Many studies have shown that the immune response highly depends on the inheritance of specific HLA
genes in promoting the generation of T cells for the elimination of pathogens. Loss or alteration of HLA
antigen expression in tumor cells has been observed in a variety of human malignancies leading to immune
escape or immune resistance. We investigated whether the inheritance of certain alleles of HLA class II
genes confers susceptibility or resistance towards the development of colorectal carcinoma (CRC).
Molecular typing of HLA DRB1, DQB1 and DPB1 alleles in 42 patients diagnosed with CRC and 50
ethnically matched healthy controls using the PCR-sequence based typing (PCR-SBT) was conducted. The
HLA DPB1*02:01:02 was significantly higher in CRC patients (38.1%, p=0.0189) compared to healthy
controls (16%). Also, HLA DQB1*05:02:01 was present in 28.6% of CRC patients but only 10% of healthy
controls (p=0.0278). The odds ratios for HLA DPB1*02:01:02 and HLA DQB1*05:02:01were 3.23 and 3.60,
respectively. There were no significant association observed for the DRB1 allele with CRC. Our study
suggests that the HLA DPB1*02:01:02 and HLA DQB1*05:02:01 alleles may confer a higher risk for CRC
Entero- and exfoliative toxin gene profiling of 237 methicillin-susceptible Staphylococcus aureus (MSSA) isolated
from Universiti Kebangsaan Malaysia Medical Centre (UKMMC) were carried out via PCR amplification. Among
the tested toxin genes, sei was found to be the most prevalent (54.9%).
Glioblastoma multiforme (GBM) is a high-grade brain tumor of which the survival patients remain poor.
Tousled-like kinase 1 (TLK1), a serine-threonine kinase, was identified to be overexpressed in cancers such
as GBM. TLK1 plays an important role in controlling survival pathways. To date, there is no structure
available for TLK1 as well as its inhibitors. We aimed to create a homology model of TLK1 and to identify
suitable molecular inhibitors that are likely to bind and inhibit TLK1 activity via in silico high-throughput
virtual screening (HTVS) protein-ligand docking. The 3D homology models of TLK1 were derived from
various servers. All models were evaluated using Swiss Model QMEAN server. Validation was performed
using multiple tools. Energy minimization was performed using YASARA. Subsequently, HTVS was
performed using Molegro Virtual Docker 6.0 and ligands derived from ligand.info database. Drug-like
molecules were filtered using ADME-Tox filtering program. Best homology model was obtained from the
Aurora B kinase (PDB ID:4B8M) derived from Xenopus levias structure that share sequence similarity with
human TLK1. Two compounds were identified from HTVS to be the potential inhibitors as it did not violate
the Lipinski rule of five and the CNS-based filter as a potential drug-like molecule for GBM
The invasion of cancer cells into the peritumoral, lymph node and perineural system could be detrimental
on cancer patients. In colorectal cancer (CRC) patients, the presence of lymphovascular (LVI) and/or
perineural (PNI) invasion could significantly influence on the survival rates, treatment options and
recurrence tendencies. To date, no study has analyzed the molecular profile of the concomitant existence of
LVI and PNI in CRC. Here, we reanalyzed The Cancer Genome Atlas (TCGA) CRC datasets and focused
on cases where the information regarding LVI and PNI are available (n=176). We performed differential
gene expression, methylation and microRNA analysis by comparing the groups having both or either LVI
and PNI with the control group (LVI negative and PNI negative). Although there was no significant
difference in the methylation and miRNA profiles, we identified a number of differentially expressed genes
(DEGs). The comparison between the LVI+PNI+ and LVI-PNI- groups revealed key DEGs including
SFTA2, PHACTR3, CRABP2, ODZ3, GRP, HAP1, CSDC2, TMEM59L and HDAC9. Meanwhile, in the
LVI-PNI+ vs LVI-PNI- group, some of the DEGs found were PTPRR, EFNA2, FGF20, IGFL4, METRN
and IGFBPL1. We believe that this study could be beneficial and add value to further understand the
complex molecular profiles of CRC.
VACTERL association is a rare genetic disorder involving at least three of the following congenital
malformations: vertebral defects (V), anal atresia (A), cardiac defects (C), trachea-oesophageal fistula with
or without oesophageal atresia (TE), renal anomalies (R) and limb abnormalities (L). Until now, the
aetiology of VACTERL association is unknown, particularly at the molecular level. Here, we performed
whole exome sequencing (WES) of an infant with VACTERL association. The patient was delivered
prematurely at 30 weeks and had 4/6 of the VACTERL malformations. Trio-WES analysis was performed
using Torrent Suite and ANNOVAR. Polymorphisms with an allele frequency of >0.01 were excluded, and
the remaining variants were filtered based on de novo mutations, autosomal recessive, X-linked and di-genic
inheritance traits. In this patient, no homozygous, compound heterozygous or X-linked mutations was
associated with VACTERL. However, we identified two heterozygous mutations; KIF27
(ENST00000297814: c.3004A> C:p.N1002H) and GNAS (ENST00000371098: c.205C>A:p.H69N) genes that
were inherited from her father and mother respectively. A de novo, IFT140 gene mutation
(ENST00000426508: c.683C>G:p.S228C) was also identified in this patient. The VACTERL phenotype in
this patient may due to heterozygous mutations affecting KIF27 and GNAS genes, inherited via autosomal
recessive trait. In addition, the IFT140 gene mutation may also be involved. These genes are known to be
directly or non-directly involved in the sonic hedgehog signalling that is known to be implicated in
VACTERL. This is the first report of these genetic mutations in association with VACTERL.
