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Dr. Mansoor Salehi, Dept. of Genetics, Medical School, Isfahan University of Medical Sciences, Isfahan, Iran
‫‪Cancer Genetics‬‬
‫دکتر منصور صالحی‬
‫‪ )1‬گروه ژنتیک‪ ،‬دانشکده‬
‫پزشکی‪ ،‬علوم پزشکی اصفهان‬
‫‪ )2‬آزمایشگاه ژنتیک‬
‫بیمارستان الزهرا (س)‬
‫‪ )3‬مرکز ژنتیک‬
Why cancer genetics?
1 in 4 deaths is due to cancer
More than half of the population will be diagnosed
with invasive cancer at some point in their lives
Many cancers are increasing in frequency; Why?
Dr. M. Salehi, Dept. of Genetics and Molecular Biology, Isfahan University Medical School
Cancer cells typically contain
multiple alterations in the
number and structure of
genes and chromosomes
Cells are programmed to develop, growth,
differentiate and die  SIGNALS
Signals:
- Growth factors
- Steroid Hormones
- Cell-Cell interaction
Dr. M. Salehi, Dept. of Genetics and Molecular Biology, Isfahan University Medical School
Cancer Genes
Genetic control of cell growth and
differentiation
Cancer causing genes
 more than 200
Growth factors:
-
Platelet Derived Growth Factor
- Epidermal Growth Factor
- Hepatocyte Growth Factor
- Lipid Molecules
- Steroid Hormones
- Cell-Cell Contacts
- Cell-Matrix interaction
Dr. M. Salehi, Dept. of Genetics and Molecular Biology, Isfahan University of Medical School
Effect of hepatocyte growth factor (HGF) on the level of Survivin & XIAP
expression in several human cancer cell lines, after treating with DNA
damaging agent.
Mol Cell Biochem. 2007;304(1-2):199-205.
Keyhanian K, Edalat R, Oghalaei A, Askary N, Golshani A, Salehi M,
Sarrami-Forooshani R, Shokrgozar MA.
Dr Mansoor Salehi, Dept of Genetics and Molecular Biology, Medical School, IUMS
Bcl-2 associated gene-1 (Bag1) overexpression in
diffuse large B-cell lymphoma.
Iran J Immunol. 2008 Jun;5(2):124-30.
Ataollahi M, Salehi M, Doostan I, Kabiri Z, Mohajeri M, Mahmoodi F,
Shokouhi R, Javan S, Meshkibaf MH, Miladpoor B.
Dr Mansoor Salehi, Dept of Genetics and Molecular Biology, Medical School, IUMS
Evaluation of ARG protein expression in mature B cell lymphomas
compared to non-neoplastic reactive lymph node
Cell Immunol. 2009;259(2):111-6
Kabiri Z, Salehi M, Mokarian F, Mohajeri MR, Mahmoodi F, Keyhanian K,
Doostan I, Ataollahi MR, Modarressi MH.
Dr Mansoor Salehi, Dept of Genetics and Molecular Biology, Medical School, IUMS
Dr. M. Salehi, Dept. of Genetics and Molecular Biology, Isfahan University Medical School
Dr. M. Salehi, Dept. of Genetics and Molecular Biology, Isfahan University Medical School
Knudson (1971)
Retinoblastoma study


