1. איבוד בקרת מחזור התא

2. הסטטיסטיקה מתייחסת לארה"ב – יחסים פופורציונים דומים לישראל סרטן

4. The Peculiar Dangers of Smoking Smoking kills lung lining rapidly. Lung cells must reproduce a lot to keep up. Many opportunities for copying errors and growth competition. Aromatic compounds in ‘tars’ intercalate in DNA leading to frame shift errors. Tobacco accumulates uranium, leads to ionizing radiation and chromosome breaks.

5. עקומת תמותה מסרטן כפונקציה של גיל

6. Male Females Cancer due to mutations

7. מה זה סרטן? יש בגופנו כ-20 טרליון תאים, לכל תא יש את הפוטנציאל להפוך לתא סרטני. סרטן הוא שם כללי ל-300 ויותר מחלות שונות. תאי הגוף מתחלקים רק כאשר הם נדרשים לכך. תאים סרטנים מתחלקים ללא בקרה ועוברים ממקומם הראשוני לרקמות אחרות. סרטןטן Can DevDev

8. Evolution of Cancer Human body has 10 14 cells descended from a single egg cell. Many mutations occur in cells over your lifetime. Mutations that favor growth of an individual cell over growth of the organism lead to cancer. A half-dozen genes must be disabled to have a full fledged malignant cancer. Cancer cells have mutations that encourage mutation – flawed DNA repair mechanisms. Radiation paradoxically induces cancer and cures it.

9. באופן עקרוני כל תא בגוף מסוגל להפוך לתא סרטני

10. כל סרטן מקורו מתא אחד שהתחיל להתחלק ללא בקרה ועפ"ר בקצב גבוה Cancer Cell Cancer cell 1

12. מה מאפיין תאים סרטנים? גידול לא מבוקר מספר כרומוזומים לא נורמלי מאבד קישור לתאים שכנים יכול לנדוד לרקמות אחרות - גרורות

13. מה ההגדרה של תא נורמלי? חלבוני הקולוגן שמופרשים מהתא יוצרים את ה-ECM מותנה בעיגון עיכוב ע"י מגע תלות בפקטורי גדילה 1 2 3 4

14. מה ההגדרה של תא סרטני (עבר טראנספורמציה)? חיי נצחאנפלואידיות איבוד חלקי או מלא של הצורך בפקטורי גידול. איבוד של עיכוב גידול ע"י מגע איבוד של הצורך להיות מעוגן לECM

15. Properties of Cancer Cells 1. Lack normal growth controls a) self-sufficiency in growth signals b) insensitivity to anti-growth signals c) evade programmed cell death (apoptosis) d) unlimited replicative potential 2. Able to invade tissues and metastasize a) loss of dependency on anchorage for growth b) loss of contact inhibition 3. Able to “conscript” normal cells promote angiogenesis

16. Transformation The genetic mechanisms of transformation were discovered through the actions of transforming viruses. DNA viruses, e.g. adenovirus, SV40, polyoma express proteins analogous to key proliferation factors; e.g. E1A or large T, that substitute for or replace the function of these factors. More importantly, RNA retroviruses express homologs of many critical regulatory factors, i.e. mutations of the cellular protein with gain of function mutations (or loss of function in the case of growth suppressors such as pRb105 or p53). The transforming activity of these retroviruses, such as Rous sarcoma virus (rsv), or Rat sarcoma virus (ras), were first mapped to specific oncogenes, src in Rous sarcoma virus (chicken), or ras in rat sarcoma virus. This in turn led to the discovery of the cellular homologs c-src and c-ras, where the cellular homologs were then found to be regulated components in a signalling system, while the viral forms are constitutively active. Oncogeneproto-oncogenevirus induced From this, a picture of the overall growth control has evolved, with many potential points where functional mutations can contribute to cell transformation.

17. Growth characteristics of cells in culture (parallels what happens in vivo) Normal primary cells: survive only a relatively short time in culture (days to weeks) Immortalized (established) cells: immortalized, but not transformed (they retain many of their in vivo characteristics) anchorage dependence (prefer to adhere to culture plate) serum dependence (require growth factors) contact inhibited (stop growing when cells are confluent) Transformed cells: will form tumors (tumorigenic) when injected into a host, but will not necessarily kill the host less dependent on substratum less dependent on growth factors not contact inhibited Metastatic cells: fully transformed cells that have the ability to migrate and invade tissues; will establish new colonies and kill the host At least 2-3 steps (which are caused by mutations)

18. normal transformed by virus contact-inhibited pile up, rounded סרטן שד

19. normal cells transformed cells scanning EM

20. Tumor Promoters Enhance tumor formation when combined with carcinogens, but are not themselves carcinogenic carcinogen tumor formation + tumor promoter - carcinogen + tumor promoter +++

