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Molecular Genetics 
& Cancer Biology 
Meshari Alzahrani 
R1 Urology Resident | KAMC-NGHA-Jeddah 
16 November 2014
Lecture Roadmap 
 Introduction 
 Basic Molecular Genetics 
 Tumor Suppressor Genes and Oncogenes 
 The Cell Cycle 
 D...
Why This Lecture !
Despite decades of intensive biomedical 
research, cancer remains a significant 
cause of morbidity and mortality 
worldwi...
World Cancer Day – 4th February 2014 
By 2025, there will be more than 20 million new 
cancer cases per year, compared wit...
IARC World Cancer Report 2014
cancer ribbon
• However, significant advances in the diagnosis 
and treatment of certain Genitourinary (GU) 
cancers have been made. 
• ...
• We have had less success with the more 
prevalent GU malignancies, such as prostate, 
bladder, and renal cancers—the sec...
 In Saudi Arabia, prostate cancer is the 6th most 
common cancer among men of all ages and the most 
common cancer among ...
 Bladder cancer ranked 13 among the most common 
cancer diagnosis in Saudi Arabia, affecting 
3.6/100,000 men and 1/100,0...
Basic Molecular Genetics
In 1953 
Co-discoverer of the structure of the DNA molecule 
Francis Crick 
James Watson 
The molecular characteristics of...
Basic Molecular Genetics 
 Somatic cell is any biological cell forming the body of an organism 
 Germ cells are cells th...
Basic Molecular Genetics 
• somatic cells contain DNA arranged 
in chromosomes. 
• If a somatic cell contains chromosomes ...
Basic Molecular Genetics 
• In humans, somatic cells contain 46 chromosomes 
organized into 23 pairs. 
• By contrast, game...
Basic Molecular Genetics 
• Chromosome: A distinct segment of linear DNA 
containing a large number of genes. In humans 
t...
Mitosis & Meiosis
Basic Molecular Genetics 
 DNA is composed of 3 basic components: 
Base : Pyrimidine or purine 
Sugar : (2-deoxyribose)...
The Nucleic Acid alphabet consists of 4 
bases: 
1. purines adenine (A) 
2. purines guanine (G) 
3. pyrimidines thymine (T...
DNA : deoxyribonucleic acid 
Nucleobases
 Hydrogen bonding occurs specifically between 
the purine adenine (A) and the pyrimidine 
thymine (T) and between the pur...
 The combination of a sugar phosphate 
group and a base constitutes a 
nucleotide. 
 The double helix is made from two 
...
Transcription 
Transcription is the first step in converting DNA into protein 
↓ 
During the process of transcription, lin...
RNA : ribonucleic acid
During transcription, a section of 
one DNA strand, or the other, is 
used as a template for the 
synthesis of mRNA. 
Th...
Protein Translation 
 Translation of mRNA into protein occurs in the 
cytoplasm where ribosomes are located. 
 Two other...
Key Points 
The information contained in DNA is 
transcribed into RNA and then translated into 
protein. 
Transcription ...
Summary
Body cells 
↓ 
loss 
↓ 
cell proliferation 
↓ 
maintaining tissue and organ homeostasis
How can Normal cell become Cancer Cell ? 
1. Genetic instability 
2. Autonomous growth 
3. Insensitivity to internal and e...
 In addition, cancer cells need to cope with 
various cellular stresses that are byproducts of 
their abnormal physiology...
Our knowledge of the molecular genetics of 
cancer is rapidly expanding, providing new 
insights that are just beginning t...
Tumor Suppressor Genes & Oncogenes
Tumor Suppressor Genes 
 Tumor suppressor genes (antioncogene) 
regulate cellular growth and play a critical role 
in the...
 Loss of function of both alleles of a tumor 
suppressor gene is typically required for 
carcinogenesis. 
 This function...
“two-hit” hypothesis 
• The “two-hit” hypothesis was first proposed 
in cases of retinoblastoma, which required 
mutations...
• Specific types of mutations in certain gene 
however, may not follow this two-hit rule and 
can function as dominant neg...
Oncogenes 
• Oncogenes (proto-oncogene): are associated with 
cellular proliferation and are the mutated form of 
normal g...
Key Point 
 Mutations in DNA can lead to changes in protein 
function or expression that increase the potential 
for canc...
