APOB, where the frequency of both PV were almost similar. About 39% of clinically diagnosed FH have PV in PCSK9 alone and two novel variants of PCSK9 were identified in this study, which have not been described in Malaysia and globally. The prevalence of genetically confirmed potential FH in the community was 1:427, with a detection rate of PV at 0.2% (12/5130). About one-fourth of clinically diagnosed FH in the Malaysian community can be genetically confirmed. The detection rate of genetic confirmation is similar between potential and possible FH groups, suggesting a need for genetic confirmation in index cases from both groups. Clinical and genetic confirmation of FH index cases in the community may enhance the early detection of affected family members through family cascade screening.

Matched MeSH terms: Mutation
RAS and BRAF genes as biomarkers and target for personalised colorectal cancer therapy: An update

Ooi ZS, Pang SW, Teow SY

Malays J Pathol, 2022 Dec;44(3):415-428.
PMID: 36591710

Colorectal cancer (CRC) remains among the most commonly diagnosed cancers and has been on the rise. It is also one of the most lethal diseases globally, being the third leading cause of cancerrelated death. Depending on the stages and disease conditions, CRC is treated by surgery, chemo-, radio-therapy, immunotherapy or in combination. However, these therapies have subpar results with unwanted side effects, hence continuous effort is ongoing to explore new type of therapeutic modalities. Among the sub-types of CRC, KRAS, BRAF and NRAS mutated CRC comprise approximately 43%, 10% and 3% of the total cases, respectively. These mutations are associated with tumour progression and anti-epidermal growth factor receptor (EGFR) treatment resistance. Due to their important role in CRC, these genes have thus become targets in the development of novel treatments. In this paper, we discuss the current and upcoming treatment on CRC by targeting these mutated genes, with more focus on KRAS and BRAF due to the higher occurrence of mutations in CRC.

Matched MeSH terms: Mutation
Fulltext Pax6 mutant cerebral organoids partially recapitulate phenotypes of Pax6 mutant mouse strains

Ferdaos N, Lowell S, Mason JO

PLoS One, 2022;17(11):e0278147.
PMID: 36441708 DOI: 10.1371/journal.pone.0278147

Cerebral organoids show great promise as tools to unravel the complex mechanisms by which the mammalian brain develops during embryogenesis. We generated mouse cerebral organoids harbouring constitutive or conditional mutations in Pax6, which encodes a transcription factor with multiple important roles in brain development. By comparing the phenotypes of mutant organoids with the well-described phenotypes of Pax6 mutant mouse embryos, we evaluated the extent to which cerebral organoids reproduce phenotypes previously described in vivo. Organoids lacking Pax6 showed multiple phenotypes associated with its activity in mice, including precocious neural differentiation, altered cell cycle and an increase in abventricular mitoses. Neural progenitors in both Pax6 mutant and wild type control organoids cycled more slowly than their in vivo counterparts, but nonetheless we were able to identify clear changes to cell cycle attributable to the absence of Pax6. Our findings support the value of cerebral organoids as tools to explore mechanisms of brain development, complementing the use of mouse models.

Matched MeSH terms: Mutation
Secukinumab in the treatment of a child with congenital ichthyosiform erythroderma with ABCA12 mutation

Albela H, Leong KF

Int J Dermatol, 2023 Jan;62(1):e27-e29.
PMID: 35933655 DOI: 10.1111/ijd.16378
Matched MeSH terms: Mutation
Anaplastic lymphoma kinase (ALK) mutations in patients with adenocarcinoma of the lung

Mohamad N, Jayalakshmi P, Rhodes A, Liam CK, Tan JL, Yousoof S, et al.