21. TPA = phorbal myristate acetate = PMA mimics 1, 2 diacylglycerol (DAG) DAG + Ca ++ activates protein kinase C (PKC) causes phosphorylation of PKC substrates changes in cell growth, cell shape and the cytoskeleton Phorbol ester

23. Two cytoskeletal elements examined: Why use Fluorescence Microscopy ? can visualize and localize individual proteins within a cell. Test the effects of different drugs on the cytoskeleton and cell shape TPA/PMA Latrunculin Taxol Nocodazole ActinMicrotubules

24. Actin structures in a fibroblast cell

25. Microtubules = green DNA = blue interphase mitosis

29. Transformed 3T3 cells

32. מוטציה שמשנה את תהליך התבטאות הגנים יכולה לגרום לסרטן 10 שנים עפ"ר יעברו בין החשיפה למוטגן לבין הופעת הסרטן

34. BRCA2 chromosome instability

35. כל תאי הסרטן מאופנים באיבוד בקרת מחזור התא

36. שלוש נקודות בקרה על מחזור התא בהן התא מדווח על מצבו אינפורמציה לגבי פגיעה ב-DNA, האם הסביבה מאפשרת גידול, האם ה-DNA סיים את הכפלתו, והאם הכרומוזומים מעוגנים למבנה הכישור

38. Cell cycle and cancer

39. איזה מוטציות גורמות לסרטן? מעלות פעילות של גנים שהחלבונים שלהם גורמים לתא להתחלק מורידות פעילות של גנים שהחלבונים שלהם גורמים לתא לא להתחלק

40. אונקוגנים – גנים הגורמים לסרטן, גנים ויראליים פרוטואונקוגנים – גנים בתא המקודדים לחלבונים המעורבים בגידול התא או חלוקתו, מסוגלים להפוך לאונקוגנים לאחר מוטצי/ות. Sarcoma virus

41. חוסמים את גידול התא או חלוקתו חלבוני תיקון DNA חלבוני עיגון מעכבי גידול

42. What are the genes responsible for tumorigenic cell growth? Normal Cancer Proto-oncogenes Cell growth and proliferation Tumor suppressor genes + - Mutated or “activated” oncogenes Malignant transformation Loss or mutation of Tumor suppressor genes ++ Proto-tumor sup1 Proto-to-tumor2

43. פרוטואונקוגנים – גנים בתא המקודדים לחלבונים המעורבים בגידול התא או חלוקתו, מסוגלים להפוך לאונקוגנים לאחר מוטצי/ות. טרנסלוקציהאמפליפיקציה מוטציה נקודתית Proto-to-oncogene

44. Molecular Basis of Philadelphia chromosome Translocation, causing chronic myelogenous leukemia (CML). Treatment by Gleevec that blokes the abnormal enzyme. chronic myelogenous leukemiachronic myelogenous leukemia cancer

45. Oncogenes are usually dominant (gain of function) cellular proto-oncogenes that have been mutated (and “activated”) cellular proto-oncogenes that have been captured by retroviruses and have been mutated in the process (and “activated”) virus-specific genes that behave like cellular proto-oncogenes that have been mutated to oncogenes (i.e., “activated”) Tumor suppressor genes are usually recessive (loss of function) loss of a cellular gene or chromosome region by deletion loss of gene function by an inactivating point mutation אונקוגנים – בד"כ דומיננטים כתוצאה ממוטציות שמעלות את רמת הפעילות שלהם: אקטיבציה של פרוטואונקוגן לאונקוגן הינה כתוצאה ממוטציות בפרוטואונקוגנים או הפעלה ע"י רטרווירוסים. אונקוגנים וירליים עפ"ר הם בעלי פעילות תאית הדומה לפרוטו-אונקוגנים. TOMOR SUPPRESSOR: בד"כ רציסיבים מאבדים את פעילותם כתוצאה מהחסרות או מוטציות נקודתיות.

46. מוטציה גורמת לרטינובלסטומה בילדים בשתי העיניים עוצר את מחזור התא בשלב G1 מוטציה ב-Rb גורמת להצטברות מוטציות בגנים אחרים

48. Sarcoma virus

49. Retrovirus oncogenes derived from normal cellular genes Retrovirus Viral oncogene Cellular proto-oncogene Rous sarcoma virus v-src c-src (src) Simian sarcoma v-sis c-sis (sis) Harvey murine sarcoma v-H-ras c-H-ras (H-ras) Kirsten murine sarcoma v-K-ras c-K-ras (K-ras) FBJ murine osteosarcoma v-fos c-fos (fos) Avian myelocytomatosis v-myc c-myc (myc) Abelson leukemia virus v-abl c-abl (abl) Avian erythroblastosis v-erbB c-erbB (erbB) viral oncogenes are ~80-99% homologous to cellular proto-oncogenes viral oncogenes in general are copies of cellular mRNA and lack introns אונקוגנים ויראלים בעלי הומולוגית רצף של 80-99% לפרוטו-אונקוגן הצלולרי (התאי). אונקוגנים ויראלים הם למעשה העתק של האונקוגן ללא האינטרונים.