Key Point 
 Loss of tumor suppressor gene function can 
occur primarily by : 
(1) homozygous deletion 
(2) loss of one al...
Key Point 
 Certain tumor suppressor genes do not follow the “two-hit” 
hypothesis and may be inactivated by dominant 
ne...
The Cell Cycle 
the cell cycle takes approximately 24 hours to complete 
Hartwell et al,1974
checkpoint mechanisms closely monitor 
DNA integrity as well as certain critical cell 
cycle events. 
If problems are dete...
Sequential activation of cyclin-dependent kinase 
complex (CDKC, cyclin-CDK) is critical to the orderly 
progression of ce...
 Many oncogenes and tumor suppressors exert 
their effects by interfering with cell cycle 
checkpoints and apoptotic path...
Some Oncogenes associate with GU 
cancers 
Oncogenes Associate with Recourse 
c-MYC prostate Ca. (Gil et al, 2005). 
c-MET...
Key Point 
• The cell cycle consists of an ordered, 
unidirectional series of events, the main goal of 
which is to replic...
Key Point 
 Mutations in pRB are common in some urologic 
malignancies (Bladder Ca.) 
 Phase-specific phosphorylation of...
Key Point 
 Primary points of cell cycle control are the G1S 
and G2M checkpoints. 
 Checkpoints employ cyclin-dependent...
Key Point 
 The TP53 tumor suppressor protein is a key 
player in cell cycle checkpoints, responding to 
DNA damage by si...
Key Point 
• TP53 is the most commonly mutated gene in 
cancer and plays a prominent role in 
genitourinary malignancies. ...
DNA Methylation 
• The covalent modification of the C-5 position 
of cytosine is mediated by DNA (cytosine-5) 
methyltrans...
• One important role for methylation is genomic 
imprinting, which results in monoallelic gene 
expression without alterin...
• Changes in global levels and regional patterns 
of DNA methylation are among the earliest 
and most frequent events know...
• Three major pathways by which DNA methylation 
may result in genetic dysregulation in human 
caner include 
(1) inherent...
DNA Methylation and Prostate Cancer 
Abnormal Mutation % Recourse 
methylation gene 
>90% PCa* (Lee et al, 1994) 
≈ 70% PI...
Role of DNA Methylation 
in Bladder Cancer 
Abnormal Mutation % Type Recourse 
methylation 
gene 
(Greenblatt et al, 1994)...
Key Point 
 Methylation occurs specifically at CpG dinucleotides in 
the genome. 
 The presence of 5-methylcytosine in D...
DNA damage & repair 
 DNA damage does not often lead to malignancy, 
because the cell possesses multiple repair 
mechanis...
 Nucleotide excision repair (NER) is a major 
defense against 
 DNA damage caused by ultraviolet radiation 
and chemical...
 Mismatch repair (MMR) removes nucleotides 
mispaired by DNA polymerase. 
 Double-stranded break repair (DSBR) is a 
maj...
Chromosome Abnormalities & 
Genetic Instability
 The chromosomal changes seen in solid 
tumors can be broken down into two main 
classes: 
1. changes in the number of wh...
Specific Chromosomal Rearrangements 
in Genitourinary Malignancies 
Recurrent Gene Rearrangements 
Cancer oncogene Recours...
Cancer Risk factor 
Family history is one of the strongest prostate cancer 
risk factors 
HPC 
• first degree relatives of...
Key Point 
 structural rearrangements, as well as 
intratumoral heterogeneity in these 
aberrations, are hallmarks of mos...
Key Point 
 family gene fusions), renal (MITF/TFE family 
translocation carcinomas), and testicular 
cancers (isochromoso...
Key Point 
 Genes discovered to have germ line 
mutations that cause familial forms of cancer 
may also be involved in th...
Telomere & Telomerase 
• Telomeres contain stretches of terminal, 
noncoding, repetitive DNA that cap the ends 
of each ch...
• Normal cells monitor their telomere lengths and 
permanently exit the cell cycle (cellular 
senescence) or commit suicid...
• A majority of cancers and premalignant 
lesions have abnormally short telomeres. 
• Most cancers express the enzyme telo...
Apoptosis 
• Apoptosis:programmed cell death 
• Apoptosis is a rapid, orderly, programmed 
form of cell death that is used...