Inherited  Bilateral
Non-inherited (sporadic)  Unilateral
↓
Two - hit model of carcinogenesis
Is the target of second hit
the normal copy of RB gene or it
could be anywhere else in the genome?
Dr. M. Salehi, Dept. of Genetics and Molecular Biology, Isfahan University Medical School
Tumour Suppressor Genes in cancer
A group of genes that suppress tumour
Dr. M. Salehi, Dept. of Genetics and Molecular Biology, Isfahan University Medical School
Dr. M. Salehi, Dept. of Genetics and Molecular Biology, Isfahan University Medical School
Dr. M. Salehi, Dept. of Genetics and Molecular Biology, Isfahan University Medical School
Dr. M. Salehi, Dept. of Genetics and Molecular Biology, Isfahan University Medical School
Examples of important
Tumour Suppressor Genes in cancers
Dr. M. Salehi, Dept. of Genetics and Molecular Biology, Isfahan University Medical School
BRCA1 and BRCA2
are the most common genes related to
hereditary breast cancer
Mutations in these genes
high risk of developing breast cancer
and several other types of cancer
Functions of BRCA
proteins in response
to DNA damage.
On DNA damage, BRCA
proteins interact with
numerous other
proteins to modulate
DNA repair
Dr. M. Salehi, Dept. of Genetics and Molecular Biology, Isfahan University Medical School
The most common hereditary colon cancer
Hereditary
nonpolyposis
colorectal
cancer
(HNPCC)
~10% of all colorectal cancers
HNPCC is caused by germline mutations
in genes from the DNA mismatch repair
(MMR) system
Dr. M. Salehi, Dept. of Genetics and Molecular Biology, Isfahan University Medical School
Genes involved
At least 5 mismatch repair genes in HNPCC
MLH1 on 3p21*
MSH2 on 2p16*
MSH6 on 2p16
PMS1 on 2q32
PMS2 on 7p22
*( high mutation frequency in HNPCC)
Dr. M. Salehi, Dept. of Genetics and Molecular Biology, Isfahan University Medical School
Two novel mutations in hMLH1 gene in Iranian
hereditary non-polyposis colorectal cancer patients.
Fam Cancer. 2012 Mar;11(1):13-7.
Shahmoradi S, Bidmeshkipour A, Salamian A, Emami MH, Kazemi Z,
Salehi M.
Dr Mansoor Salehi, Dept of Genetics and Molecular Biology, Medical School, IUMS
Association between Mismatch Repair Gene MSH3 codons 1036 and 222
Polymorphisms and Sporadic Prostate Cancer in the Iranian Population.
Asian Pac J Cancer Prev. 2012;13(12):6055-7.
Salehi M, Sedghi M, Nouri N, Jafary F, Sadeghi F, Motamedi S, Talebi M.
Dr Mansoor Salehi, Dept of Genetics and Molecular Biology, Medical School, IUMS
TP53 PIN3 polymorphism associated with
breast cancer risk in Iranian women
Indian J Cancer. 2011 Jul-Sep;48(3):298-302
Faghani M, Ghasemi FM, Nikhbakht M, Salehi M.
Dr Mansoor Salehi, Dept of Genetics and Molecular Biology, Medical School, IUMS
Missense and nonsense mutations of p53 gene in patients with
colorectal adenocarcinoma in Isfahan, central Iran.
Iran Red Crescent Med J. 2011 Mar;13(3):215-6.
Golmohammadi R, Namazi MJ, Nikbakht M, Salehi M.
Dr Mansoor Salehi, Dept of Genetics and Molecular Biology, Medical School, IUMS
Oncogenes
- Originate from: Proto-oncogenes
- Member of cell signaling pathway
- Mostly somatic mutations
- No gremlin mutation (sporadic)
- Dominant at cellular level
Dr. M. Salehi, Dept. of Genetics and Molecular Biology, Isfahan University Medical School
Apoptosis inhibition or inflammation:
the role of NAIP protein expression in
Hodgkin and non-Hodgkin lymphomas
compared to non-neoplastic lymph node.
J Inflamm (Lond). 2012 Feb 23;9(1):4
Mazrouei S, Ziaei A, Tanhaee AP, Keyhanian K, Esmaeili M, Baradaran A,
Salehi M.
Dr Mansoor Salehi, Dept of Genetics and Molecular Biology, Medical School, IUMS
Systematic DNA sequencing
- estimates ofhundreds to thousands
of point mutations in some tumors
Certainly, 20 or more chromosomal aberrations
detectable by cytogenetic techniques are not
unusual in an advanced carcinoma.
It is therefore very appropriate
to regard cancer as a genetic disease