Br J Biomed Sci, 2017 Oct;74(4):176-180.
PMID: 28705139 DOI: 10.1080/09674845.2017.1331520

BACKGROUND: Non-small cell lung cancer (NSCLC) is a major cause of cancer-related death. Approximately 2-16% of NSCLC patients with wild-type epidermal growth factor receptor (EGFR) harbour anaplastic lymphoma kinase (ALK) mutations. Both EGFR and ALK mutations occur most commonly in Asian patients with NSCLC. As targeted therapy is available for NSCLC patients with these mutations, it is important to establish reliable assays and testing strategies to identify those most likely to benefit from this therapy.
MATERIALS AND METHODS: Patients diagnosed with adenocarcinoma of the lung between 2010 and 2014 were tested for EGFR mutations. Of these, 92 cases were identified as EGFR wild type and suitable candidates for ALK testing utilising immunohistochemistry and the rabbit monoclonal antibody D5F3. The reliability of the IHC was confirmed by validating the results against those achieved by fluorescence in situ hybridisation (FISH) to detect ALK gene rearrangements.
RESULTS: Twelve (13%) cases were positive for ALK expression using immunohistochemistry. Of the 18 evaluable cases tested by FISH, there was 100% agreement with respect to ALK rearrangement/ALK expression between the assays, with 11 cases ALK negative and 7 cases ALK positive by both assays. ALK tumour expression was significantly more common in female compared to male patients (29.6% vs. 6.2%, P

Matched MeSH terms: Mutation
Communication about positive BRCA1 and BRCA2 genetic test results and uptake of testing in relatives in a diverse Asian setting

Lee DS, Meiser B, Mariapun S, Hassan T, Yip CH, Mohd Taib NA, et al.

J Genet Couns, 2021 Jun;30(3):720-729.
PMID: 33245177 DOI: 10.1002/jgc4.1360

The vast majority of studies assessing communication of BRCA1/2 results with relatives and family uptake of BRCA1/2 testing have been conducted in Western societies, and a dearth of studies have been conducted in Asia among relatives of diverse carriers of pathogenic BRCA1/2 germline variants. This study aimed to present rates of BRCA1/2 result disclosure by probands and probands' motivators and barriers of family communication and predictive testing uptake among eligible relatives. It also examined patterns of disclosure and testing uptake among different types of relatives. Eighty-seven carriers with either breast or ovarian cancer, who had previously been found to be carriers of a pathogenic variant in BRCA1/2, were interviewed over the phone using a semi-structured interview guide. Fifty-six percent of patients were Chinese, 21% were Indian, and 23% were Malay. It was found that 62.0% of eligible first- and second-degree relatives were informed by the proband about the testing result and that 11.5% of eligible first- and second-degree relatives had genetic testing. First-degree relatives were more likely to have been informed and tested compared to second-degree relatives, as were sisters compared to brothers. The low rates of family communication and testing uptake documented in this study suggest that interventions should focus on encouraging probands to inform male and second-degree relatives and targeting such relatives to increase informed decisions and accessibility to testing. Promotion strategies should be culturally sensitive to optimize outcomes.

Matched MeSH terms: Mutation
Fulltext Pathology of Tumors Associated With Pathogenic Germline Variants in 9 Breast Cancer Susceptibility Genes

Breast Cancer Association Consortium, Mavaddat N, Dorling L, Carvalho S, Allen J, González-Neira A, et al.

JAMA Oncol, 2022 Mar 01;8(3):e216744.
PMID: 35084436 DOI: 10.1001/jamaoncol.2021.6744