• Apoptosis is believed to play an important role in 
tumor suppression because many of the signals that 
induce apoptosis...
• Apoptosis is mediated by a conserved family 
of proteases known as caspases. Initiator 
caspases begin caspase proteolyt...
• Two main apoptotic pathways have been 
identified: 
In the intrinsic pathway, BCL-2 family members 
modulate the releas...
• In addition to its functions in cell cycle arrest 
and DNA repair, TP53 also plays a key role in 
apoptosis. 
• BCL-2 is...
• Therapeutic response is often dependent 
upon the integrity of apoptotic pathways in 
cancer cells. Most TGCT retain int...
Cancer Stem Cells 
 Stem cells are defined by their ability to 
differentiate along multiple lineages and their 
immortal...
 The hedgehog signaling pathway is required 
for regeneration of prostate epithelium and 
has been implicated in transfor...
References 
• Campbell-Walsh Urology – 10th Edition - 
Chapter 18 page 530
Molecular Genetics and Cancer Biology
Molecular Genetics and Cancer Biology
Molecular Genetics and Cancer Biology
Molecular Genetics and Cancer Biology
Molecular Genetics and Cancer Biology
Molecular Genetics and Cancer Biology
Molecular Genetics and Cancer Biology
Molecular Genetics and Cancer Biology
Molecular Genetics and Cancer Biology
Molecular Genetics and Cancer Biology
Molecular Genetics and Cancer Biology
Molecular Genetics and Cancer Biology
Molecular Genetics and Cancer Biology
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Molecular Genetics and Cancer Biology

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my first presentation in my residency year in Urology speciality

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Molecular Genetics and Cancer Biology

  1. 1. Molecular Genetics & Cancer Biology Meshari Alzahrani R1 Urology Resident | KAMC-NGHA-Jeddah 16 November 2014
  2. 2. Lecture Roadmap  Introduction  Basic Molecular Genetics  Tumor Suppressor Genes and Oncogenes  The Cell Cycle  DNA Methylation  DNA Damage and Repair  Chromosomal Abnormalities and Genetic Instability  Telomeres and Telomerase  Apoptosis  Stem Cells and Cancer
  3. 3. Why This Lecture !
  4. 4. Despite decades of intensive biomedical research, cancer remains a significant cause of morbidity and mortality worldwide. Campbell-Walsh Urology 10th Edition
  5. 5. World Cancer Day – 4th February 2014 By 2025, there will be more than 20 million new cancer cases per year, compared with 14.1 million in 2012, according to the World Cancer Report 2014, released on 3 February by the World Health Organization’s International Agency for Research on Cancer. IARC World Cancer Report 2014
  6. 6. IARC World Cancer Report 2014
  7. 7. cancer ribbon
  8. 8. • However, significant advances in the diagnosis and treatment of certain Genitourinary (GU) cancers have been made. • For example, the cure rate for testicular cancer now approaches 100%. (Einhorn, 2002; Horwich et al, 2006) • Unfortunately, this cancer is unusual in its responsiveness to therapy and is relatively uncommon Campbell-Walsh Urology 10th Edition
  9. 9. • We have had less success with the more prevalent GU malignancies, such as prostate, bladder, and renal cancers—the second, eighth and tenth most common cancers, respectively. Campbell-Walsh Urology 10th Edition
  10. 10.  In Saudi Arabia, prostate cancer is the 6th most common cancer among men of all ages and the most common cancer among men over the age of 75.  It accounts for 6.1% of all newly diagnosed cases among males in year 2010 with an age - standardized incidence rate of 5.5/100,000 among the male population.  Stage at the time of diagnosis is localized in 43.9% of cases with the remainder being either locally advanced, metastatic or unknown. Saudi Cancer Registry Annual Report, 2010
  11. 11.  Bladder cancer ranked 13 among the most common cancer diagnosis in Saudi Arabia, affecting 3.6/100,000 men and 1/100,000 women.  In 2010, there were an estimated 243 new cases of bladder cancer accounting for 2.5% of all newly diagnosed cases.  It affected 193 (78.4%) males and 50 (21.6%) females with a male : female ratio of 385:100.  The most common histological subtypes is TCC (82%) followed by SCC(4%). Saudi Cancer Registry Annual Report, 2010
  12. 12. Basic Molecular Genetics
  13. 13. In 1953 Co-discoverer of the structure of the DNA molecule Francis Crick James Watson The molecular characteristics of DNA were first described in 1953 (Watson and Crick, 1953). This molecule serves as the blueprint for determination of structure and function of all living organisms. “ “
  14. 14. Basic Molecular Genetics  Somatic cell is any biological cell forming the body of an organism  Germ cells are cells that give rise to gametes  Gametes : is a cell that fuses with another cell during fertilization (conception) in organisms that sexually reproduce, witch carry half the genetic information of an individual.  Stem cells are cells that can divide through mitosis and differentiate into diverse specialized cell types.
