Molecular Human Genetics. Cancer, Tumor suppressor genes, Oncogenes

Transcription

1 Youtube ARCC It's Our Time - American Association for Cancer Research (AACR) Molecular Human Genetics Cancer, Tumor suppressor genes, Oncogenes Hum 2014/15 1

2 Cancer, Tumor Cancer (Krebs, Karzinom): malign neoplasia of epithelial origin Sarkome: mesothelial origin Tumor: general term new patients with cancer/year 10 to 15 percent have a genetic mutation, which display a hereditary predisposition. Depending on the involved gene and kind of mutation or penetrance, respectively the risk can be 100 % for a tumor. Hum 2014/15 2

3 How a tumor develops? Hum 2014/15 3

4 How a tumor develops? Protection Damage of DNA Normal cell Progression Proliferation Repair Apoptosis Hypomethylation of TSGs, Hypermethylation of von parasitic genes Neoplastic cell Mutation, Loss of check points, Proliferation Hypermethylation of TSGs, Hypomethylation of parasitic Genes, Activation of Telomerase Mutation Apoptosis Telomerase activity Senescence Immortality Nekrosis Tumor cell Angiogenesis Therapy Metastasis (Bertram, 2000; modifiziert) Hum 2014/15 4

5 In the past single genes or proteins were investigated, because scientist assume that the mutation of one gene is sufficient to develop cancer. Hum 2014/15 5

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9 But what are the causes of cancer? until now nobody know it for sure Hum 2014/15 9

10 The Hallmarks Die of 6 Kennzeichen Cancer der Tumorentstehung Cell, Volume 100, Issue 1, Pages Hanahan, D.; Weinberg, R.A Hum 2014/15 10

11 VEGF Hum 2014/15 11

12 How cancer develop? Hum 2014/15 12

13 Figure 6 Hallmarks of Cancer: The Next Generation Douglas Hanahan and Robert A. Weinberg Cell Volume 144, Issue 5, Pages (March 2011) DOI: /j.cell Copyright 2011 Elsevier Inc. Terms and Conditions Hum 2014/15 13

14 Figure 2 Source: Cell, Volume 144, Issue 5, Pages (DOI: /j.cell ) Hum 2014/15 14

15 New Cancer cases and death Hum 2014/15 15

16 How cancer looks like? Hum 2014/15 16

17 History of cancer The earliest known descriptions of cancer appear in seven papyri contain descriptions of cancer written around 1600 B.C., and are believed to date from sources as early as 2500 B.C. Hippocrates (ca. 460 BC ca. 370 BC) described several kinds of cancer, referring to them with the Greek word carcinos (crab or crayfish), among others.[1] This name comes from the appearance of the cut surface of a solid malignant tumour, with "the veins stretched on all sides as the animal the crab has its feet, whence it derives its name".[2] Since it was against Greek tradition to open the body, Hippocrates only described and made drawings of outwardly visible tumors on the skin, nose, and breasts. Treatment was based on the humor theory of four bodily fluids (black and yellow bile, blood, and phlegm). According to the patient's tumor, treatment consisted of diet, blood-letting, and/or laxatives. Through the centuries it was discovered that cancer could occur anywhere in the body, but tumor-theory based treatment remained popular until the 19th century with the discovery of cells. Celsus (ca. 25 BC - 50 AD) translated carcinos into the Latin cancer, also meaning crab. Galen (2nd century AD) called benign tumours oncos, Greek for swelling, reserving Hippocrates' carcinos for malignant tumours. He later added the suffix -oma, Greek for swelling, giving the name carcinoma. [Wikipedia] Hum 2014/15 17

18 How a tumor develops? Genetically mutated cell Hyperplasia Dysplasia Pre-invasive Tumor (Carcinoma in-situ) Invasive Tumor Basal lamina Hum 2014/15 18

19 Metastasis Breakthrough basal lamina Invading a capillary Passage through blood stream (only 1 of 1000 will survive) Hum 2014/15 19

20 Normal dysplastic invasive carcinom Hum 2014/15 20

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22 Figure 4 Hum 2014/15 22

23 Metastasis Genetic determinants of cancer Metastasis, Don X. Nguyen and Joan Massagué Nature reviews Genetics 2007 Hum 2014/15 23