IMPORTANCE: Rare germline genetic variants in several genes are associated with increased breast cancer (BC) risk, but their precise contributions to different disease subtypes are unclear. This information is relevant to guidelines for gene panel testing and risk prediction.
OBJECTIVE: To characterize tumors associated with BC susceptibility genes in large-scale population- or hospital-based studies.
DESIGN, SETTING, AND PARTICIPANTS: The multicenter, international case-control analysis of the BRIDGES study included 42 680 patients and 46 387 control participants, comprising women aged 18 to 79 years who were sampled independently of family history from 38 studies. Studies were conducted between 1991 and 2016. Sequencing and analysis took place between 2016 and 2021.
EXPOSURES: Protein-truncating variants and likely pathogenic missense variants in ATM, BARD1, BRCA1, BRCA2, CHEK2, PALB2, RAD51C, RAD51D, and TP53.
MAIN OUTCOMES AND MEASURES: The intrinsic-like BC subtypes as defined by estrogen receptor, progesterone receptor, and ERBB2 (formerly known as HER2) status, and tumor grade; morphology; size; stage; lymph node involvement; subtype-specific odds ratios (ORs) for carrying protein-truncating variants and pathogenic missense variants in the 9 BC susceptibility genes.
RESULTS: The mean (SD) ages at interview (control participants) and diagnosis (cases) were 55.1 (11.9) and 55.8 (10.6) years, respectively; all participants were of European or East Asian ethnicity. There was substantial heterogeneity in the distribution of intrinsic subtypes by gene. RAD51C, RAD51D, and BARD1 variants were associated mainly with triple-negative disease (OR, 6.19 [95% CI, 3.17-12.12]; OR, 6.19 [95% CI, 2.99-12.79]; and OR, 10.05 [95% CI, 5.27-19.19], respectively). CHEK2 variants were associated with all subtypes (with ORs ranging from 2.21-3.17) except for triple-negative disease. For ATM variants, the association was strongest for the hormone receptor (HR)+ERBB2- high-grade subtype (OR, 4.99; 95% CI, 3.68-6.76). BRCA1 was associated with increased risk of all subtypes, but the ORs varied widely, being highest for triple-negative disease (OR, 55.32; 95% CI, 40.51-75.55). BRCA2 and PALB2 variants were also associated with triple-negative disease. TP53 variants were most strongly associated with HR+ERBB2+ and HR-ERBB2+ subtypes. Tumors occurring in pathogenic variant carriers were of higher grade. For most genes and subtypes, a decline in ORs was observed with increasing age. Together, the 9 genes were associated with 27.3% of all triple-negative tumors in women 40 years or younger.
CONCLUSIONS AND RELEVANCE: The results of this case-control study suggest that variants in the 9 BC risk genes differ substantially in their associated pathology but are generally associated with triple-negative and/or high-grade disease. Knowing the age and tumor subtype distributions associated with individual BC genes can potentially aid guidelines for gene panel testing, risk prediction, and variant classification and guide targeted screening strategies.

Matched MeSH terms: Germ-Line Mutation
Fulltext The spectrum of beta-globin gene mutations in children with beta-thalassaemia major from Kota Kinabalu, Sabah, Malaysia

Thong MK, Soo TL

Singapore Med J, 2005 Jul;46(7):340-3.
PMID: 15968446

Beta-thalassaemia major is one of the commonest genetic disorders in South East Asia. The strategy for the community control of beta-thalassaemia major requires the characterisation of the spectrum of beta-globin gene mutations in any multi-ethnic population. There is only a single report of mutation analyses of the beta-globin gene in an isolated Kadazandusun community in Kota Belud, Sabah, Malaysia, which showed the presence of a common 45 kb deletion.

Matched MeSH terms: Mutation
Improving the substrate binding of acetyl-CoA carboxylase (AccB) from Streptomyces antibioticus through computational enzyme engineering

Ali I, Wei DQ, Khan A, Feng Y, Waseem M, Hussain Z, et al.

Biotechnol Appl Biochem, 2024 Apr;71(2):402-413.
PMID: 38287712 DOI: 10.1002/bab.2548