53. Retinoblastoma

54. Cell-cycle dependent phosphorylation of Rb G1 S G2 M G0 Quiescent cells phase Rb p p p p p p p p p p p p p p p p p p Restriction point Rb p p Phosphorylation of Rb allows cells to transit the restriction point and enter S phase Hyperphosphorylated Rb Hypophosphorylated Rb

55. Function of the Rb protein E2F Rb E2F p p Rb p p p p p p p p E1A Growth suppressionRelief of growth suppression G1 phase phosphorylation releases E2F Adenovirus E1A oncoprotein binding releases E2F Gene mutation affecting binding pocket releases E2F E2F is a transcription factor that mediates growth-dependent activation of genes required to make the transition into and through S phase Rb binds and inactivates E2F under conditions of growth suppression There are several ways to alleviate growth suppression resulting in controlled or uncontrolled cell growth

59. Transforming viruses Viral classViral genome Oncogenes adenovirus ds DNA E1A & E1B papovavirus ds DNA T antigens SV40 (monkey) Polyoma (human) retrovirus ss RNA mutated cellular proto-oncogenes

60. Activities of viral oncogenes Oncogene activity Virus Immortalizing Transforming adenovirus (human) E1A E1B papovavirus SV40 (monkey) large T antigen small T antigen Polyoma (human) large T antigenmiddle T antigen retrovirus Avian myelocytomatosis myc Harvey murine sarcoma ras

61. gag pol env gag pol env onc Gene organization of a retrovirus Gene organization of a transforming retrovirus 5’ 3’ gag = group specific antigen pol = reverse transcriptase env = envelope onc = oncogene Gene organization of a cellular proto-oncogene 5’3’ mRNA

62. 4. Nuclear Proteins: Transcription Factors Cell Growth Genes 3. Cytoplasmic Signal Transduction Proteins 1. Secreted Growth Factors 2. Growth Factor Receptors Functions of cellular proto-oncogenes

63. Functions of selected proto-oncogenes Proto-oncogene Biochemical property 1. Secreted growth factors c-sis Platelet derived growth factor 2. Growth factor receptors c-erbBEpidermal growth factor receptor 3. Signal transduction proteins c-ablProtein kinase c-srcProtein kinase H-rasSmall G-protein K-rasSmall G-protein 4. Nuclear proteins c-mycTranscription factor c-fosTranscription factor

64. Oncogenes in human tumors Mechanisms of activation of proto-oncogenes point mutations chromosomal rearrangements or translocations gene amplifications

65. Identification of oncogene mutations in human tumors most human tumors contain mutated or “activated” proto-oncogenes demonstrated by isolating the mutated genes from human tumors Tumor cells Isolate DNA Transfer fragments of DNA into normal cells Isolate transformed clones of cells (by virtue of their growth advantage) Isolate new DNA gained by transformed cells 10-20% of spontaneous human tumors have DNA that will transform cells in culture; most are due to ras gene mutations

66. Ras family proteins the c-ras family contains three genes: H-ras, K-ras, and N-ras the Ras proteins encoded by these genes are small G-proteins the proteins transmit growth signals from cell surface receptors the Ras proteins are activated by binding GTP the proteins are inactivated by GTP to GDP hydrolysis mutations in the c-ras genes inactivate the Ras GTPase mutated Ras proteins are constitutively active constitutively active Ras proteins result in uncontrolled cell growth

67. amino acid position Ras gene 12 59 61 Tumor c-ras (H, K, N)GlyAlaGlnnormal cells H-rasGlyAlaLeulung carcinoma ValAlaGlnbladder carcinoma K-rasCysAlaGlnlung carcinoma ArgAlaGlnlung carcinoma ValAlaGlncolon carcinoma N-rasGlyAlaLysneuroblastoma GlyAlaArglung carcinoma Murine sarcoma virus H-rasArgThrGlnHarvey strain K-rasSerThrGlnKirsten strain Amino acid substitutions in Ras family proteins

68. Chromosomal rearrangements or translocations NeoplasmTranslocationProto-oncogene Burkitt lymphomat(8;14)80% of cases c-myc 1 t(8;22)15% of cases t(2;8) 5% of cases Chronic myelogenoust(9;22)90-95% of cases bcr-abl 2 leukemia Acute lymphocytict(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

