Download Why Oral Cancer?

“One Size Fits All”-Does It?
Vidudala V.T.S. Prasad, Ph.D
Head
Research and Development
Basavatarakam Indo-American Cancer Hospital
and Research Institute
Road No.14, Banjara Hills
Hyderabad-500034, India
Cell: 9618207495, e-mail: [email protected]
[email protected]
Cancer Helpline: 9989524365
Our Group
•
•
•
•
•
•
•
•
Dr. Guru Prasad
Dr. Ram Prasad
Padma
Satish
Satish Kumar
Ravi
Shiva Satish
Ph.D Students: Sarika, Srivani and Padma
• Dr. Saritha (Volunteer Researcher)
Research
Oral Cancer (OC)
Low incidence and low Priority accorded by the
developed Countries, as judged by the
publications.
3.5% (M+F) of publications as compared to over
10% of female BC
Why Oral Cancer?
 In India, it is one of the most prevalent Cancers,
especially in males
 Coupled with the low priority status of the OC in
Developed Countries, the onus to address OC is on us,
but not on US and others.
 Paucity of gender and site specific data, on global
perspective
Polymorphims
Functional Consequences of Polymorphisms
Disease
Susceptibility/
Resistance
Receptor
Sensitivity
Drug
Transport
Adverse Drug
Reactions
Complications
Polymorphisms
Drug
Metabolism
Ultra Responders/
Poor Responders/Non-Responders
Poor/No Clinical Outcome
A case for setting up specific data bases
(DBs)
Polymorphisms
Glucosylcerebrosidase
Lipoxygenases
FAS and FASL
TP53
Cell Culture
Selective Cellular Death
CASPs, SULT1A1 CYP3A5 etc.,
Epigenetic aspects of gene
regulatory aspects and
Expression Profiles
Epigenetic Mechanisms
UV therapy
4-HPR
Paclitaxel
Etoposide
SDZ PSC833
Anthracyclines
Vincs alkaloids
CerS
Sphinganine
De novo pathway
Salvage pathway
Ser + Palm CoA
Sphingomyelin
CERAMIDE
CERT/GTs
Glu/Gal-Cer
GCB
UV radiation
CD95
Anthracyclines
Ara-C
TNF-α
DT GM-CSF
S/Gtransferases
Ceramide
kinase
Fatty acid +
Sphinganine
CP
Sphingosine
Sphingosine
kinase
Lipid
phosphatases
SP
Growth factors
Cytokines
SP lyase
ELP & HXD
Tamoxifen
Toremifene
Mifepristone
Cyclosporin A
Ketoconazole
Verapamil
PPMP
NB-DNJ
CSLs
Glucosyl
cerebrosidase
Pro-apoptotic
Sphingo
myelinase
Cer Phosphatase
Pro-sur vival
Pro-sur vival
Anti-apoptotic
CERAMIDE
Glu-Cer
SP lyase
SM
Mitogenic
Anti-apoptotic,
Pro-proliferative
CP
Glucosylceramide synthase
Sphingomyelin synthase
Ceramide kinase Sphingosine
kinase/ Ceramidase
Ratio of sphingolipids decides cellular fate
SP
Arachidonic acid Lipoxygenases
Inflammation and Cancer
 In 1863, German physician Rudolf Virchow hypothesized that certain
classes of irritants, together with the tissue injury and inflammation,
promote enhanced cell proliferation.
 In 1918, Yamagiwa and Ichikawa, who showed that repeated painting of
coal tar onto rabbits' ears causes carcinomas.
Rudolf Virchow
the world’s first man-made cancer on the ears of a rabbit
FAS and FASL promoter SNPs
 Gene Loci: FAS 10q24.1; FASL 1q23
 The SNPs of the FAS -1377 G>A, block the binding of Sp1 transcription
factor and
 FAS -670 A>G SNPs, STAT1 transcriptional factor binding site,
leading to down regulation of the FAS gene expression (Huang et al., 1997
and Sibley et al., 2003).
 The FASL -844 T>C SNP at the binding site for CAAT/enhancer binding
protein. The CC variant was shown to upregulate FASL gene compared
to the TT variant (Wu et al., 2003).
 Various ethnic groups have been shown to harbor variants of the FAS
and FASL. All cancers have genetic basis and genetic pre-disposition to
cancer is well established (Robson and Offit 2007 and Tan 2009).