Malonyl-CoA serves as the main building block for the biosynthesis of many important polyketides, as well as fatty acid-derived compounds, such as biofuel. Escherichia coli, Corynebacterium gultamicum, and Saccharomyces cerevisiae have recently been engineered for the biosynthesis of such compounds. However, the developed processes and strains often have insufficient productivity. In the current study, we used enzyme-engineering approach to improve the binding of acetyl-CoA with ACC. We generated different mutations, and the impact was calculated, which reported that three mutations, that is, S343A, T347W, and S350W, significantly improve the substrate binding. Molecular docking investigation revealed an altered binding network compared to the wild type. In mutants, additional interactions stabilize the binding of the inner tail of acetyl-CoA. Using molecular simulation, the stability, compactness, hydrogen bonding, and protein motions were estimated, revealing different dynamic properties owned by the mutants only but not by the wild type. The findings were further validated by using the binding-free energy (BFE) method, which revealed these mutations as favorable substitutions. The total BFE was reported to be -52.66 ± 0.11 kcal/mol for the wild type, -55.87 ± 0.16 kcal/mol for the S343A mutant, -60.52 ± 0.25 kcal/mol for T347W mutant, and -59.64 ± 0.25 kcal/mol for the S350W mutant. This shows that the binding of the substrate is increased due to the induced mutations and strongly corroborates with the docking results. In sum, this study provides information regarding the essential hotspot residues for the substrate binding and can be used for application in industrial processes.

Matched MeSH terms: Mutation
Fulltext Thymic involution and rising disease incidence with age

Palmer S, Albergante L, Blackburn CC, Newman TJ

Proc Natl Acad Sci U S A, 2018 02 20;115(8):1883-1888.
PMID: 29432166 DOI: 10.1073/pnas.1714478115

For many cancer types, incidence rises rapidly with age as an apparent power law, supporting the idea that cancer is caused by a gradual accumulation of genetic mutations. Similarly, the incidence of many infectious diseases strongly increases with age. Here, combining data from immunology and epidemiology, we show that many of these dramatic age-related increases in incidence can be modeled based on immune system decline, rather than mutation accumulation. In humans, the thymus atrophies from infancy, resulting in an exponential decline in T cell production with a half-life of ∼16 years, which we use as the basis for a minimal mathematical model of disease incidence. Our model outperforms the power law model with the same number of fitting parameters in describing cancer incidence data across a wide spectrum of different cancers, and provides excellent fits to infectious disease data. This framework provides mechanistic insight into cancer emergence, suggesting that age-related decline in T cell output is a major risk factor.

Matched MeSH terms: Mutation
Fulltext Somatic mutations of CADM1 in aldosterone-producing adenomas and gap junction-dependent regulation of aldosterone production

Wu X, Azizan EAB, Goodchild E, Garg S, Hagiyama M, Cabrera CP, et al.

Nat Genet, 2023 Jun;55(6):1009-1021.
PMID: 37291193 DOI: 10.1038/s41588-023-01403-0

Aldosterone-producing adenomas (APAs) are the commonest curable cause of hypertension. Most have gain-of-function somatic mutations of ion channels or transporters. Herein we report the discovery, replication and phenotype of mutations in the neuronal cell adhesion gene CADM1. Independent whole exome sequencing of 40 and 81 APAs found intramembranous p.Val380Asp or p.Gly379Asp variants in two patients whose hypertension and periodic primary aldosteronism were cured by adrenalectomy. Replication identified two more APAs with each variant (total, n = 6). The most upregulated gene (10- to 25-fold) in human adrenocortical H295R cells transduced with the mutations (compared to wildtype) was CYP11B2 (aldosterone synthase), and biological rhythms were the most differentially expressed process. CADM1 knockdown or mutation inhibited gap junction (GJ)-permeable dye transfer. GJ blockade by Gap27 increased CYP11B2 similarly to CADM1 mutation. Human adrenal zona glomerulosa (ZG) expression of GJA1 (the main GJ protein) was patchy, and annular GJs (sequelae of GJ communication) were less prominent in CYP11B2-positive micronodules than adjacent ZG. Somatic mutations of CADM1 cause reversible hypertension and reveal a role for GJ communication in suppressing physiological aldosterone production.

Matched MeSH terms: Mutation
Fulltext Germline breast cancer susceptibility genes, tumor characteristics, and survival

Ho PJ, Khng AJ, Loh HW, Ho WK, Yip CH, Mohd-Taib NA, et al.

