Introduction

INTRODUCTION
 The human cancer genome, or oncogenome harbors
numerous alterations at the level of the
chromosomes, the chromatin (the fibres that
constitute the chromosomes), and the nucleotides.
These alterations include irreversible aberrations in
the DNA sequence or structure and in the number of
particular sequences genes or chromosomes, (that is
the copy number of the DNA). They also include
potentially reversible changes known as epigenetic
modifications to the DNA and/ or to the histone
proteins, which are closely associated with the DNA
in chromatin. These reversible, and irreversible
changes can affect hundreds to thousands of gene
and/or regulatory transcripts. Collectively they result
in the activation and inhibition of various biological
events thereby causing aspects of cancer
pathophysiology including angiogenesis, immune
GENOMIC AND EPIGENOMIC ABERRATIONS IN
CANCER
DETECTING CANCER BIOMARKERS
 In this work we report for the first time an in 
silico approach for the detection and screening 
of  genes  which  might  be  upregulated  in 
cancer.  The  approach  involves  the 
identification and analyses of regulatory motif 
binding  sites  in  the  genes  implicated  in 
various  human  carcinomas  and  correlating 
them with the reported expression patterns of 
the genes. 

 ComA TnrA

Positive regulator of genes involved in late-growth expression and in response to Positively regulates many genes for degrading
environmental stress; is phosphorylated by ComP; may cause DNA bending by nitrogen-containing compounds but negatively
bridging two binding sites regulates glnR. Binds to the same sequence with
GlnR (repressor).
RocR
Xre

NtrC/NifA transcriptional activator (cf. LevR). Sigma 54-dependent activators generally

bind two inverted repeat sequences called UAS, which are located approx. 100bp
upstream from the -12/-24 promoters. DNA bending is used for activation (AhrC may be Repressor of a phage-like bacteriocin, PBSX (phibacin
involved). Inducible by ornithine or citrulline? At least upstream UAS1 is the target of damaged-prophage). Helix-turn-helix protein. Acts at the
RocR. operator-promoter region.

AbrB GlnR

Originally identified as a repressor of glnRA operon;

Bi-functional; expressed during the transition state between vegetative growth and the binds to the same sequence with TnrA (activator).
onset of stationary phase and sporulation; acts as the Spo0A-AbrB circuit; also involved in
catabolite repression
DegU
CcpA

Pleiotropic regulator involved in various post-exponential

Also called AlsA; common repressor in catabolite repression (CR) but may act as a positive phase responses; makes a two component system with
regulator of genes involved in excretion of excess carbon; its binding site is called CRE; it DegS kinase
binds to fructose-1,6-bisphosphate and HPr.
 CtsR GerE

Binding to a directly repeated heptanucleotide operator sequence (A/GGTCAAANANA/GGTCAAA);

three functional domains: HTH DNA-binding, dimerization, and putative heat-sensing domains; Positive(?) regulator which affects
active as a dimer; specifically degraded by ClpP and ClpX at 37 degrees C; labile and substrate of transcription of many genes in the mother
the ClpCP protease under stress conditions (autoregulation by controlled proteolysis); negatively cell during the late stages of sporulation.
regulates its own synthesis.

HrcA MntR

Regulation of manganese transport

The promoters of class I heat-inducible genes are sigA-dependent and have an inverted repeat, (repression of mntH in high Mn(II) conditions,
called the CIRCE (controlling IR of chaperone expression) element, which is highly conserved activation of mntABCD under low Mn(II)
among eubacteria; heat-shock and general stress responses are reviewed in Hecker, M. et al., conditions).
1996.

PerR GltR

Transcription induced by hydrogen peroxide, by general stress, or by entry into stationary phase It activates the transcription of gltAB in the
under conditions of iron and manganese limitation (class III stress response); expression absense of the normal regulator, GltC. It also
modulated by Ca2+; mutants lead to higher expression from all peroxide regulon promoters (mrgA, negatively regulates its own expression. cf. GltC.
katA, hemAXCDBL, and ahpCF), but has no effect on spore resistance to alkyl hydroperoxides,
heat or hydrogen peroxide.

FNR
PucR
Same binding consensus with E. coli CAP
exists in the narK-fnr operon.
Regulation of puc genes (purine degradation).
 AhrC ResD

Novel mode of DNA recognition; represses the arginine biosynthesis genes and ResD seems to form a two-component signal transduction system
activates the arginine catabolism genes; positive role of AhrC may involve protein- with resE and plays a regulatory role in respiration. Interactions
protein interaction with RocR. with resABCDE operon and ctaA may be indirect.