Recent association studies have described genetic variants among type 2 diabetes mellitus (T2DM) and their related traits. Gestational diabetes mellitus (GDM) is pathophysiologically similar to T2DM and may share genetic susceptibility.However, genetic susceptibility within GDM in our own population is still not yet explored. This study was to determine the association of GDM genetic variants in the Malaysian population. We genotyped 384 T2DM related SNPs among 174 cases of GDM and 114 controls of pregnant women using Illumina’s Golden Gate genotyping assay. In this case-control study, a custom of 384-SNP plex of 236 candidate genes was designed using the Illumina’s Assay Design Tool. The data analysis showed 12 SNPs had a significant association with GDM among Malaysians with p values 0.002 to 0.048 with their respective odd ratios. The SNPs rs7754840, rs10946398, rs9465871, rs7756992, rs6823091, rs7935082,rs237889, rs7903146, rs7961581 were significant under additive model while rs10811661, rs1016472, rs2270031 were associated with GDM under recessive model. Three SNPs namely rs7935082, rs1016472 and rs2270031 had reduced risk towards GDM while another nine SNPs which were rs7754840, rs10946398, rs9465871, rs7756992,rs10811661, rs6823091, rs237889, rs7903146 and rs7961581 had increased risk as much 1.75 to 2.62 times. Twelve genetic variants of T2DM were replicated in the SNP profiling among Malaysians GDM. Thus with a more significant result in a bigger sample, SNP screening is potentially a useful method in predicting the risk of gestational diabetes mellitus.
Study name: The Malaysian Cohort (TMC) project
Glioma is the most common primary brain tumour of the central nervous system. Many genetic alterations
and mutations have been identified in glioma using various approaches. We performed DNA sequencing on
the tumours of 16 patients with Grade I, II, III and IV glioma. The AmpliSeq Cancer Primers Pool was used
to generate the amplicons. The targeted-ion sphere particles were prepared using the Ion One Touch and
Ion Enrichment systems. DNA sequencing was performed on the Ion Torrent Personal Genome Machine
(PGM) and the data were analysed using the Torrent Suite Software.
In total, 14 mutations were identified in the following genes: KDR (Q472H), MLH1 (V384D), MET (N375S),
PTPN11 (E69K), BRAF (V600E), TP53 (D149E, E154K, V157F), IDH1 (R132H), PIK3CA (H1047R), CSF1R
(c1061_1061 ins A), KIT (M541L), PTEN (c1373_1373 del A) and PDGFRA (E556V). In addition, there were
four novel mutations identified; TP53 (E154K, and D149E), CSF1R (c1061_1061 ins A) and PDGFRA
(E556V). The pathogenicity prediction showed that only three mutations were pathogenic: PTPN11 (E69K),
BRAF (V600E) and Tp53 (E154K). These mutations result in changes of the proteins’ structure and could
affect their functions. Pathway analyses suggested that these genes are closely related to the pathogenesis of
GBM through several pathways such as proliferation and invasion, metabolism and angiogenesis.
In conclusion, PGM in combination with the AmpliSeq Cancer Panel could be utilised as a potential
molecular diagnostic tool not only for glioma but also for other cancers.
Nor Azian Abdul Murad, Sue-Mian, Then, Mohd Ridhwan Abdul Razak, Conjeevaram, Rajendrarao Thambidorai, Sri Noraima Othman, Rosniza Mohamad Hussain, et al.
Hirschsprung’s disease (HSCR) is a disorder associated with congenital absence of ganglion cells in the
gastrointestinal tract. Molecular analyses have identified variants in various genes including RET, GDNF,
EDN3 and EDNRB that are involved in the development, migration and survival of neural cells. Variants
in the receptor tyrosine kinase (RET) are most common and have been identified in 10-20% of sporadic
HSCR patients. The objective of this study was to screen for RET gene variants in Malaysian patients with
HSCR. Thirty-two patients with HSCR and 30 normal controls were recruited for this study. Mutations
were screened using the Polymerase Chain Reaction – Denaturing High Performance Liquid
Chromatography (PCR-dHPLC) approach. Mutations identified were then confirmed using Sanger
sequencing. We identified one novel rare variant in exon 4 (A268A c807 G>C) in one patient. We also
identified the common coding sequence variantsA45A (c135G>A), A432A (c1296A>G), L769L (c2307 T>G)
and the G691S in our cohort of patients. In conclusion, our Malaysian patients with HSCR diseases showed
the presence of similar RET gene common variants which have been described in other populations. We
have also identified a novel variant in exon 4 (A268A).
Precision medicine is mainly about genome-driven
clinical decision-making which is the use of genome
data from the patient to decide on tailoring the best
treatment for the patient. The completion of the human
genome project in 2003 has paved the way for a deeper
understanding of diseases at the molecular level. The
term genomics medicine has since emerged as
clinicians and researchers capitalized on the
knowledge of the genome to improve the management
of many diseases. In the past decade, the term
personalized or precision medicine was introduced to
represent the tailoring of treatment to each individual
based on a person’s unique genetic makeup,
environment and lifestyle [1]. The coining of the term
precision medicine, as opposed to the more common
term ‘personalised medicine’, was intended to
highlight the principle that subgroups of patients could
be defined, often by genomics, and given treatment in
more specific ways [2]. In simple terms, it means
giving the right treatment to the right patient at the
right time with the right outcome. The concept is not
entirely new as it has been applied before in the
practice of blood transfusion where each patient is
given the appropriate blood units based on their blood
groups. However, the emergence of genome data has
allowed a more comprehensive application of
personalized medicine to make it more precise. The
unravelling of the molecular events in certain diseases
like cancers has also led to the development of targeted
therapies. (Copied from article)