  15. 15. Basic Molecular Genetics • somatic cells contain DNA arranged in chromosomes. • If a somatic cell contains chromosomes arranged in pairs, it is called diploid and the organism is called a diploid organism. • The gametes of diploid organisms contain only single unpaired chromosomes and are called haploid. • Each pair of chromosomes comprises one chromosome inherited from the father and one inherited from the mother
  16. 16. Basic Molecular Genetics • In humans, somatic cells contain 46 chromosomes organized into 23 pairs. • By contrast, gametes of diploid organisms contain only half as many chromosomes. • In humans, this is 23 unpaired chromosomes. • When two gametes (i.e. a spermatozoon and an ovum) meet during conception, they fuse together, creating a zygote. • Due to the fusion of the two gametes, a human zygote contains 46 chromosomes (i.e. 23 pairs)
  17. 17. Basic Molecular Genetics • Chromosome: A distinct segment of linear DNA containing a large number of genes. In humans there are 23 such segments, each containing hundreds to thousands of genes. • Gene: A segment of DNA that contributes to the formation of a protein, including both the introns (noncoding regions) and the exons (coding regions), as well as the regulatory regions preceding and following the coding regions.
  18. 18. Mitosis & Meiosis
  19. 19. Basic Molecular Genetics  DNA is composed of 3 basic components: Base : Pyrimidine or purine Sugar : (2-deoxyribose) Phosphate
  20. 20. The Nucleic Acid alphabet consists of 4 bases: 1. purines adenine (A) 2. purines guanine (G) 3. pyrimidines thymine (T) 4. pyrimidines cytosine (C). 5. There is a fifth base that can be found in DNA known as 5- methylcytosine (5-mC).  Uracil (U) is substituted for thymine in the case of RNA.  The combination of a base and a sugar (deoxyribose) is referred to as a nucleoside nucleoside
  21. 21. DNA : deoxyribonucleic acid Nucleobases
  22. 22.  Hydrogen bonding occurs specifically between the purine adenine (A) and the pyrimidine thymine (T) and between the purine guanine (G) and the pyrimidine cytosine (C)  The connection between repeating phosphates and sugars creates a Helical Chain.  In the RNA molecule, adenine base pairs with uracil (U).
  23. 23.  The combination of a sugar phosphate group and a base constitutes a nucleotide.  The double helix is made from two polynucleotide chains, each of which consists of a series of 5′– to 3′–sugar phosphate links that form a backbone from which the bases protrude.  The double helix maintains a constant width because purines always face pyrimidines in complementary A-T and G-C base pairs, respectively.
  24. 24. Transcription Transcription is the first step in converting DNA into protein ↓ During the process of transcription, linear DNA is converted to linear messenger RNA (mRNA) ↓ The process of translation consists of the conversion of linear mRNA to a linear set of amino acids that will eventually form a functional protein ↓ Single strand of RNA is copied from one of the strands of DNA. ↓ The sugar element in the RNA molecule is ribose and the pyrimidine uracil substitutes for thymine ↓ RNA polymerase II is the enzyme that synthesizes the first copy of RNA This primary strand of RNA is called heterogeneous nuclear RNA (hnRNA) ↓ hnRNA contains coding sequences (exons) of DNA and noncoding sequences (introns).
  25. 25. RNA : ribonucleic acid
  26. 26. During transcription, a section of one DNA strand, or the other, is used as a template for the synthesis of mRNA. This synthesis always occurs in a 5′ to 3′ direction.
