Mohammed El-Khateeb. Tumor Genetics. MGL-12 July 21 st 2013 台大農藝系遺傳學 Chapter 22 slide 1

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1 Mohammed El-Khateeb Tumor Genetics MGL-12 July 21 st 2013 台大農藝系遺傳學 Chapter 22 slide 1

2 Cellular Basis of Cancer Cancer is a collection of diseases characterized by abnormal and uncontrolled growth Cancer arises from a loss of normal growth control In normal tissues, the rates of new cell growth and old cell death are kept in balance In cancer, this balance is disrupted This disruption can result from 1) uncontrolled cell growth or 2) loss of a cell's ability to undergo apoptosis 2

3 Cancer Cell Do Not Grow Faster Than Normal Cells Rather, Their Growth is Just Uncontrolled 3

4 Cellular equilibrium Proliferation Differentiation Death Renewing Proliferating Transit Exiting 4

5 Cancer: disruption of cellular equilibrium Proliferation Differentiation Death5

6 Stem cells as the target of carcinogens Stem cell Differentiated Post mitotic Normal senescent differentiated cell Benign tumor Grade 2 malignancy Grade 3 or 4 malignancy 6

7 CELL GROWTH Cancer is a Disease of the Cell Cycle Cells in the body are "programmed" to: To develop To grow To differentiate To die in response to a complex system of biochemical signals. Cancer results from the emergence of a clone of cells freed of these developmental programming constraints and capable of inappropriate proliferation

8 Response to the Environmental Signals SIGNALS Growth Factors Steroids Cell to Cell Interaction RESPONSE Differentiation Growth and Death Mitosis

9 8.2, Regulation of cell division by signal transduction.

10 Five types of proteins encoded by proto-oncogenes participate in control of cell growth: Class I: Growth Factors Class II: Receptors for Growth Factors and Hormones Class III: Intracellular Signal Transducers Class IV: Nuclear Transcription Factors Class V: Cell-Cycle Control Proteins 10

11 Types of Growth Factors for Differentiation

12 Oncogenes and Proto-Oncogenes Products 1.Growth Factors 2.TM GF R (TKase) 3. Integral MR 4. Ras GTPase 5. Cytoplasmic Oncogenes 6. Nuclear Oncogene

13 Cancer cells have acquired the ability to proliferate in the absence of appropriate signals

14 Cancer: General Etiology and Pathogenesis Etiologic agents: Environmental (chemical, physical, and biological) Hereditary (familial cancer syndromes) General mechanisms: Acquired capabilities (Self-maintained replication, longer survival, genetic instability, neoangiogenesis, invasion and metastasis) Activation of oncogenes, inactivation of TSG, noneffective DNA repair Caretaker and gatekeeper pathways

15 THE CAUSES OF GENOMIC CHANGES IN CANCER : Somatic Changes Cause Damage Cancer Risk Signals Physical Chemical UV Radiation Skin Ca, Melanoma Thyroid Ca., Leucemia P53 (CC-TT) Translokation Benzopren Lung Ca. p53 (G-T) Aflatoxin Liver Ca. p53 (249 G-T) Oxidative Stress Geriatric Ca Biological HBV Liver Ca. P53 (C-T) Virus DNA Integration 15

16 Chemical Signals that Control the Cell Cycle 1. Cyclin and Kinase proteins that initiate mitosis requires buildup of cyclin to pair with kinase 2. Hormones chemical signals from specialized glands that stimulate mitosis 3. Growth Factors chemical factors produced locally that stimulate mitosis

17 Cell cycle and cancer: Cell differentiation occurs as cells proliferate to form tissues. Cell differentiation correlates with loss of ability to proliferate; highly specialized cells are terminally differentiated. Terminally differentiated cells have a finite life span, and are replaced with new cells produced from stem cells. Stem cells are capable of self-renewal; cells divide without undergoing terminal differentiation.

18 Cell Cycle Checkpoints Apoptosis Checkpoint Mitosis Spindle Assembly Checkpoint DNA Damage Checkpoints G2 assembly of components for division S chromosomes replicate P M A G1 T cytokinesis cytoplasm doubles DNA Damage Checkpoint

19 The Cell Cycle Oncogenes M (mitosis) G 1 (cell growth) G 2 DNA repair genes REPAIRS AHEAD S (synthesis) G 0 (resting) Tumor suppressor genes ASCO

20 Normal cell cycle is controlled by signal transduction: Growth factors bind to surface receptors on the cell; transmembrane proteins relay signals into the cell. Two types of growth factors: 1. Growth factors stimulate cell division. 2. Growth-inhibiting factors inhibit cell division Healthy cells divide only when growth factor and growthinhibiting factor balance favors cell division. Cancer cells divide without constraint (e.g., mutations in growth and growth-inhibiting factor genes).