FAS-FASL and Apoptosis
nduction of Cell Death: Trimerization of the Fas receptor by Fas ligand results in activation
of caspase 8 (FLICE/MACH1), mediated by the adapter protein Fas-associated death
domain (FADD)/mediator of receptor-induced toxicity (MORT1). Active caspase 8 is then
responsible for activation of downstream caspases and cell death. DNA-damaging agents,
such as doxorubicin, can result in increased Fas expression via a p53-dependent pathway
and hence induce killing by the Fas/Fas ligand pathway, if the newly synthesized Fas
engages Fas ligand. Other modes of cellular stress, such as removal of simple media
supplements like mercaptoethanol, can also result in enhanced Fas expression.
Our Data
Caucasians
Chinese
Askhenzi
Jews
Hetero Homo Hetero Homo Heter Homo Heter Homo
%
%
%
%
o% %
o% %
GBA VAL394LEU
3
0
0.3
0
GBA ASP409HIS
GBA ASN370SER
GBA
LEU444PRO
3
0
0
0
0
0.5
0
0
0
0
0
0
5 LOX -292C > T
17
0
5
12 LOX 835 A>G
32.5
24
0.5
9
39
8
FAS -1377 G>A
P 53 215 G>C
P 53 216 bp
delition
--
--
--
--
-0.7
-0
-4.3
-0
1.1
0
2.4
0
0
--
--
--
--
45
17
14
0.4
51
47
25
11
---
---
24
42
10
--
--
--
--
22
17
2
--
--
--
--
Variations in Genotypes Among Different Ethnic Populations
Genetic Variants Affecting Drug Response
Primary CYP 450 Enzymes in Drug Metabolism
% of total enzyme
% of drugs metabolized
1A2
5%
1A2
19%
2C9
2C19
19%
3A4/5
42%
2C9
2C19
26%
2E1
10%
3A4/5
51%
2D6
24%
2D6
3%
2E1
1%
Biotransformation of Tamoxifen,
pro-drug to active drug
CYP 3A4/5 converts TAM to N-desmethyl tamoxifen, whereas the generation of 4-hydroxy
tamoxifen and ENDOXIFEN are predominantly catalyzed by CYP2D6. CYP2C19, CYP2C9, and
CYP2B6 play less important roles in tamoxifen metabolism in vitro at therapeutically relevant
concentrations.
Jin, Y. et al. J Natl Cancer Inst 2005;97:30-39
The table below lists common drug metabolism gene variants and their
frequencies in major ethnic groups.
Gene and Variant
Caucasians
African-Americans
Asians
CYP2D6*3
2%
0
0
CYP2D6*4
12-21%
2%
1%
CYP2D6*5
2-7%
4%
6%
CYP2D6*10
1-2%
6%
51%
CYP2D6*17
0
34%
0%
CYP2D6*2xN
1-5%
2%
0-2%
CYP2C9*2
8-14%
1%
0%
CYP2C9*3
4-16%
1-2%
2-3%
CYP2C9*5
-
1.7%
-
CYP2C9*6
-
0.6%
-
CYP2C19*2
15%
17%
30%
CYP2C19*3
0.04%
0.40%
5%
Adapted from Blue Cross Blue Shield Special report
Germline mutations of BRCA1 and BRCA2
A very high frequency: 31.6 %; non-Jewish Americans of
Spanish ancestry from the San Luis Valley, Colorado
(Mullineaux et al. 2003).
Moderate: 16.4% in India (Vaidhyanathan)
Low Frequency: 1.13–5.9%;white Americans, the Spanish from
Spain, Polish, Iranian, Pakistani and Turkish women (Grzybowska
et al.2002; Shih et al. 2002; Guran et al. 2005; Weitzel et al. 2005; Mehdipour et
al. 2006; Rashid et al. 2006).
Absence of the 185delAG mutation: Chinese and
Japanese families with breast cancer (Ikeda et al. 2001; Zhi
et al. 2002).
Other Genetic Variations among
different populations
• G6PD: Specific mutations are found in Indians and
Africans.
• ALDH 1: Deficient activity in Orientals (Chinese&
Japanese) results in high sensitivity to alcohol.
• Sickle cell anaemia: A mutation in sickle cell anaemia is
not found across the globe but in specific geographical
regions like Africa and Asia, mostly.
