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1 Special topics in tumor biochemistry oncogenes-and- tumour-suppressor-genes) Speaker: Prof. Jiunn-Jye Chuu

2 Genetic Basis of Cancer Cancer-causing mutations Disease of aging (more mutation over time) Clonal proliferation or expansion Mutation leads to a Darwinian Survival advantage ( growth or apoptosis) Multiple mutations are required before cancer can develop (how many?)

3 Types of Genetic Lesions in Cancer Point mutation Subtle alterations (insertions, deletions, translocation) Chromosome changes (aneuploidy and loss of heterozygosity) Amplification Gene silencing Exogenous sequences (tumor viruses)

4 Mutations of Normal Genes Cancer Genes Point mutation (most common) Change of one or a few nucleotide base pairs ras gene (pancreatic, colon) Gene mutations (oncogenes, tumor suppressor genes)

5 Oncogenes and Tumor-Suppressor Genes Proto-oncogene/Oncogenes Mutant genes that in their non-mutant state direct protein synthesis and cellular growth (acceleration-pedal to the metal) Tumor-suppressor genes Encoded proteins that in their normal state negatively regulate proliferation Also referred to as antioncogenes (put the brakes on)

6 Oncogenes

7 Oncogenes overexpression of certain genes abnormal activity of certain genes their mutant protein products.

8 Activation mechanisms of proto-oncogenes

9 Proto-Oncogenes The proteins encoded by viral oncogenes are similar to cellular proteins with important regulatory functions. These cellular homologues are called protooncogenes or normal cellular genes. The normal c-oncogenes have introns; the viral v- oncogenes often lack introns. From c-onco to v-onco.. Replication-defective viruses John Wiley & Sons, Inc.

10 Activation mechanisms of proto-oncogenes

11 Activation mechanisms of proto-oncogenes

12 The Ras genes are proto-oncogenes that regulate cell division A mutation in the ras gene converts it to an oncogene that continually signals cell division

13 The Ras genes are proto-oncogenes that regulate cell division

14 Normal Ras Protein Signaling

15 Mutant Ras Protein is Unregulated

16 Identification of Ras Oncogene Chiaho Shih, PhD Robert A. Weinberg, PhD

17 Amino acid substitutions in Ras family proteins (inactivates GTPase) amino acid position Ras gene Tumor c-ras (H, K, N) Gly Ala Gln normal cells H-ras Gly Ala Leu lung carcinoma Val Ala Gln bladder carcinoma K-ras Cys Ala Gln lung carcinoma Arg Ala Gln lung carcinoma Val Ala Gln colon carcinoma N-ras Gly Ala Lys neuroblastoma Gly Ala Arg lung carcinoma Murine sarcoma virus H-ras Arg Thr Gln Harvey strain K-ras Ser Thr Gln Kirsten strain

18 Types of Mutated Gene Secretion of growth factors (autocrine stimulation) Increased growth factor receptors (HER2/neu) Signal from cell-surface receptors is mutated to the on position Mutation in the ras intracellular signaling protein (cell growth without growth factors) : kinase all lead to increase growth

19 Molecular Abnormalities in Solid Tumors, EGFR The EGFR oncogene encodes another of the same family of epidermal growth factor receptors. This gene is mutated or amplified in several types of cancer cells. Tumors with activating mutations in EGFR are sensitive to tyrosine kinase inhibitors (TKI). The HER2/neu gene encodes one of a family of human epidermal growth-factor receptors. This gene is frequently amplified in breast cancer cells, resulting in increased amounts of HER2 cell surface protein. HER2-expressing tumors are sensitive to herceptin, a monoclonal antibody therapy.