Genome Med, 2021 Dec 02;13(1):185.
PMID: 34857041 DOI: 10.1186/s13073-021-00978-9

BACKGROUND: Mutations in certain genes are known to increase breast cancer risk. We study the relevance of rare protein-truncating variants (PTVs) that may result in loss-of-function in breast cancer susceptibility genes on tumor characteristics and survival in 8852 breast cancer patients of Asian descent.
METHODS: Gene panel sequencing was performed for 34 known or suspected breast cancer predisposition genes, of which nine genes (ATM, BRCA1, BRCA2, CHEK2, PALB2, BARD1, RAD51C, RAD51D, and TP53) were associated with breast cancer risk. Associations between PTV carriership in one or more genes and tumor characteristics were examined using multinomial logistic regression. Ten-year overall survival was estimated using Cox regression models in 6477 breast cancer patients after excluding older patients (≥75years) and stage 0 and IV disease.
RESULTS: PTV9genes carriership (n = 690) was significantly associated (p < 0.001) with more aggressive tumor characteristics including high grade (poorly vs well-differentiated, odds ratio [95% confidence interval] 3.48 [2.35-5.17], moderately vs well-differentiated 2.33 [1.56-3.49]), as well as luminal B [HER-] and triple-negative subtypes (vs luminal A 2.15 [1.58-2.92] and 2.85 [2.17-3.73], respectively), adjusted for age at diagnosis, study, and ethnicity. Associations with grade and luminal B [HER2-] subtype remained significant after excluding BRCA1/2 carriers. PTV25genes carriership (n = 289, excluding carriers of the nine genes associated with breast cancer) was not associated with tumor characteristics. However, PTV25genes carriership, but not PTV9genes carriership, was suggested to be associated with worse 10-year overall survival (hazard ratio [CI] 1.63 [1.16-2.28]).
CONCLUSIONS: PTV9genes carriership is associated with more aggressive tumors. Variants in other genes might be associated with the survival of breast cancer patients. The finding that PTV carriership is not just associated with higher breast cancer risk, but also more severe and fatal forms of the disease, suggests that genetic testing has the potential to provide additional health information and help healthy individuals make screening decisions.

Matched MeSH terms: Germ-Line Mutation
Fulltext The distribution and host range of the banana Fusarium wilt fungus, Fusarium oxysporum f. sp. cubense, in Asia

Mostert D, Molina AB, Daniells J, Fourie G, Hermanto C, Chao CP, et al.

PLoS One, 2017;12(7):e0181630.
PMID: 28719631 DOI: 10.1371/journal.pone.0181630

Fusarium oxysporum formae specialis cubense (Foc) is a soil-borne fungus that causes Fusarium wilt, which is considered to be the most destructive disease of bananas. The fungus is believed to have evolved with its host in the Indo-Malayan region, and from there it was spread to other banana-growing areas with infected planting material. The diversity and distribution of Foc in Asia was investigated. A total of 594 F. oxysporum isolates collected in ten Asian countries were identified by vegetative compatibility groups (VCGs) analysis. To simplify the identification process, the isolates were first divided into DNA lineages using PCR-RFLP analysis. Six lineages and 14 VCGs, representing three Foc races, were identified in this study. The VCG complex 0124/5 was most common in the Indian subcontinent, Vietnam and Cambodia; whereas the VCG complex 01213/16 dominated in the rest of Asia. Sixty-nine F. oxysporum isolates in this study did not match any of the known VCG tester strains. In this study, Foc VCG diversity in Bangladesh, Cambodia and Sri Lanka was determined for the first time and VCGs 01221 and 01222 were first reported from Cambodia and Vietnam. New associations of Foc VCGs and banana cultivars were recorded in all the countries where the fungus was collected. Information obtained in this study could help Asian countries to develop and implement regulatory measures to prevent the incursion of Foc into areas where it does not yet occur. It could also facilitate the deployment of disease resistant banana varieties in infested areas.