Spo0A Mta

A key bi-functional regulator to control developmental transcription activities. The N-terminal domain of Mta(MtaN) acts as a constitutive
Increases its affinity after phosphorylation (phosphorelay system). Spo0F is required activator of the transcription of bmr and blt genes.
for the phosphorylation. Two-domain structure. Binding consensus is called 0A box
and can be located downstream of the initiation site. Often, two adjacent boxes are
found. These listed sites might be viewed in its complementary strand.
Fur
PurR
Negative regulation of siderophore biosynthesis and transcription of
ferri-siderophore uptake genes.
A purine repressor which mediates adenine nucleotide-dependent regulation of pur
operon. GAAC-N24-GTTC motif seems necessary for its binding but this motif was
not required for its binding to purA.
AraR
SinR

Dual-function regulator which is essential for the late-growth processes of
competence and motility and is also a repressor of others, e.g., sporulation and
subtilisin synthesis. Might be a leucine zipper protein. In aprE there are two binding
sites and SinR binds more strongly to the distal site, which contains two dyad
symmetry sites.
Transcriptional regulator (LacI family); negative regulation of
the L-arabinose metabolic operon (araABDLMNPQ); alternate
gene name: araC, yvbS.
 GltC LevR

Like many members of LysR family, GltC is encoded just upstream of and in the Activator which regulates the neighboring operon. Note that
opposite orientation to its target genes (gltAB); it negatively autoregulates itself. The -144:-130 and -108:-120 makes a palindromic structure.
binding site for the autoregulation is the same with the box I of gltA (-71:-57) in its
genome position. Box II of gltA overlaps with its -35 region. cf. GltR.

CodY SpoiiiD

Transcriptional regulator; negative regulation of srfA and A bi-functional transcription factor which regulates temporal expression of many
comK genes (in the presence of casamino-acids), dpp genes in the mother cell as well as GerE.
operon.

Iolr Zur

A negative regulator (presumably a repressor) which exists

Zinc-specific repression of operons implicated in zinc uptake (yciC, ycdHI-
immediately upstream of the iol operon in the opposite direction.
yceA).0

BkdR ComK
 The results indicate that the genes reported to 
be  upregulated  in  cancer  possess  a  specific 
pattern  of  regulatory  motif  binding  sites  and 
future cancer biomarkers can be screened and 
tested  with  the  presence  of  the  same  set  of 
regulatory  motif  binding  sites.  A 
correspondence  analysis  was  also  performed 
along  with  a  correlation  analysis  to  further 
establish  our  findings.  This  approach  could 
prove  to  be  beneficial  for  screening  of  the 
specific  genes  before  workers  embark  upon 
wet lab experiments. 

Selected Genes (on the basis of Correspondence 
Analysis)
 CORRESPONDENCE PLOT

CorrespondencePlot

14

7 1.3
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0
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DIM(2)

3.3
7 18

0 83
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77
.6
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9
0
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.9
32
8
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25
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1
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8

-7
1.23
2

-14
-14 -7 0 7 14
DIM(1)
 SCATTER PLOT MATRIX
Transcription Factors

Total number of Genes

We  wish  to  develop  a  tool  for  the  analysis 
and  screening  of  the  possible  cancer  gene 
sequences, thus making wet lab experiments 
more  specific,  which would be  beneficial for 
controlling the deadly disease. We provide an 
overview  of  gene  expression  analyses  and 
upregulation,  in  case  of  human  oncogene, 
and  suggest  future  uses  of  transcription 
regulatory  analyses  to  rationalise  the 
observations  made  through  computational 
 FUTURE PROSPECT Contd…

        We  can  construct  a  large  number  of  different 



profile  matrices  from  a  given  sample,  by 

varying  the  starting  positions,  and  may  grade 
them  against  the  predicted  set  of  motifs  found 
from  already  determined  human  oncogenes. 
Based  on  this  grading  and  on  different 
principles. We can formulate the human cancer 
biomarker  finding  problem  to  give  efficient 
algorithm.  The  algorithms  can  be  integrated  to 
design  a  "Human  Cancer  Biomarker  Finding 
Tool".  Thus  users  can  submit,  nucleotide 
sequences of novel genes, to this tool in order to 
find  patterns/  motifs  related  to  human 
oncogenes.
FUTURE PROSPECT Contd …..

      Improvement  in  cancer  classifications  have 



been  central  to  advances  in cancer  treatment. 

Although  the  distinction  between  different 
forms of cancer has been well established , it is 
still  not  possible  to  establish  a  clinical 
diagnosis  on  the  basis  of  a  single  test.  In  a 
recent  study,  acute  myeloid  leukaemia  and 
acute  lymphoblastic  leukaemia  were 
successfully  distinguished  based  on  the 
expression  profiles  of  these  cells.  Thus  the 
human  oncogene  expression  profiles  may 
provide  a  generic  strategy  for  classifying  all