24 Hallmarks of cancer e. g. oncogenes e. g. tumor suppressor genes Hum 2014/15 24

25 What are Tumor Suppressor Genes, what are Onkogenes? Onkogene (engine of cell division) Proliferation Tumor suppressor gene (Brake of cell proliferation) Hum 2014/15 25

26 What are Oncogenes? proto-oncogene is a normal gene that can become an oncogene due to mutations or increased expression. Proto-oncogenes code for proteins that help to regulate cell growth and differentiation. Proto-oncogenes are often involved in signal transduction and execution of mitogenic signals, usually through their protein products. Upon activation, a proto-oncogene (its product) becomes a tumor-inducing agent, an oncogene. Examples of proto-oncogenes include RAS, WNT, MYC, ERK, and TRK. Activation: The proto-oncogene can become an oncogene by a relatively small modification of its original function. 1. Mutation 2. Amplification 3. Translocation 4. Virus Hum 2014/15 26

27 1. Mutation Hum 2014/15 27

28 2. Amplification Double minutes, DM Homogeneously staining region, HSR Detection with e.g. FISH Hum 2014/15 28

29 Detection of Oncogene Amplification Hum 2014/15 29

30 3. Activation by translocation Hum 2014/15 30

31 4. Onkogene activation by Virus Hum 2014/15 31

32 Heriditary Cancer There are hereditary and sporadic Tumors Tumorsuppressorgene: Familiäres Retinoblastom RB1 13q14 Familiäre adenomatöse Polyposis (FAP) APC 5q21 Familiärer Brust-/Ovarialkrebs BRCA1 17q21 BRCA2 13q12 Li-Fraumeni-Syndrom TP53 17p13 Multiple endokrine Neoplasie (MEN) Typ 1 MEN1 11q13 Neurofibromatose Typ 1 NF1 17q11 Neurofibromatose Typ 2 NF2 22q12 Familiäres Melanom P16 9p21 Gorlin-Syndrom, Basalzellkarzinom PTCH 9q22 Familiärer Wilms-Tumor WT1 11p13 Tuberöse Sklerose TSC1 9q34 TSC2 16p13 von Hippel-Lindau-Syndrom VHL 3p26 Onkogene: Familiäres medulläres Schilddrüsenkarzinom, MEN Typ 2A RET 10q11 und 2B Papilläres Niersnzellkarzinom MET 7q31 DNA-Reparaturgene: Hereditäre Form kolorektaler Karzinome ohne Polyposis (HNPCC, Lynch- Syndrom) MLH1 MSH2 3p p16 Hum 2014/15 32

33 What are Tumor Suppressor Genes? A tumor suppressor gene is a gene that protects a cell from one step on the path to cancer. A Mutation in this gene that to cause a loss or reduction in its function, the cell can progress to cancer, usually in combination with other genetic changes. Tumor-suppressor genes, or more precisely, the proteins for which they code, either have a dampening or repressive effect on the regulation of the cell cycle or promote apoptosis, and sometimes do both. The functions of tumor-suppressor proteins fall into several categories including the following: Repression of genes that are essential for the continuing of the cell cycle. If these genes are not expressed, the cell cycle will not continue, effectively inhibiting cell division. Coupling the cell cycle to DNA damage As long as there is damaged DNA in the cell, it should not divide. If the damage can be repaired, the cell cycle can continue. If the damage cannot be repaired, the cell should initiate apoptosis (programmed cell death) to remove the threat it poses for the greater good of the organism. Some proteins involved in cell adhesion prevent tumor cells from dispersing, block loss of contact inhibition, and inhibit metastasis. These proteins are known as metastasis suppressors. Hum 2014/15 33

34 Two-hit hypothese Suppressor genes generally follow the 'two-hit hypothesis', which implies that both alleles that code for a particular gene must be affected before an effect is manifested. This is due to the fact that if only one allele for the gene is damaged, the second can still produce the correct protein. Hum 2014/15 34