20 The EGFR Gene Family

21 Identification of Her2/Neu Oncogene Mien-Chie Hung, PhD Robert A. Weinberg, PhD

22 Functions of Cellular Proto-Oncogenes 1. Secreted Growth Factors 2. Growth Factor Receptors 3. Cytoplasmic Signal Transduction Proteins 4. Nuclear Proteins: Transcription Factors 5. Cell Growth Genes

23 Viral Oncogenes and Cancer Some viral oncogenes produce more protein than their cellular counterpart. Other viral oncogenes express their proteins at inappropriate times. Other viral oncogenes express mutant forms of the cellular proteins.

24 Normal gene Cell-oncogene (c-onc)

25 The Discovery of Cellular Oncogenes

26 Mutations of Normal Genes Cancer Genes Chromosome structural abnormalities (translocations, deletions, insertions) Chromosome number abnormalities (aneuploidy, polysomy) Chromosome translocation A piece on one chromosome is transferred to another t(8;14) Burkitt Lymphoma t(9;22) chronic myeloid leukemia (Philadelphia chromosome 1960)

27 Translocations and Hybrid Genes Can Lead to Leukemia Many proto-oncogenes are located at or close to the breakpoints of chromosomal translocations involved with specific forms of leukemia In CML, the C-ABL gene (chromosome 9) is moved next to the BCR gene (chromosome 22) The hybrid gene encodes an abnormal protein that signals CML cells to divide

28 The Philadelphia Chromosome and CML Philadelphia chromosome Abnormal chromosome produced by translocation between the long arms of chromosomes 9 and 22 Linked to chronic myelogenous leukemia (CML) Fig , p. 281

29 The Philadelphia Chromosome

30 Targeted Therapies Offers a new approach to Cancer Treatment Targeted therapies use drugs that selectively block the activity of specific oncogenes Gleevec blocks the BCR-Abl oncogene in CML Herceptin blocks the HER2 receptor on certain breast cancers

31 STI-571--an inhibitor of BCR-ABL function PET scanning to show efficacy of STI-571 on tumor metastasis

32 Translocations Associated with Cancers

33 Chromosomal Rearrangements: Burkitt s Lymphoma Burkitt s lymphoma is associated with reciprocal translocations involving chromosome 8 and a chromosome carrying an immunoglobulin gene (2, 14, or 22). The translocations juxtapose c-myc to the genes for the immunoglobulin genes, causing overexpression of c-myc in B cells. The c-myc gene encodes a transcription factor that activates genes for cell division.

34 GENE AMPLIFICATION Oncogene Amplification Source of tumor c-myc ~20-fold leukemia and lung carcinoma N-myc 5-1,000-fold neuroblastoma retinoblastoma L-myc fold small-cell lung cancer c-abl ~5-fold chronic myoloid leukemia c-myb 5-10-fold acute myeloid leukemia colon carcinoma c-erbb ~30-fold epidermoid carcinoma K-ras 4-20-fold colon carcinoma fold adrenocortical carcinoma

35

36 Mechanisms of Oncogene Activation 1. Overexpression 2. Point mutation 3. Translocation

37

38 TUMOR SUPPRESSOR GENES

39 TUMOR SUPPRESSOR GENES Disorders in which gene is affected Gene (locus) Function Familial Sporadic DCC (18q) cell surface unknown colorectal interactions cancer WT1 (11p) transcription Wilm s tumor lung cancer Rb1 (13q) transcription retinoblastoma small-cell lung carcinoma p53 (17p) transcription Li-Fraumeni breast, colon, syndrome & lung cancer BRCA1(17q) transcriptional breast cancer breast/ovarian tumors BRCA2 (13q) regulator/dna repair

40 Retinoblastoma A random mutation of the remaining RB locus in any retinal cell completely removes the inhibition provided by the Rb protein, and the affected cell grows into a tumour. So, in this form of the disease, a germline mutation plus a somatic mutation of the second allele leads to the disease.