  27. 27. Protein Translation  Translation of mRNA into protein occurs in the cytoplasm where ribosomes are located.  Two other forms of RNA are important for protein translation: transfer RNA (tRNA) and ribosomal RNA (rRNA)  The mRNA message is translated in segments of three adjacent nucleotides called a codon  Each codon is translated into one of 20 amino acids
  28. 28. Key Points The information contained in DNA is transcribed into RNA and then translated into protein. Transcription of RNA is tightly regulated and is tissue specific. A single gene can encode for multiple unique proteins by including or excluding certain exons in the mRNA transcript by alternative splicing. Post-transcriptional gene regulation can occur by a mechanism involving the expression of noncoding RNAs that have the capability of binding to and degrading mRNAs
  29. 29. Summary
  30. 30. Body cells ↓ loss ↓ cell proliferation ↓ maintaining tissue and organ homeostasis
  31. 31. How can Normal cell become Cancer Cell ? 1. Genetic instability 2. Autonomous growth 3. Insensitivity to internal and external antiproliferative signals 4. Resistance to apoptosis and other forms of induced cell suicide 5. Unlimited cell division potential 6. The ability to induce new blood vessel formation , a process termed angiogenesis. 7. Locally invasive behavior, which uniquely distinguishes malignant from benign neoplasms. 8. Evasion of the immune system. (Hanahan and Weinberg, 2000; Solimini et al, 2007; Luo et al,2009).
  32. 32.  In addition, cancer cells need to cope with various cellular stresses that are byproducts of their abnormal physiology.  Finally, many cancers develop an additional, lethal attribute—the ability to leave the site of the primary tumor to colonize and thrive in distant organs or tissues as metastases. (Hanahan and Weinberg, 2000; Solimini et al, 2007; Luo et al,2009).
  33. 33. Our knowledge of the molecular genetics of cancer is rapidly expanding, providing new insights that are just beginning to be successfully exploited for use in novel diagnostic, prognostic, and therapeutic applications. Campbell-Walsh Urology 10th Edition
  34. 34. Tumor Suppressor Genes & Oncogenes
  35. 35. Tumor Suppressor Genes  Tumor suppressor genes (antioncogene) regulate cellular growth and play a critical role in the normal processes of the cell cycle.  These genes are also important for DNA repair and cell signaling.  The absence of tumor suppressor gene function may lead to dysregulation of normal growth control and malignancy.
  36. 36.  Loss of function of both alleles of a tumor suppressor gene is typically required for carcinogenesis.  This functional loss can occur by : 1. homozygous deletion 2. loss of one allele and mutational inactivation of the second allele, 3. mutational events involving both alleles, 4. loss of one allele and inactivation of the second allele by DNA methylation
  37. 37. “two-hit” hypothesis • The “two-hit” hypothesis was first proposed in cases of retinoblastoma, which required mutations in both alleles for disease manifestation (Knudson, 1971).
  38. 38. • Specific types of mutations in certain gene however, may not follow this two-hit rule and can function as dominant negative mutations that produce altered protein. • Mutant protein products have been reported to inhibit function of normal protein from unaltered alleles (Baker et al, 1990). • Mutation of a single allele may result in haploinsufficiency, causing increased carcinogen susceptibility as in the case of the TP27 Kip1 gene (Fero et al, 1998).
  39. 39. Oncogenes • Oncogenes (proto-oncogene): are associated with cellular proliferation and are the mutated form of normal genes. • Two oncogenes that have been found to be overexpressed in a variety of cancers include : c-MYC and c-MET (Wong et al, 1986; Bottaro et al, 1991).
  40. 40. Key Point  Mutations in DNA can lead to changes in protein function or expression that increase the potential for cancer initiation, progression, or metastasis.  Tumor suppressor genes regulate and control cellular growth.  Oncogenes promote cell growth.
  41. 41. Key Point  Loss of tumor suppressor gene function can occur primarily by : (1) homozygous deletion (2) loss of one allele and mutational inactivation of the second allele (3) mutational events involving both alleles (4) loss of one allele and inactivation of the second allele by DNA methylation.
  42. 42. Key Point  Certain tumor suppressor genes do not follow the “two-hit” hypothesis and may be inactivated by dominant negative mutations or haploinsufficiency.  Proto-oncogenes can be converted to oncogenes by : (1) mutation of the proto-oncogene resulting in an activated form of the gene (2) gene amplification (3) chromosomal rearrangement.