35 Two-hit hypothesis Hum 2014/15 35

36 Tumor supressor genes are: - genetically recessive but - clinically dominant Hum 2014/15 36

37 Heriditary Cancer There are hereditary and sporadic Tumors Important in heriditary Cancer Tumorsuppressorgene: Familiäres Retinoblastom RB1 13q14 Familiäre adenomatöse Polyposis (FAP) APC 5q21 Familiärer Brust-/Ovarialkrebs BRCA1 17q21 BRCA2 13q12 Li-Fraumeni-Syndrom TP53 17p13 Multiple endokrine Neoplasie (MEN) Typ 1 MEN1 11q13 Neurofibromatose Typ 1 NF1 17q11 Neurofibromatose Typ 2 NF2 22q12 Familiäres Melanom P16 9p21 Gorlin-Syndrom, Basalzellkarzinom PTCH 9q22 Familiärer Wilms-Tumor WT1 11p13 Tuberöse Sklerose TSC1 9q34 TSC2 16p13 von Hippel-Lindau-Syndrom VHL 3p26 Onkogene: Familiäres medulläres Schilddrüsenkarzinom, MEN Typ 2A RET 10q11 und 2B Papilläres Niersnzellkarzinom MET 7q31 DNA-Reparaturgene: Hereditäre Form kolorektaler Karzinome ohne Polyposis (HNPCC, Lynch- Syndrom) MLH1 MSH2 3p p16 Hum 2014/15 37

38 Hereditary Colon Carcinoma o Most of colon carcinoma cases ( new cases / year) affect people over 50 years. o Over deaths o 30 Percent have a familiar risk. o 5-10 Percent of patients show an autosomal-dominant tumor disposition for the 3 heriditary colon cancer syndromes Hum 2014/15 38

39 Hereditary Colon Cancer 1. Hereditary Non-Polyposis Colorectal Cancer (HNPCC) (Erblicher Nicht-polypöser Darmkrebs), or Lynch syndrome 2. Familial Adenomatöse Polyposis (FAP) 3. Peutz-Jeghers Syndrom 4. Familial Juvenile Polyposis. Hum 2014/15 39

40 Hereditary Colon Cancer 1. Hereditary Non-Polyposis Colorectal Cancer (HNPCC) HNPCC acts dominant Mutations in 5 DNA mismatch repair genes MSH2 (60%) / MLH1 (30%) (MSH2 = 73 kb, 16 Exons (3 kb cdna), MLH1 = 100 kb, 19 Exons (2.5 kb of cdna) PMS1, PMS2 und MSH6 (GT binding proteins) (10%). Hum 2014/15 40

41 Hereditary Colon Cancer Diagnosis: Mutations in gene MSH2 oder MLH1 leads to DNA replication errors! Most of the tumors display genomic instability, Microsatellite Instability (MSI). Tumores with instable Microsatellites have a loss of function in both alleles of MSH2 or MLH1 (LOH) HNPCC Patients show also a higher incidence of cancers in other organs: uterus, ovaries, stomach, small intestine, urinary and bilary tract, also skin and brain. Hum 2014/15 41

42 Amsterdam criteria The following clinical criteria were established in 1991 to facilitate consistency in research. The criteria are now applied in diagnosing Hereditary Non-Polyposis Colorectal Cancer (HNPCC): 3 or more cases of colorectal cancer in a minimum of 2 generations 1 affected individual should be first-degree to the other cases of colorectal cancer 1 case of colorectal cancer should be diagnosed under age 50 A diagnosis of Familial Adenomatous Polyposis (FAP) should be excluded The criteria have since been modified - summary below: 2 cases of colorectal cancer where families are small (one age under 55) 2 cases of colorectal cancer and 1 case of endometrial cancer, or other early onset cancer Hum 2014/15 42

43 Hereditary Colon Cancer Early diagnosis of HNPCC patients Preventive medical check up starting at 25 years physical examination Abdomen sonography Komplette Koloskopie gynecological examination of Endometrium and Ovarian Cancer as well as transvaginal Sonography Urine cytology Ösophago-Gastro-Duodenoskopy annually annually annually annually annually annually Hum 2014/15 43