Matched MeSH terms: Mutation
Detection of somatic mutations in the mitochondrial DNA control region D-loop in brain tumors: The first report in Malaysian patients

Mohamed Yusoff AA, Mohd Nasir KN, Haris K, Mohd Khair SZN, Abdul Ghani ARI, Idris Z, et al.

Oncol Lett, 2017 Nov;14(5):5179-5188.
PMID: 29098023 DOI: 10.3892/ol.2017.6851

Although the role of nuclear-encoded gene alterations has been well documented in brain tumor development, the involvement of the mitochondrial genome in brain tumorigenesis has not yet been fully elucidated and remains controversial. The present study aimed to identify mutations in the mitochondrial DNA (mtDNA) control region D-loop in patients with brain tumors in Malaysia. A mutation analysis was performed in which DNA was extracted from paired tumor tissue and blood samples obtained from 49 patients with brain tumors. The D-loop region DNA was amplified using the PCR technique, and genetic data from DNA sequencing analyses were compared with the published revised Cambridge sequence to identify somatic mutations. Among the 49 brain tumor tissue samples evaluated, 25 cases (51%) had somatic mutations of the mtDNA D-loop, with a total of 48 mutations. Novel mutations that had not previously been identified in the D-loop region (176 A-deletion, 476 C>A, 566 C>A and 16405 A-deletion) were also classified. No significant associations between the D-loop mutation status and the clinicopathological parameters were observed. To the best of our knowledge, the current study presents the first evidence of alterations in the mtDNA D-loop regions in the brain tumors of Malaysian patients. These results may provide an overview and data regarding the incidence of mitochondrial genome alterations in Malaysian patients with brain tumors. In addition to nuclear genome aberrations, these specific mitochondrial genome alterations may also be considered as potential cancer biomarkers for the diagnosis and staging of brain cancers.

Matched MeSH terms: DNA Mutational Analysis; Mutation
Gefitinib as first line therapy in Malaysian patients with EGFR mutation-positive non-small-cell lung cancer: A single-center retrospective study

Abdullah MM, Bhat A, Mohamed AK, Ching FY, Ahmed N, Gantotti S

Oncol Lett, 2016 Apr;11(4):2757-2762.
PMID: 27073548

The present retrospective, single-center study evaluated the objective response rate (ORR) and progression-free survival (PFS) of epidermal growth factor receptor (EGFR) mutation-positive Malaysian patients with advanced lung adenocarcinoma treated with gefitinib. During May 2008 to July 2013, 33 patients with Stage IV, EGFR mutation-positive non-small-cell lung cancer (NSCLC) were identified and received gefitinib (250 mg) as first line treatment. The primary and secondary end points were ORR, PFS and safety, respectively. A total of 18 (54.5%) and 2 (6.1%) patients achieved partial response (PR) and complete response (CR) to gefitinib therapy, respectively, yielding an ORR of 60.6% (95% CI, 42.1-77.1%). Patients with exon 20 or 21 mutations (n=6, 66.7%) tended to have better ORR compared with exon 19 (n=22, 59.1%). The median PFS was 8.9 months in Malaysian patients with EGFR mutation-positive NSCLC, treated with gefitinib. The majority of treatment-related toxicity was mild in nature. The most frequently reported adverse events included dry skin (39.4%), skin rash (27.2%), and dermatitis acneiform (15.2%). In conclusion, Malaysian patients with locally advanced and metastatic EGFR mutation-positive NSCLC responded favorably to gefitinib therapy in terms of ORR, median PFS, and tolerability, the results of which were consistent with those of the IPASS study conducted in an Asian population. Considering the efficacy and safety profile of gefitinib, it is a favorable option for the first-line treatment of Malaysian patients with EGFR mutation-positive NSCLC. However, future long-term studies in a larger population of Malaysian patients are required to support whether the prolonged PFS conferred by gefitinib will translate into prolonged overall survival.