Asian Belly
Specific fat depots are influenced by ethnicity
and gender
Kohli et al., 2009, Obesity Jr. DOI 10 1038/oby, 2010. 94;
Liu et al., 2011, BMC Public Health, 11, 500
Cancer may occur in any part of the body
Dr. V. V. T. S Prasad, Ph.D, Chief, R&D, E mail :[email protected] , Cell: 09618207495
Increased risk of buccal mucosa cancer for females
but not for males
FASL homozygous variant decreases risk of Female cancers
while those of FAS variants alters the risk divergently
SULT1A heterozygous variant decreases Oral Cancer Risk but
increase the Cancer Risk for females
The CYPA35*3 homozygous variant offers protection
against breast cancer but not that of oral cancer
TP53 E-4 215G>C heterozygous variant increases Tongue Cancer risk
in males but the homozygous variant increase risk of tongue and BM
cancers in males. Intron 6 G>A het variant confers protection against
tongue cancer in males
TP53 intron 3 homozygous variant lowers risk of both
tongue and BM cancers in females
15-LOX promoter polymorphism (-292C>T) increases risk of the female
cancers, though the degree of the risk varies for each of the cancers
12-LOX 835A>G heterozygous variant increases breast cancer but decreases
risk of Cervical and Ovarian Cancers, whereas the homozygous variant
increases risk for BC, Cx and OC cancers.
Rising Incidence of Breast cancer in India
www.breastcancerindia.net/statistics
Age shift: Breast cancer now is more common in 30’s and 40’s
www.breastcancerindia.net/statistics
Our Research, Mitochondria and Cancer
Ceramide, Ceramide-1-Phosphate and LOXs*
Membrane
Potential
ROS
LOX mutation & cancers
Inflammation
Inhibits mt
function
Cell Death
FAS/FASL, CASPases
*Cer and CP upregulate 12-LOX pathway and generate 12-HETE involved in cell
proliferation, inflammation, VEGF) expression.
Ceramide elevates 12-hydroxyeicosatetraenoic acid levels and upregulates 12lipoxygenase in rat primary hippocampal cell cultures containing predominantly
astrocytes. Vidudala V.T.S. Prasad *, Kassem Nithipatikom, David R. Harder.
Neurochemistry International 53 (2008) 220–229.
CP manuscript is in review
Personalized Medicine
“Here is my genomic sequence”
Sensitivity of cells even from same
organ differs to anti-cancer agents
P-1
F-1
Tamoxifen
Tamoxifen
F-1
Medium control
A) CAL-27 48hrs
Annexin-V-FITC
Propidium Iodide
Overlay
B) SCC9 48hrs
Propidium Iodide
Annexin-V-FITC
Overlay
C)
P-1
Tamoxifen
F-1
Medium control
Annexin-V-FITC
MCF-7 48hrs
Propidium Iodide
D)
Overlay
Annexin-V-FITC
MCF-10A 48hrs
Propidium Iodide
Overlay
Ratio of cell death
CAL-27 Vs. SCC-9 apoptosis
CAL-27 Vs. SCC-9 cell death
6.00
5.00
4.00
3.00
2.00
1.00
0.00
Your Genes Dictate
Your Response
Genomics
24H
48H
F-1 25ul Curcumin Tam 50ul P-1 100ul
100uM
F-1 25ul Curcumin Tam 50ul P-1 100ul
100uM
MCF-7 Vs. MCF-10A apoptosis
MCF-7 Vs. MCF-10A cell death
2.50
2.00
1.50
1.00
3.50
3.00
2.50
2.00
1.50
1.00
0.50
0.00
4.00
3.50
3.00
2.50
2.00
1.50
1.00
0.50
0.00
“One Size Doesn’t Fit All”
24H
48H
0.50
0.00
F-1 25ul Curcumin Tam 50ul P-1 100ul
100uM
F-1 25ul Curcumin Tam 50ul P-1 100ul
100uM
24H
48H
24H
48H
Fig. 3: Cytotoxic extract mediated cell death in breast cancer cell lines
MCF-7
ZR-75
*
FE0.1Tam0.2
Tam0.2
FE0.2
FE0.15
Treatment
One-way Anova
*p 0.05
**p0.005
***p0.001
**
*
*
FE0.1
FE0.05
*
PE0.2Tam0.2
**
PE0.2
100
90
80
70
60
50
40
30
20
10
0
Control
% Dead cells
MDAMB-435
CYP2D6 Alleles in South Indians
(% Allele frequency)
CYP2D6
Allele
TN
Kerala
Karnatak AP
a
South
India
*3
0.0
0.0
0.0
0.0
0.0
*4
6.1
7.5
4.8
10.8
7.3
*5
1.1
1.7
1.1
1.4
1.9
*10
12.9
7.0
11.2
9.0
10.2
Theophilus et al., Biol Pharm Bull, 29(8) 1655-1658, 2006
Note: Existence of CYP2D6 PM phenotype in south Indian population is also reported
based on dextromethorphan and its metabolite levels in urine Abraham, B.K., et al.,
Acta Pharma Sin 21 (6) 494-4980
“Every individual is different from another and
hence should be considered as a different
entity. As many variations are there in the
Universe, all are seen in Human being”
Charak Samhita
Most Drugs
Do Not Work Similarly
in All Patients
The tiny difference in human genome translates into 3
million separate “spelling” differences in a genome of 3
billion bases, creates wide variety of phenotypesgh
Obvious enough!!!