  43. 43. The Cell Cycle the cell cycle takes approximately 24 hours to complete Hartwell et al,1974
  44. 44. checkpoint mechanisms closely monitor DNA integrity as well as certain critical cell cycle events. If problems are detected (e.g., DNA damage), the cell cycle will pause to allow repair (Hartwell and Weinert, 1989). If repair is not possible, normal cells often will commit cellular suicide through an active process termed apoptosis.
  45. 45. Sequential activation of cyclin-dependent kinase complex (CDKC, cyclin-CDK) is critical to the orderly progression of cell replication.
  46. 46.  Many oncogenes and tumor suppressors exert their effects by interfering with cell cycle checkpoints and apoptotic pathways, allowing cancer cells to divide continuously and accumulate.  Loss of the ability to respond appropriately to damaged DNA is particularly dangerous, because it fosters genetic instability, a key attribute of cancer cells.  Loss of DNA damage checkpoint controls results in an increased mutation rate, accelerating the mutation of cancer-associate genes, thus contributing to carcinogenesis and disease progression. (Bartek et al, 1999).
  47. 47. Some Oncogenes associate with GU cancers Oncogenes Associate with Recourse c-MYC prostate Ca. (Gil et al, 2005). c-MET RCC (Pisters et al, 1997) MET proto-oncogene hereditary RCC (Schmidt et al, 1997). c-MYC bladder Ca. (Schmitz-Drager et al, 1997) pRB bladder Ca. (Horowitz et al, 1990)
  48. 48. Key Point • The cell cycle consists of an ordered, unidirectional series of events, the main goal of which is to replicate the cell’s genome and partition one copy into each of two resulting daughter cells. • The cell cycle is divided up into 4 phases; G1, S, G2, and M phase. • The transition from G1 into S is critically dependent on phosphorylation of the pRB tumor suppressor protein.
  49. 49. Key Point  Mutations in pRB are common in some urologic malignancies (Bladder Ca.)  Phase-specific phosphorylation of substrate proteins by cyclin-dependent kinases (CDK) orchestrate progression through the cell cycle.  The activities of CDKs are dependent upon their association with specific cyclin proteins.  Cyclins accumulate and are rapidly degraded in a phase-specific manner, thus assuring the proper sequencing and irreversibility of key events throughout the cell cycle.
  50. 50. Key Point  Primary points of cell cycle control are the G1S and G2M checkpoints.  Checkpoints employ cyclin-dependent kinase inhibitor proteins (CDK1) to pause the cell cycle in response to a variety of stress signals, including DNA damage, cell– cell contact, cytokine release, and hypoxia.
  51. 51. Key Point  The TP53 tumor suppressor protein is a key player in cell cycle checkpoints, responding to DNA damage by signaling cell cycle arrest and repair of the damage.  If the DNA damage cannot be repaired, TP53 may trigger cell death (apoptosis).
  52. 52. Key Point • TP53 is the most commonly mutated gene in cancer and plays a prominent role in genitourinary malignancies. • Defects in cell cycle checkpoints lead to unregulated cell proliferation and genetic instability.
  53. 53. DNA Methylation • The covalent modification of the C-5 position of cytosine is mediated by DNA (cytosine-5) methyltransferase, resulting in the formation of 5-methylcytosine. • Methylation of cytosine occurs primarily at the CpG palindrome in DNA.
  54. 54. • One important role for methylation is genomic imprinting, which results in monoallelic gene expression without altering the genetic sequence. • Loss of imprinting (LOI) is a reduction in the methylation of the normally methylated allele, which can lead to activation of the normally silent copy of a growthpromoting gene. (Feinberg and Tycko, 2004).
  55. 55. • Changes in global levels and regional patterns of DNA methylation are among the earliest and most frequent events known to occur in human cancer. (Jones and Baylin, 2002)
  56. 56. • Three major pathways by which DNA methylation may result in genetic dysregulation in human caner include (1) inherent mutational effects of 5-methylcytosine (2) epigenetic effects of promoter methylation on gene transcription, (3) potential gene activation and induction of chromosomal instability by DNA hypomethylation (Gonzalgo and Jones, 1997).