Point mutations

Splice mutations

Alternative splicing

Mutations in regulatory sequences

Deletions

Insertions

Viral genomes

Chromosomal translocations

Chromosomal inversions

Polyploidy and aneuploidy

Numerical chromosomal aberrations

Gene amplification

Structural chromosomal aberrations
Detection of Philadelphia
Chromosome
(BCR / ABL) by FISH
Dr Mansoor Salehi, Dept of Genetics and Molecular Biology, Medical School, IUMS
epigenetic changes in Cancer
Epigenetics:
stable inheritance of
alterations in gene expression
without changes in DNA sequence.
Study of promoter methylation pattern of 14-3-3 sigma gene in normal
and cancerous tissue of breast: A potential biomarker for detection of
breast cancer in patients.
Adv Biomed Res. 2012;1:80.
Gheibi A, Kazemi M, Baradaran A, Akbari M, Salehi M.
Dr Mansoor Salehi, Dept of Genetics and Molecular Biology, Medical School, IUMS
New approaches to the
genetic basis of cancer
Dr. Mansoor Salehi, Dept. of Genetics, Medical School, Isfahan University of Medical Sciences, Isfahan, Iran
Non-Coding RNAs (microRNA) in Cancer
as Biomarkers in Human Cancers
Dr. Mansoor Salehi, Dept. of Genetics, Medical School, Isfahan University of Medical Sciences, Isfahan, Iran
MicroRNAs
are small 19- to 25-nucleotide genes
involved in regulating gene expression
Dr. Mansoor Salehi, Dept. of Genetics, Medical School, Isfahan University of Medical Sciences, Isfahan, Iran
microRNAs
are causally involved in the
initiation,
progression and
metastases
of human cancers
Dr. Mansoor Salehi, Dept. of Genetics, Medical School, Isfahan University of Medical Sciences, Isfahan, Iran
directly targeting miRNAs
or
Possible use of miRNAs
or compounds interacting with miRNAs
as new therapeutic agents in cancer patients
A microRNA Assay that Differentiates
Pancreatic Ductal Adenocarcinoma
from
Chronic Pancreatitis
95.24% sensitivity, 94.87% specificity
(miR-196a and miR-217 )
Pharmacogenomics Services, Asuragen, Inc.
Dr. Mansoor Salehi, Dept. of Genetics, Medical School, Isfahan University of Medical Sciences, Isfahan, Iran
Associations between stem cells and cancer
Cancer Stem Cells
Cambridge Healthtech Institute's Third Annual
Targeting Cancer Stem Cells
New Opportunities for Oncology Therapeutics
February 13-14, 2014 - San Francisco, CA
- Bringing CSC-targeting compounds to the clinic
- Latest results from the clinic for advanced candidates
Myriad Releases Three New Tests
myPath,
Melanoma
myRisk, Hereditary Cancer
myPlan,
Lung Cancer
Dr. Mansoor Salehi, Dept. of Genetics, Medical School, Isfahan University of Medical Sciences, Isfahan, Iran
myPath Melanoma,
a diagnostic test meant to effectively differentiate
malignant melanoma from benign pigmented skin lesions
myPath Melanoma selling price is $1,500.
Dr. Mansoor Salehi, Dept. of Genetics, Medical School, Isfahan University of Medical Sciences, Isfahan, Iran
myRisk Hereditary Cancer,
a multi-gene diagnostic test analyzing 25 genes
associated with eight major cancers including:
breast (BRCA1 and BRCA2),
colorectal,
ovarian,
endometrial,
pancreatic,
prostate,
gastric
melanoma.
myRisk selling price is $3,700
Dr. Mansoor Salehi, Dept. of Genetics, Medical School, Isfahan University of Medical Sciences, Isfahan, Iran
myPlan Lung Cancer
Is an RNA expression panel of
31 cell-cycle-progression genes
the test predicts
a patient's risk of dying from lung cancer within five years
myPlan Lung Cancer selling price is $3,400
Dr. Mansoor Salehi, Dept. of Genetics, Medical School, Isfahan University of Medical Sciences, Isfahan, Iran
Identification of disease-causing genes using microarray data mining and
Gene Ontology
BMC Med Genomics. 2011 Jan 26;4:12.
Mohammadi A, Saraee MH, Salehi M
Dr Mansoor Salehi, Dept of Genetics and Molecular Biology, Medical School, IUMS
Incidence rate of mycosis fungoides in Isfahan (Iran).
J Dermatol. 2010 Aug;37(8):703-7
Salehi M, Azimi Z, Fatemi F, Rajabi P, Kazemi M, Amini G.
Dr Mansoor Salehi, Dept of Genetics and Molecular Biology, Medical School, IUMS