Menacing !
Gotram
• Science of Genetics behind the Hindu Gotram
System
• People within the gotra are regarded as kin
Gotra is the lineage or clan assigned to a Hindu
at birth
• The Gotra is a system which associates a person
with his most ancient or root ancestor in an
unbroken male lineage.
• to avoid cousin marriages which have been
proved to increase the risk of genetic disorders
in the off springs
The Jewish Rabbi as a DB
Concerns
•
•
•
•
•
•
Privacy Issues
Ethical aspects
Integrity
Accuracy
Ownership
Genetic discrimination
The volume of information held in genetic research
databases and quick access magnify these concerns.
India Needs G-P-L-M -Omics DBs more
than any other countries
• Close Marriages
– Caste
– Distantly Related
– Within family
– What we need is not only genetic DBs but also disease
specific DBs----- Diabetes Mellitus, Cardiac Diseases
and Cancer to start with
Late than Never
Let’s Develop Data Bases that Caters to
the Needs of Diverse India
Let all Indians, “Have and Have Nots”,
Reap the Benefits of Biotechnological
Advancements, alike.
Let us Light the Lamp of Knowledge
and Drive Away Ignorance
Sooner the Better
Dhanyawad
Databases
• A ‘database’ is any methodical or systematic collection of data,
structured that allows accessibility to individual or collective
elements of that database .
• The human genetic research databases have been created
primarily for the purposes of medical or other human research.
Variations in the frequencies of the ALOX 12 polymorphism (A835G;
Gln261Arg) in different populations (%)
Variant
India
USA
USA
USA
Brazil
China
Korea
Spain
Gln/Gln
(AA)
59.5
17
37
40.9
22.5
23.7
31.4
19
Gln/Arg
(AG)
39.6
49.3
50.5
45.5
37.5
51
49.4
47
Arg/Arg
(GG)
0.9
33.7
13.5
13.6
40
25.3
19.3
34
Gln/Arg
(AG) +
Arg/Arg
(GG)
40.5
83
64
59.1
77.5
76.3
68.7
81
Caucasians
Female
(52%)
Blacks
(52%)
Brazilian
Female
(69% )
Chinese
Female
(37.2%)
Koreans
Female
(62.0% )
Spain
Male
(100%)
Goodman et Goodman Fridman
al., 2004
et al.,
et al.,
2004
2005
Tan et
al., 2007
Kim et
al., 2010
Quintana
et al.,
2006
Population / Indian
Predominantly
Gender
Female Caucasians (88%),
(100%)
Female (41% )
Reference
Our
Study
Gong et al., 2007
12-LOX polymorphism in control males and females
Samples
Parameter
Frequency
AA
AG
N
Male, N =151
Female , N=166
p-value
*
N
(%)
(%)
104
46
(68.9)
(30.4)
94
69
(56.6)
GG
N
AG +GG
N
(%)
A allele
N
G Allele
N
(%)
(%)
1
47
254
(0.7)
(40.1)
3
72
257
(41.6)
(1.8)
(43.4)
(77)
(23)
0.03*
0.28
0.025*
0.50
0.02*
Statistically significant (p<0.05); N = Number of samples
(84)
(%)
48
(16)
76
Three
Billion
Big
3 million
‘spelling’
variations,
Just differ
by 0.1%,
99.9
identical
12-LOX influences Cancer Related Processes
Proliferation
ALOX12
12-LOX
Adhesion
ALOX12
That tiny 0.1% difference in human genome
translates into 3 million separate “spelling”
differences in a genome of 3 billion bases,
accounting for wide variety of phenotypes
Prevalence
Population
Indian
Ashkenazi Jews
Allele
Frequency
16.4%