Matched MeSH terms: Mutation
Morindone as a potential therapeutic compound targeting TP53 and KRAS mutations in colorectal cancer cells

Chee CW, Mohd Hashim N, Nor Rashid N

Chem Biol Interact, 2024 Apr 01;392:110928.
PMID: 38423379 DOI: 10.1016/j.cbi.2024.110928

There is an increasing demand for anticancer agent in treating colorectal cancer (CRC) with frequently mutated TP53 and KRAS genes. Phytochemical compounds are suitable as chemoprevention for CRC since dietary factor is a major risk factor. Anthraquinones from Morinda citrifolia L. were previously reported with various pharmacological properties. Various in vitro experiments were conducted to investigate the effects of two anthraquinones: damnacanthal and morindone on the cell proliferation, cell cycle, apoptosis, gene expression and protein expression in two CRC cells: HCT116 and HT29. Real-time monitoring of CRC cells showed that both anthraquinones exerted significant anti-proliferative effects in a dose- and time-dependent manner. Next, cell cycle analysis revealed an increase in the percentage of CRC cells in the G1 phase under anthraquinones treatment. Fluorescence microscopy also showed an increment of apoptotic cells under anthraquinones' treatment. siRNA transfection was conducted to evaluate the mediating effect of gene knockdown on mutated TP53 and KRAS in CRC cells. Before transfection, qRT-PCR analysis showed that only morindone downregulated the gene expression of mutated TP53 and KRAS and then further downregulated them after transfection. Both damnacanthal and morindone treatments further downregulated the expression of these two genes but upregulated at the protein expression level. Furthermore, gene knockdown also sensitised CRC cells to both damnacanthal and morindone treatments, resulting in lowered IC50 values. The accumulation of cells at the G1 phase was reduced after gene knockdown but increased after damnacanthal and morindone treatments. In addition, gene knockdown has increased the number of apoptotic cells in both cell lines and further increment was observed after anthraquinone treatment. In conclusion, morindone could be a competitive therapeutic agent in CRC by exhibiting multiple mechanism of anti-cancer actions.

Matched MeSH terms: Mutation
Molecular target therapeutics of EGF-TKI and downstream signaling pathways in non-small cell lung cancers

Liu CY, Lin HF, Lai WY, Lin YY, Lin TW, Yang YP, et al.

J Chin Med Assoc, 2022 Apr 01;85(4):409-413.
PMID: 35383703 DOI: 10.1097/JCMA.0000000000000703

Lung carcinoma (LC) is the third most common cancer diagnosis and accounted for the most cancer-related mortality worldwide in 2018. Based on the type of cells from which it originates, LC is commonly classified into non-small cell lung cancers (NSCLC) and small cell lung cancers (SCLC). NSCLC account for the majority of LC and can be further categories into adenocarcinoma, large cell carcinoma, and squamous cell carcinoma. Accurate classification of LC is critical for its adequate treatment and therapeutic outcome. Since NSCLC express more epidermal growth factor receptor (EGFR) with activation mutations, targeted therapy EGFR-tyrosine kinase inhibitors (TKIs) have been considered as primary option of NSCLC patients with activation EGFR mutation. In this review, we present the genetic alterations, reported mutations in EGFR, and TKIs treatment in NSCLC patients with an emphasis on the downstream signaling pathways in NSCLC progression. Among the signaling pathways identified, mitogen activation protein kinase (MAPK), known also as extracellular signal-regulated protein kinase (Erk) pathway, is the most investigated among the related pathways. EGFR activation leads to the autophosphorylation of its kinase domain and subsequent activation of Ras, phosphorylation of Raf and MEK1/2, and the activation of ERK1/2. Phosphatidylinositol 3-kinase (PI3K)/Akt is another signal pathway that regulates cell cycle and has been linked to NSCLC progression. Currently, three generations of EGFR TKIs have been developed as a first-line treatment of NSCLC patients with EGFR activation and mutation in which these treatment options will be further discussed in this review. The Supplementary Appendix for this article is available at http://links.lww.com/JCMA/A138.