44 Hereditary Colon Cancer Therefore we need new molecular markers: -> lecture: Search for tumor marker Hum 2014/15 44

45 Hereditary Colon Cancer Familial adenomatous Polyposis (FAP) (dominant inheritance) Hundreds to thousand polyps in early life! 100% incidence that a polyp develop to cancer. Colon cancer can therefore start at 20 years. Hum 2014/15 45

46 Hereditary Colon Cancer Familiäre Adenomatöse Polyposis (FAP) Hum 2014/15 46

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48 Hereditary Colon Cancer Early diagnosis programm (FAP): Examination of eyes in the whole family: In case of FAP there are some harmless changes of retina Ablation of rectum befor 20th year is recomended. Alter Untersuchung Frequenz ab dem 10. Lebensjahr Körperliche Untersuchung einmal jährlich Abdomensonographie einmal jährlich Rektosigmoidoskopie, bei Nachweis von Polypen komplette Koloskopie einmal jährlich augenärztliche Untersuchung einmalig vor der prophylaktischen Darmentfernung (Kolektomie) erste Ösophago-Gastro- Duodenoskopie - ab dem 30. Lebensjahr Ösophago-Gastro-Duodenoskopie bei Nachweis von Adenomen einmal jährlich Ösophago-Gastro-Duodenoskopie ohne Nachweis von Adenomen alle drei Jahre Hum 2014/15 48

49 Hereditary Colon Cancer Familiäre Adenomatöse Polyposis (FAP) Two-Hit Hypothese One defect allele (FAP) is inherited The other mutates somatically Hum 2014/15 49

52 Hereditary Colon Cancer Peutz-Jeghers-Syndrom: (1 of ) Polypes in the small intestine 50% of patients who inherited a mutation in the STK11 gene get a maligne tumor until 60th year Familial Juvenile Polyposis: Polyps in childhood Hum 2014/15 52

53 Hereditary Cancer Tumorsuppressorgene: Familiäres Retinoblastom RB1 13q14 Familiäre adenomatöse Polyposis (FAP) APC 5q21 Familiärer Brust-/Ovarialkrebs BRCA1 17q21 BRCA2 13q12 Li-Fraumeni-Syndrom TP53 17p13 Multiple endokrine Neoplasie (MEN) Typ 1 MEN1 11q13 Neurofibromatose Typ 1 NF1 17q11 Neurofibromatose Typ 2 NF2 22q12 Familiäres Melanom P16 9p21 Gorlin-Syndrom, Basalzellkarzinom PTCH 9q22 Familiärer Wilms-Tumor WT1 11p13 Tuberöse Sklerose TSC1 9q34 TSC2 16p13 von Hippel-Lindau-Syndrom VHL 3p26 Onkogene: Familiäres medulläres Schilddrüsenkarzinom, MEN Typ 2A RET 10q11 und 2B Papilläres Niersnzellkarzinom MET 7q31 DNA-Reparaturgene: Hereditäre Form kolorektaler Karzinome ohne Polyposis (HNPCC, Lynch- Syndrom) MLH1 MSH2 3p p16 Hum 2014/15 53

54 von-hippel-lindau-syndrom Hum 2014/15 54

58 von-hippel-lindau-syndrom Oxygen deficit leads to angiogenesis in tissue Stable Degradation Hum 2014/15 58

60 Hereditary Cancer Li-Fraumeni-Syndrom Hum 2014/15 60

62 Hereditary Cancer Familiärer Brust- und Ovarialkrebs Hum 2014/15 62

63 Folie: 63 Hum 2014/15 63

64 Hereditary Cancer Familiärer Brust- und Ovarialkrebs Hum 2014/15 64

65 Hereditary Cancer Hum 2014/15 65

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67 Tumorsuppressorgene Hum 2014/15 67

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71 Folie: 71 Hum 2014/15 71

72 What are Tumor Suppressor Genes, what are Onkogenes? Hum 2014/15 72

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74 FIGURE 1 Ten Leading Cancer Types for the Estimated New Cancer Cases and Deaths by Sex, 2010 From Jemal, A. et al. CA Cancer J Clin 2010;0:caac.20073v1 Hum 2014/15 74

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76 Metabolism and Hallmarks of Cancer Tumor Cell Metabolism: Cancer's Achilles' Heel Cancer Cell 2008 Hum 2014/15 76