  57. 57. DNA Methylation and Prostate Cancer Abnormal Mutation % Recourse methylation gene >90% PCa* (Lee et al, 1994) ≈ 70% PIN* GSTP1* CpG island RASSF1A* RASSF1A 60% to 70% (Kuzmin et al, 2002) GSTP1 glutathione-S-transferase Pi RASSF1A RAS association domain-containing protein 1 Pca Prostate Cancer PIN prostatic intraepithelial neoplasim
  58. 58. Role of DNA Methylation in Bladder Cancer Abnormal Mutation % Type Recourse methylation gene (Greenblatt et al, 1994) (Rideout et al, 1990; Tornaletti and Pfeifer, 1995). (Spruck et al,1994b) urothelial dysplasia carcinoma in situ (CIS) invasive bladder Ca C→T 24 transition TP53 (Chan et al, 2002; Chang et al,2003) primary urothelial carcinomas TP16 TP16 allele 27-60 (Graff et al, 1995; Horikawa et al, 2003) high-grade urothelial carcinoma, Hypermeth - ylation CDH1 (Lee et al, 2001) (Maruyama et al, 2001). primary bladder tumors High tumor grade, nonpapillary growth pattern muscle invasive disease RASSF1A RASSF1A 97 (Kimura et al,2003) (Jurgens et al, 1996). Hypomethy Bladder Ca. lation DNMT1 DNMT3A, DNMT3B
  59. 59. Key Point  Methylation occurs specifically at CpG dinucleotides in the genome.  The presence of 5-methylcytosine in DNA can result in spontaneous deamination to thymine and formation of C→T transition mutations.  DNA methylation can affect gene function by mutational events or epigenetic mechanisms.  Methylation of CpG islands associated with the promoter region of genes may result in down-regulation of transcription and suppression of gene expression.  Loss of methylation of normally methylated genes can lead to the potential for gene expression.
  60. 60. DNA damage & repair  DNA damage does not often lead to malignancy, because the cell possesses multiple repair mechanisms.  Defects in DNA repair facilitate the accumulation of the mutations critical for tumor formation and progression.  The cell cycle and the DNA damage response (DDR) are closely integrated. In response to DNA damage, the first step is to arrest the cell cycle so that the DNA can be repaired. TP53 plays a key role at this interface. Key Point
  61. 61.  Nucleotide excision repair (NER) is a major defense against  DNA damage caused by ultraviolet radiation and chemical exposure.  Base excision repair (BER) repairs damage caused by spontaneous  deamination of bases, radiation, oxidative stress alkylating agents, and replication errors. Key Point
  62. 62.  Mismatch repair (MMR) removes nucleotides mispaired by DNA polymerase.  Double-stranded break repair (DSBR) is a major defense against DNA damage caused by ionizing radiation, free radicals, and chemicals.  Many syndromes involving inherited defects in DNA repair exhibit marked increases in cancer susceptibility; strongly linking genomic instability and cancer. Key Point
  63. 63. Chromosome Abnormalities & Genetic Instability
  64. 64.  The chromosomal changes seen in solid tumors can be broken down into two main classes: 1. changes in the number of whole chromosomes 2. changes in chromosomal structure.
  65. 65. Specific Chromosomal Rearrangements in Genitourinary Malignancies Recurrent Gene Rearrangements Cancer oncogene Recourse Tomlins and colleagues (2005), •ETS transcription factor family members Pca (Hemesath et al, 1994; Argani et al, 2005). MITF/TFE family translocation carcinomas RCC (Atkin and Baker, 1982; Rodriguez et al, 1993; Rosenberg et al, 1998; Verdorfer et al, 2004). short arm of chromosome 12 Testicular Cancer Hereditary Prostate Cancer HPC families (Smith et al, 1996). Sporadic Prostate Cancer chromosome 8 (Gnarra et al, 1994; Shuin et al, 1994). germ line mutations VHL gene von Hippel-Lindau syndrom sporadic ccRCC (Tsai et al, 1990; Cairns et al, 1993; Linnenbach et al, 1993) chromosome 9 RAS family Bladder Ca. transitional cell typ (urothelial cell carcinomas)
  66. 66. Cancer Risk factor Family history is one of the strongest prostate cancer risk factors HPC • first degree relatives of patients with bladder cancer are at increased risk of developing the disease • high-risk families are very rare and lack clear mendelian inheritance patterns, precluding classical linkage analysis. • Bladder cancer is therefore not considered a familial Disease Bladder Cancer
  67. 67. Key Point  structural rearrangements, as well as intratumoral heterogeneity in these aberrations, are hallmarks of most human solid tumors.  The extent of chromosomal abnormalities typically correlates with disease severity and aggressiveness.  Recurrent structural rearrangements occur in prostate (ETS
  68. 68. Key Point  family gene fusions), renal (MITF/TFE family translocation carcinomas), and testicular cancers (isochromosome 12p).  Copy number alteration in a particular gene, coupled with changes in the other allele is strong evidence for that gene functioning as a disease-relevant oncogene or tumor suppressor gene.