Matched MeSH terms: Mutation
Fulltext Case Series of Genetically Confirmed Index Cases of Familial Hypercholesterolemia in Primary Care

Kamal A, Kanchau JD, Shahuri NS, Mohamed-Yassin MS, Baharudin N, Abdul Razak S, et al.

Am J Case Rep, 2023 Apr 27;24:e939489.
PMID: 37185657 DOI: 10.12659/AJCR.939489

BACKGROUND In Malaysia, the prevalence of genetically confirmed heterozygous familial hypercholesterolemia (FH) was reported as 1 in 427. Despite this, FH remains largely underdiagnosed and undertreated in primary care. CASE REPORT In this case series, we report 3 FH cases detected in primary care due to mutations in the low-density lipoprotein receptor (LDLR), apolipoprotein-B (APOB), and proprotein convertase subtilisin/kexin type 9 (PCSK9) genes. The mutations in case 1 (frameshift c.660del pathogenic variant in LDLR gene) and case 2 (missense c.10579C>T pathogenic variant in APOB gene) were confirmed as pathogenic, while the mutation in case 3 (missense c.277C>T mutation in PCSK9 gene) may have been benign. In case 1, the patient had the highest LDL-c level, 8.6 mmol/L, and prominent tendon xanthomas. In case 2, the patient had an LDL-c level of 5.7 mmol/L and premature corneal arcus. In case 3, the patient had an LDL-c level of 5.4 mmol/L but had neither of the classical physical findings. Genetic counseling and diagnosis were delivered by primary care physicians. These index cases were initially managed in primary care with statins and therapeutic lifestyle modifications. They were referred to the lipid specialists for up-titration of lipid lowering medications. First-degree relatives were identified and referred for cascade testing. CONCLUSIONS This case series highlights different phenotypical expressions in patients with 3 different FH genetic mutations. Primary care physicians should play a pivotal role in the detection of FH index cases, genetic testing, management, and cascade screening of family members, in partnership with lipid specialists.

Matched MeSH terms: Mutation
Identification of Four Novel Candidate Genes for Non-syndromic Intellectual Disability in Pakistani Families

Ahmed I, Muzammal M, Khan MA, Ullah H, Farid A, Yasin M, et al.

Biochem Genet, 2024 Aug;62(4):2571-2586.
PMID: 37985543 DOI: 10.1007/s10528-023-10556-w

Intellectual disability, a genetically and clinically varied disorder and is a significant health problem, particularly in less developed countries due to larger family size and high ratio of consanguineous marriages. In the current genetic study, we investigate and find the novel disease causative factors in the four Pakistani families with severe type of non-syndromic intellectual disability. For genetic analysis whole-exome sequencing (WES) and Sanger sequencing was performed. I-TASSER and Cluspro tools were used for Protein modeling and Protein-protein docking. Sanger sequencing confirms the segregation of novel homozygous variants in all the families i.e., c.245 T > C; p.Leu82Pro in SLC50A1 gene in family 1, missense variant c.1037G > A; p.Arg346His in TARS2 gene in family 2, in family 3 and 4, nonsense mutation c.234G > A; p.Trp78Term and missense mutation c.2200G > A; p.Asp734Asn in TBC1D3 and ANAPC2 gene, respectively. In silico functional studies have found the drastic effect of these mutations on protein structure and its interaction properties. Substituted amino acids were highly conserved and present on highly conserved region throughout the species. The discovery of pathogenic variants in SLC50A1, TARS2, TBC1D1 and ANAPC2 shows that the specific pathways connected with these genes may be important in cognitive impairment. The decisive role of pathogenic variants in these genes cannot be determined with certainty due to lack of functional data. However, exome sequencing and segregation analysis of all filtered variants revealed that the currently reported variants were the only variations from the respective families that segregated with the phenotype in the family.

Matched MeSH terms: Mutation, Missense

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