41 Retinoblastoma: Mutation of a Tumor Suppressor Gene Retinoblastoma A malignant tumor of the eye arising in retinoblasts (embryonic retinal cells that disappear at about 2 years of age) Because mature retinal cells do not transform into tumors, this tumor usually occurs only in children Associated with a deletion in the long arm of chromosome 13 The responsible gene, Rb, is located on chromosome 13

42 The RB1 Gene The tumor-suppressing protein prb controls the G1/S transition in the cell cycle Regulates the activity of an important protein called E2F Without prb, cell division is uncontrolled

43 prb Regulates the Cell Cycle

44 prb Regulates the Cell Cycle

45 Identification of 1st Tumor Suppressor Gene-Rb Wen-Hwa Lee, PhD Robert A. Weinberg, PhD

46 Two Types of Retinoblastoma Familial retinoblastoma Individuals inherit one mutant copy of RB1 gene 85% to 95% chance of developing the disease Sporadic retinoblastoma Mutations of both copies of RB1 gene occur in a single cell Occurs with a frequency of approximately 1 in 15,000

47 The Cellular Function of p53 Expression of p53 is very low in normal cells. Expression of p53 increases in response to DNA damage due to a decrease in degradation. p53 can inhibit cell division or induce apoptosis.

48 P53 is a Transcription Factor Most mutations in that inactivate p53 are in the DNAbinding domain (DBD) and impair its ability to bind enhancer sequences in its target genes. Mutations in this domain are lost-of-function. OD: homo-oligomerazation domain. Mutations in this domain are dominant negative. TAD: transcriptional activation domain

49 P53 Regulates Cell Cycle and Apoptosis The p53 tumor suppressor protein is encoded by the TP53 gene (53 KDa). Inherited mutations in TP53 are associated with Li- Fraumeni syndrome. Somatic mutations that inactivate both copies of TP53 are associated with the majority of cancers.

50 [ increase ] p-p53

51

52

53

54 papc controls proliferation and differentiation of cells. papc mutations are associated with adenomatous polyposis coli, which often leads to colorectal cancer. papc regulates the renewal of cells in the epithelium of the large intestine. Loss of papc function results in the formation of polyps. papc binds to catenin, which binds to transcription factors. Cells with mutations in papc lose their ability to control catenin levels. Familial adenomatous polyposis (FAP):rare autosomal dominant dissease.

55 papc

56 Familial adenomatous polyposis (FAP) Familial adenomatous polyposis (FAP) An autosomal dominant trait resulting in the development of polyps and benign growths in the colon Polyps often develop into malignant growths and cause cancer of the colon and/or rectum

57 Three Steps in FAP-Associate Colon Cancer 1. Mutation in the APC (tumor suppressor gene) gene on chromosome 5 2. Mutation of one copy of the k-ras proto-oncogene in a polyp cell transforms the polyp into an adenoma; mutations in both alleles of any of several downstream genes, including DCC, leads to formation of late-stage adenomas 3. Mutations in both alleles of the p53 (tumor suppressor gene) gene on chromosome 17 cause the late-stage adenoma to become cancerous

58 A Multi-step Model For Colon Cancer

59 pbrca1 and pbrca2 regulate DNA repair. Mutations in the tumor suppressor genes BRCA1 (Ch17) and BRCA2 (Ch13) have been implicated in hereditary breast and ovarian cancer. Both genes encode proteins that are localized in the nucleus and have putative transcriptional activation domains. pbrca1 and pbrca2 may be involved in DNA repair in human cells.

60 BRCA1 and BRCA2 are DNA Repair Genes BRCA1 protein, found only in the nucleus, is activated when DNA is damaged Stops DNA replication Binds to Rap80 protein to identify DNA damage and initiate repair Mutant forms are unable to repair DNA Mutations accumulate; cell become cancerous

61

62

63

64 Types of Mutated Genes:Bowel Cancer

65 Pathway to Metastatic Colorectal Cancer Carcinoma-epithelial cells. Adenoma-glandular cells.

66 Pathway to Androgen-Independent Prostate Cancer

67

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