21 Genetic Mechanisms of Tumors Gene deletions / amplifications Mutations Inserstional Point Mutations Genetic Instability Microsatellite Instability (MSI) Chromosomal Instability (CIN)

22 EXAMPLES

23 Environmental vs. Hereditary Cancer

24 Familial Clustering of Cancer Epidemiological studies show an increased relative risk of cancer in individuals with a family history of cancer This is probably due to a mixture of rare highly penetrant genes, commoner lower penetrance genes and environmental effects

25 Cancer Inheritance MULTIPLE HITS PROCESS The first hit it could be embryonic as in Retinoplastoma The others could be due to: Point mutation Loss of reduplication Deletion Mutation of normal gene Somatic recombination

26 Inherited Cancer Genes Neurofibromatosis type-1 P53 gene Familial Polyposis Gene (APC) Hereditary nonpolyposis colon cancer (HNCC) Breast Cancer Genes (BRCAI, BRCA2) P16 Familial Melanoma RET proto-oncogene and multiple endocrine neoplasia

27 SOLID TUMORS SARCOMAS In addition to leukemias and lymphomas some sarcomas also have specific chromosomal abnormalities One example is t(11;22) seen in Ewing s sarcoma in which the DNA binding domain of a transcription factor FLI1 is fused with the transactivation domain of EWSR1 gene

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29 RECURRENT ABNORMALITIES EPITHELIAL TUMORS Small cell ca of the lung del(3)(p14- p24) Wilm s tumor del(11)(p13) Breast Her-2/neu amplification Mostly multiple abnormalities

30 Ovarian Cancer > 400 cases karyotyped 2 cytogenetic pathways 1: +7,+8q and +12 2: 6q- and 1q- 3 phases of karyotypic evolution 1. step wise changes 2. Increased chromosome instability 3. Triploidization with 6q- and 1q- CGH reveal multiple changes in the malignant and fewer changes in borderline tumors

31 Uterine leiomyomas and leiomyosarcomas Benign tumors such as leiomyomas also show recurrent chromosomal abnormalities such as t(12;14) and deletion of 7q 40% of leiomyomas show abnormal karyotypes Leiomyosarcomas show complex chromosomal rearrangements

32 COPY NUMBER CHANGES IN LEIOMYOSARCOMA LOSS GAIN 13q (59%) 10q(59%) 2q(35%) 16q(29%) 5p(35%) 6p amplification 17p amplification

33 The Familial Polyposis Gene (A PC), The familial polyposis gene (APC), which strikingly predisposes to colon cancer, was ultimately identified by mutations in patients. The inherited gene is also involved in the great majority of sporadic cases of colon polyps and colon cancer. This tumor suppressor gene has been shown to function as a major regulator of the Wnt pathway, a signaling system that is well characterized both biochemically and developmentally

34 Moderate Colorectal Cancer Risk Two first-degree relatives affected (0.4% population) One first-degree relative diagnosed <45y (0.2% population) Suggest colonoscopy at 35y (2% risk of polyp) and 55y (17-21% risk of polyp)

35 Morphological and Molecular Changes in Adenoma and Carcinoma Sequence

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37 The Hereditary Nonpolyposis Colon Cancer Genes HNPCC is an inherited form of colorectal cancer that is caused by mutations in any of several genes involved in DNA mismatch repair. It represents an example of a cancer syndrome caused by genomic instability

38 Hereditary Non-Polyposis Colon Cancer 80% lifetime risk of colorectal cancer (males) 60% lifetime risk of endometrial cancer 10% risk of ovarian cancer Surveillance 1-2 yearly colonoscopies from 25y Consider endometrial screening by ultrasound and endometrial pipelle biopsy Consider ovarian screening by transvaginal ultrasound

39 Cancer and repair: HNPCC Mismatch repair defects Normal epithelium Adenoma Carcinoma Metastasis Accumulation of mutations in multiple genes Oncogenes: (gain of function) =increased proli-feration, etc. Tumor supressors: (loss of function) =loss of control: apoptosis, etc.