18.0%
Non-Jewish
Americans of
Spanish
31.6%
Vaidyanathan et al., 2009 J. Biosci. 34(3)415–422
CYP450 genotypes: Patient classifications
1) Extensive metabolizers (EM) = 2 good copies
2) Intermediate metabolizers (IM) = 1 defective copy
3) Poor metabolizers (PM) = 2 defective copies
4) Ultra-rapid metabolizers (UM) = 3+ good copies
SULT1A1 Prevalence
Population
Turkish
Caucasian
Allele
Frequency
23.8%
36.5%
African Japanese
American
29.4%
Chinese
Korean
8.0%
12.4%
16.0%
R&D Data (2010-Present )
Homozygous
Heterozygous
Mutated
Normals
3.3%
21.7%
25.0%
Breast cancer
6.7%
53.3%
60%
Ovarian Cancer
13.3%
46.7%
60%
Arslan, 2010 Biochem genet 48:987-994
MTHFR Prevalence
R&D Data (2010-present )
Homozygous
Heterozygous
Homo+Het
Normals
0.5%
6.0%
6.5%
Colorectal cancer
0%
13.8%
13.8%
Acute Lymphoblastic
Leukemia
1.5%
4.3%
5.8%
Population
Indian
Caucasian
Chinese
Japanese
Frequency of
homozygous
mutation
2.16 %
8.9%
16.9%
15.6%
Kumar et al., 2005 J Hum Genet 50:655-63
MTHFR Prevalence
R&D Data (2010-present )
Homozygous
Heterozygous
Homo+Het
Normals
0.5%
6.0%
6.5%
Colorectal cancer
0%
13.8%
13.8%
Acute Lymphoblastic
Leukemia
1.5%
4.3%
5.8%
Population
Indian
Caucasian
Chinese
Japanese
Frequency of
homozygous
mutation
2.16 %
8.9%
16.9%
15.6%
Kumar et al., 2005 J Hum Genet 50:655-63
UGT1A1*28
Mutation: Seven TA repeat sequence in the promoter
region
Locus: Chr 2q37
Impact of Mutation:
Decrease enzyme production, leading to reduced
glucuronidation (Iyer et al., 1998 and Iyer et al., 2002)
Drug
Irinotecan
Major
Condition
Clinical
Implication
Comment
Colorectal cancer
Decreased UGT1A1
Genotyping is useful
activity may increase the for dosage regimens
risk of toxicity
>250 mg/m2.
Lee and McLeod, 2011 J Pathol; 223: 15–27
Drug
Irinotecan
Major
Condition
Clinical
Implication
Comment
Colorectal cancer
Decreased UGT1A1
Genotyping is useful
activity may increase the for dosage regimens
risk of toxicity
>250 mg/m2.
Lee and McLeod, 2011 J Pathol; 223: 15–27
FDA advisory Committee’s Recommendation.
Oct 18, 2006
Tamoxifen label should be updated to reflect
the fact postmenopausal women with ER
positive breast cancer who are CYP2D6 poor
metabolizers with tamoxifen treatment (by
genotype or drug interactions) are at
increased risk for breast cancer recurrence.
The recommendation has not been
withdrawn to the best of my knowledge
DPD
Mutation: *2A Exon-14-skipping
Gene location: Chromosome 1p22
Impact of Mutation: Nonfunctional enzyme
Drug
5-Fluorouracil
Major Condition Clinical
Implication
Colorectal,
stomach,
pancreatic
cancer
DPD deficiency
is associated
with
higher risk of
toxicity
Comment
Phenotyping
may be needed
in some cases.
Lee and McLeod, 2011 J Pathol; 223: 15–27
Metabolic pathways of pyrimidines and dihydropyrimidine dehydrogenase (DPD)
Tanaka et al., 2005 Nagoya J. Med. Sci. 67. 117-124
DPD Prevalence
R&D Data (2010-Present )
Homozygous
Heterozygous
Mutated
0%
5.8%
5.8%
R&D data indicates the prevalence of the mutation in
Indian population.