  69. 69. Key Point  Genes discovered to have germ line mutations that cause familial forms of cancer may also be involved in the sporadic form of the disease (e.g., VHL in ccRCC).  High-density single nucleotide polymorphism (SNP) microarrays have been used in genome-wide association studies (GWAS) to identify DNA sequence variants associated with cancer risk.
  70. 70. Telomere & Telomerase • Telomeres contain stretches of terminal, noncoding, repetitive DNA that cap the ends of each chromosome, thereby stabilizing them. • Telomere DNA repeats are progressively lost as cells divide and as a result of oxidative DNA damage at the telomeres.
  71. 71. • Normal cells monitor their telomere lengths and permanently exit the cell cycle (cellular senescence) or commit suicide (apoptosis) in response to telomere shortening. This tumor-suppressive telomere length checkpoint involves TP53 and pRB. • Loss of telomere length checkpoints can lead to critical telomere shortening that initiates chromosomal instability, thus contributing to carcinogenesis.
  72. 72. • A majority of cancers and premalignant lesions have abnormally short telomeres. • Most cancers express the enzyme telomerase, which restabilizes the telomeres and allows unlimited cell division potential (“immortalization”), thus telomerase represents an attractive therapeutic target.
  73. 73. Apoptosis • Apoptosis:programmed cell death • Apoptosis is a rapid, orderly, programmed form of cell death that is used by multicellular organisms to eliminate unwanted cells. Through this process, cells are preprogrammed to commit suicide in response to various internal and external signals.
  74. 74. • Apoptosis is believed to play an important role in tumor suppression because many of the signals that induce apoptosis arise from potentially tumorigenic cell stresses such as DNA damage. • Cancer is characterized by interruptions in the normal process of apoptosis, resulting in inappropriate cell survival.
  75. 75. • Apoptosis is mediated by a conserved family of proteases known as caspases. Initiator caspases begin caspase proteolytic cascades that result in the activation of downstream executioner caspases, which, in turn, target several cellular proteins.
  76. 76. • Two main apoptotic pathways have been identified: In the intrinsic pathway, BCL-2 family members modulate the release of cytochrome c from mitochondria, which then participates in the activation of initiator caspases. The extrinsic pathway activates caspases in response to signals from extracellular “death receptors.”
  77. 77. • In addition to its functions in cell cycle arrest and DNA repair, TP53 also plays a key role in apoptosis. • BCL-2 is a classic inhibitor of the mitochondrial pathway of apoptosis and is overexpressed in some genitourinary malignancies.
  78. 78. • Therapeutic response is often dependent upon the integrity of apoptotic pathways in cancer cells. Most TGCT retain intact DDR, wild-type TP53, and apoptotic responses, providing high cure rates with DNA-damaging agents. • Novel agonists and antagonists of apoptosis, such as ceramide and clusterin, may be successfully controlled to combat cancer.
  79. 79. Cancer Stem Cells  Stem cells are defined by their ability to differentiate along multiple lineages and their immortality.  Cancer is believed to be a stem cell disease in which a small population of cancer stem cells maintains the larger tumor.
  80. 80.  The hedgehog signaling pathway is required for regeneration of prostate epithelium and has been implicated in transformation of prostate progenitor cells.  Cancer may ultimately be eradicated by targeting only the cancer stem cell.
  81. 81. References • Campbell-Walsh Urology – 10th Edition - Chapter 18 page 530

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