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41 Retinoblastoma Deletions 13q14 or mutations of the RB1 gene Cell cycle regulatory protein that inhibits G1 to S phase transition 80% de novo mutations High rate of loss of heterozygosity in tumor tissue

42 Retinoplastoma Inheritance Inheritance of RB1 heterozygous Second hit occurs during embryonic life due to Point mutation Loss of reduplication Deletion Mutation of normal gene Somatic recombination

43 The Development of Hereditary Cancer 2 normal genes 1 damaged gene 2 damaged genes 1 normal gene Tumor develops In hereditary cancer, one damaged gene is inherited. 1 damaged gene 1 normal gene 2 damaged genes Tumor develops

44 Sporadic and Familial (Mendelian) forms of Cancer Knudson s Two-Hit Hypothesis Sporadic Normal tumor suppressor gene Somatic mutation in one allele Somatic mutation in other allele Single tumors, unilateral, later-onset two mutations (two hits) are required for loss of tumor suppressor function

45 Sporadic and Familial (Mendelian) Forms of Cancer Knudson s two-hit hypothesis Familial Tumor suppressor gene containing a germline mutation in one allele - heterozygous for the mutation Somatic mutation in other allele Multiple tumors, bilateral, early-onset two mutations (two hits) are required for loss of tumor suppressor function the first hit is inherited and the second hit is somatic

46 Neurofibromatosis Type 1 The gene responsible for NFl chro. 17q GAP Protein, and a similar role in signal transduction.

47 BRCA1 and BRCA2 High (60-80%) lifetime risk of breast cancer, both genes. Increased ovarian cancer risk (BRCA1>BRCA2) Surveillance for both indicated; mammography, MRI, TV ultrasound Consider prophylactic surgery

48 The Inherited Breast Cancer Genes: BRCA 1 and BRCA2 Mutations in BRCA 1 and BRCA2 are responsible for a large proportion of inherited breast cancer cases. These mutations usually result in a truncated protein product and loss of function. The protein products of both of these genes interact with RAD51, a DNA repair protein.

49 BRCA1-Linked Hereditary Breast and Ovarian Cancer 92 Breast, dx d Ovary, dx 59 d. 62 Breast, dx Breast, dx 59 Noncarrier BRCA1-mutation carrier Affected with cancer

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51 p16 and Familial Melanoma Can be aused by loss-of-function mutations in the p 16 tumor suppressor gene or by gain-offunction mutations in the target of p16, the CDK4 proto-oncogene. Both mutations result in a loss of cell cycle control via the pri pathway.

52 CHROMOSOMAL ABNORMALITIES IN MALIGNANCIES 7/21/2013 MSK/UJ/GL2 52

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54 Three classes of error lead to aneuploidy in tumor cells

55 Chronic Myelogenous Leukemia Invariably fatal The Philadelphia Chromosome Reciprocal Translocation long arm of HAS 22 < > small part of HSA 9 2 chromosomal changes Translocation causes oncogene activation

56 MOST FREQUENT CLONAL CHROMOSOME ABNORMALITIES IN HEMATOLOGIC MALIGNANCIES DIAGNOSIS: ABNORMALITY: CML, ALL t(9;22)(q34;q11.2) AML t(8;21)(q22;q22) APL t(15;17)(q22;q12~21) AML with EO inv(16)(p13q22) MDS /AML 5q-, -7, 7q-,+8, 20q- CLL del(13q), +12 ALL t(1;19)(q23;p13) t(4;11)(q21;q23) Burkitt s Lymphoma t(8;14)(q24;q32) Follicular Lymphoma t(14;18)(q32;q21) Mantle Cell Lymphoma t(11;14)(q13;q32)

57 Chromosomal Rearrangements or Translocations Neoplasm Translocation Proto-oncogene Burkitt lymphoma t(8;14) 80% of cases c-myc 1 t(8;22) 15% of cases t(2;8) 5% of cases Chronic myelogenous t(9;22) 90-95% of cases bcr-abl 2 leukemia Acute lymphocytic t(9;22) 10-15% of cases bcr-abl 2 leukemia 1 c-myc is translocated to the IgG locus, which results in its activated expression 2 bcr-abl fusion protein is produced, which results in a constitutively active abl kinase

58 Examples of Chromosomal Regions That Show Loss of Heterozygosity in Tumors Chormosome Region Disorder(s) Associated TSG lq Breast carcinoma Unknown 3p Small~celllung carcinoma Unknown 5q Familial polyposis coli; colorectal carcinoma MCC 11 p Wilms tumor; rhabdomyosarcoma WTl 13q Retinoblastoma; breast carcinoma; osteosarcomas RB 1 17p Colorectal carcinoma; breast cancer TP53 18q Colorectal carcinoma DCC 22 Neurofibromatosis, type 2 Unknown

59 Cancer: General Etiology and Pathogenesis