Population Caucasian
Allele
Frequency
3-5%
(Jane et al.,
2007)
African
American
Finnish
Dutch
8%
2.2%
1.2% (Eidens et
(Saif et al., 2007) (Eidens et al., 2009)
al., 2009)
UGT1A1 Prevalence
Population
African
European
Asian
R&D Data
(2010-present )
Allele
Frequency
43%
39%
16%
Work in progress
Beutler et al., 1998 Proc Natl Acad Sci USA; 95:8170-74
Need for Data Bases pertinent to
Diverse India
Age shift: Breast cancer now is more common in 30’s and
40’s
www.breastcancerindia.net/statistics
Age shift: Breast cancer now is more common in 30’s and
40’s
www.breastcancerindia.net/statistics
Rising Incidence of Breast cancer in India
www.breastcancerindia.net/statistics
“Every individual is different from another and
hence should be considered as a different
entity. As many variations are there in the
Universe, all are seen in Human being”
Charak Samhita
Other Genetic Variations among
different populations
• G6PD: Specific mutations are found in Indians and
Africans.
• ALDH 1: Deficient activity in Orientals (Chinese&
Japanese) results in high sensitivity to alcohol.
• Sickle cell anaemia: A mutation in sickle cell anaemia is
not found across the globe but in specific geographical
regions like Africa and Asia, mostly.
Many Races, Many Faces
with Varied features
Yet, human DNA sequence is 99.9% identical,
differs by just 0.1% but still -----
Table 2: Variations in the frequencies of the ALOX 12 polymorphism
(A835G; Gln261Arg) in different populations
Variant
India
USA
USA
USA
Gln/Gln
59.5
17
37
40.9
(AA)
Gln/Arg
39.6
49.3
50.5
45.5
(AG)
Arg/Arg
0.9
33.7
13.5
13.6
(GG)
Gln/Arg
40.5
83
64
59.1
(AG) +
Arg/Arg
(GG)
Population Indian Predominantly Caucasian Blacks
/ Gender Female Caucasians
Female
(52%)
(100%)
(88%),
(52%)
Brazil
22.5
China
23.7
Korea
31.4
Spain
19
37.5
51
49.4
47
40
25.3
19.3
34
77.5
76.3
68.7
81
Brazil Chinese Koreans Spain
Female Female Female Male
(69% ) (37.2%) (62.0%
Female (41% )
)
Reference Present Gong et al., Goodman Goodma Fridman Tan et Kim et Quintana
Study
2007
et al.,
n et al., et al., al., 2007
al.,
et al.,
2004
2004
2003
2010
2006
Table 2: Variations in the frequencies of the ALOX 12 polymorphism
(A835G; Gln261Arg) in different populations
Variant
India
USA
USA
USA
Gln/Gln
59.5
17
37
40.9
(AA)
Gln/Arg
39.6
49.3
50.5
45.5
(AG)
Arg/Arg
0.9
33.7
13.5
13.6
(GG)
Gln/Arg
40.5
83
64
59.1
(AG) +
Arg/Arg
(GG)
Population Indian Predominantly Caucasian Blacks
/ Gender Female Caucasians
Female
(52%)
(100%)
(88%),
(52%)
Brazil
22.5
China
23.7
Korea
31.4
Spain
19
37.5
51
49.4
47
40
25.3
19.3
34
77.5
76.3
68.7
81
Brazil Chinese Koreans Spain
Female Female Female Male
(69% ) (37.2%) (62.0%
Female (41% )
)
Reference Present Gong et al., Goodman Goodma Fridman Tan et Kim et Quintana
Study
2007
et al.,
n et al., et al., al., 2007
al.,
et al.,
2004
2004
2003
2010
2006
HGP: The most ambitious project in biological
science was envisaged to spell out the human
genome in toto.
In other words, the project was meant to sequence
the complete human genome of 3 billion bases
Many Races, Many Faces
with Varied features
Yet, human DNA sequence is 99.9% identical,
differs by just 0.1%
What does it mean!
http://nihroadmap.nih.gov/epigenomics/epigeneticmechanisms.asp
-- Sun Kim group at IU --
86
Your Genes Dictate
Your Response
“One Size Doesn’t Fit All”
The Human Genome Program of the US DOE
• Human Genome Project started as US component 1990
US$3billion 15-year effort to find the estimated 80,000 human
genes and determine the sequence of the 3-billion DNA
building blocks that underlie all life's diversity.
• A new goal focuses on identifying regions of the human
genome that differ from person to person. Our DNA
sequences are estimated to be 99.9% identical genetically these DNA sequence variations can have a major impact on
how our bodies respond to disease; environmental insults,
such as bacteria, viruses, and toxins; and drugs and other
therapies.
• http://www.er.doe.gov/production/ober/HELSRD_top.html
!
Many Races, Many Faces
with Varied features
Yet, human DNA sequence is 99.9% identical,
differs by just 0.1%
What does it mean!
That tiny 0.1% difference in human genome
translates into 3 million separate “spelling”
differences in a genome of 3 billion bases,
accounting for wide variety of phenotypes
Does it matter in
practicing medicine?
Many Races, Many Faces
with Varied features
Yet, human DNA sequence is 99.9% identical,
differs by just 0.1%
What does it mean!
Pharmacogenomics
“Best Fit”
Right Drug(s) @ Right Dose, and no ADRs
Personalized Medicine
However, 0.1% difference in human genome translates into 3 million
separate “spelling” differences in a genome of 3 billion bases,
accounting for wide variety of phenotypes
What these variations in DNA
Sequence can do?
 May results in a different phenotype
 May impact expression of mRNA/protein
 May serve as an unique molecular marker for a given
pathological condition
Genome: All the genetic material in the chromosomes of a
particular organism; its size is generally given as its total
number of base pairs.
Genomics: the study of genes and their function. Recent
advances in genomics are bringing about a revolution in
our understanding of the molecular mechanisms of disease,
including the complex interplay of genetic and
environmental factors. Genomics is also stimulating the
discovery of breakthrough healthcare products by revealing
thousands of new biological targets for the development of
drugs, and by giving scientists innovative ways to design
new drugs, vaccines and DNA diagnostics. Genomics-based
therapeutics include "traditional" small chemical drugs,
protein drugs, and potentially gene therapy.
Much before the advent of human genome
Project ---- our Ancient Wisdom proclaimed
that;
“Every individual is different from another
and hence should be considered as a
different entity. As many variations are there
in the Universe, all are seen in Human being”
Charak Samhita
How these variations are identified and put to use
in practicing medicine!
Association of 12-LOX polymorphism with colorectal cancer.
Subjects (Gender and
Sample Size)
Frequency
AA
AG
N (%)
GG
N (%)
N (%)
AG + GG
A allele
G Allele
N (%)
N (%)
N (%)
Control (M+F, N=317)
198 (62.5)
115 (36.3)
4 (1.3)
119(37.5)
511(81)
123(19)
Colorectal Cancer
38 (36.5)
64 (61.5)*
2 (2.0)
66(64)*
140(65)*
68(35)*
0.0001
0.262
0.0001
0.0001
0.0001
2. 9
2.61
2.9
6.3
2.9
1.8-4.6
0.46-14.7
1.83-4.6
4.1-9.7
1.8-4.6
(M+F, N=104)
p-value
OR
CI (at 95%)
Control (F, N = 166)
94 (56.6)
69 (41.6)
3 (1.8)
72 (43)
257(77)
75(23)
Colorectal Cancer
21 (46.6)
23 (51.1)
1 (2.3)
24(53)
65(72)
25(28)
0.24
0.73
0.234
0.66
0.23
1.5
1.5
1.5
1.1
1.5
0.77-2.92
0.15-15.1
0.77-2.9
0.66-2.0
0.35-2.9
254(84)
48(16)
(F, N= 45) p-value
OR
CI (at 95%)
Control (M, N=151)
104 (68.9)
46 (30.4)
1 (0.7)
47 (31)
Colorectal Cancer,
17(28.8)
41(69.5)*
1(1.6)
42(71)*
75(64)*
43(36)*
0.0001
0.154
0.0001
0.041
0.0001
5.5
6.2
5.5
1.8
5.5
2.9-10.6
0.37-102
2.8-10.6
1.0-3.2
2.8-10.6
(M, N=59) p-value
OR
CI (at 95%)
*
Statistically significant (p<0.05).