69. c-myc is translocated to the IgG locus, which results in its activated expression bcr-abl fusion protein is produced, which results in a constitutively active abl kinase bcr-abl bcr abl c-mycIgG IgG enhancer c-myc is activated by the IgG enhancer in lymphocytes

70. Gene amplification Proto-oncogen to OncogeneAmplification Source of tumor c-myc ~20-foldleukemia and lung carcinoma N-myc 5-1,000-foldneuroblastoma retinoblastoma L-myc 10-20-foldsmall-cell lung cancer c-abl ~5-foldchronic myoloid leukemia c-myb 5-10-foldacute myeloid leukemia colon carcinoma c-erbB ~30-foldepidermoid carcinoma K-ras 4-20-foldcolon carcinoma 30-60-foldadrenocortical carcinoma

71. כיצד תא סרטני אינו מותנה בפקטורי גידול.

72. חוסמים את גידול התא או חלוקתו חלבוני תיקון DNA חלבוני עיגון מעכבי גידול

73. Tumor suppressor genes Disorders in which gene is affected Gene (locus) Function Familial Sporadic DCC (18q) cell surface unknowncolorectal interactions cancer מעי גס WT1 (11p) transcription Wilm’s tumorlung cancer Rb1 (13q) transcription retinoblastomasmall-cell lung carcinoma p53 (17p) transcription Li-Fraumeni breast, colon, syndrome & lung cancer

74. Sporadic and familial (Mendelian) forms of cancer Knudson’s two-hit hypothesis Sporadic Normal tumor suppressor gene Single tumors, unilateral, later-onset Somatic mutation in one allele Somatic mutation in other allele two mutations (two hits) are required for loss of tumor suppressor function

75. 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 Multiple tumors, bilateral, early-onset Somatic mutation in other allele two mutations (two hits) are required for loss of tumor suppressor function the first “hit” is inherited and the second “hit” is somatic

79. מוטציה ב-p53 גורמת למוטציות בגנים אחרים להתרחש 50% מחולי הסרטן בעלי מוטציה/יות בגן p53

80. p53 is the “guardian of the genome” germline p53 mutations are found in Li-Fraumeni syndrome p53 is frequently found mutated in human tumors the p53 protein functions as a transcription factor that regulates cell-cycle and DNA repair genes UV irradiation causes cell-cycle arrest in G1 that is dependent on p53; cells that contain a mutated p53 cannot arrest and go into S phase and replicate damaged DNA p53 loss-of-function mutations result in the replication of cells with damaged DNA and to the further accumulation of other mutations affecting oncogenes and tumor suppressor genes, and to an increased likelihood of cancer

81. The role of p53 in the cell cycle G1 S G2 M G0 DNA synthesis Growth and preparation for cell division Quiescent cells phase Mitosis apoptosis (cell death) p53 UV irradiation leads to cell cycle arrest

86. 4 מוטציות בארבעה גנים שונים נדרשות להופעת סרטן המעי הגס ColCan

87. Figure 19.15 A multi-step model for the development of colorectal cancer

88. 16. Oncogenes and Cancer a). Multistep carcinogenesis i). Stages in the evolution of colon cancer ii). Growth characteristics of cells in culture b). Genes responsible for tumorigenic cell growth i). Proto-oncogenes and oncogenes transforming viruses functions of proto-oncogenes oncogene activation ii). Tumor suppressor genes Knudson’s two-hit hypothesis loss of heterozygosity functions of tumor suppressor genes retinoblastoma p53

89. Normal colon cell Increased cell growth Adenoma I Adenoma II Adenoma III Carcinoma Metastasis Multistep carcinogenesis Stages in the evolution of colon cancer Chromosome 5q gene loss or mutation Ras gene mutation Chromosome 18 loss or mutation DCC tumor suppressor gene Chromosome 17 loss or mutation p53 tumor suppressor gene Other chromosome losses מסקנה - יותר ממוטציה אחת נדרשת להופעת מחלת הסרטן

91. יותר ממוטציה אחת נדרשת להופעת מחלת הסרטן

93. Cancer: a genetic disease of inherited and somatic mutations Gene mutations and/or genetic instability are involved in many cancers. Viruses and environmental agents implicated in cancer are believed to act by causing mutations. Mutated gene include those classified as “gatekeepers” (oncogenes and tumor suppressor genes) or “caretakers” (encoding proteins involved in DNA repair and chromosome segregation). For the most part, these genes confer predisposition or susceptibility to cancer.

94. רקע גנטי לחלק מחולות סרטן השד Cancer immu

96. Hereditary Risk : Genes Affecting DNA repair and Genetic Stability גורמי סביבה

97. רק 5% מחולות סרטן השד נושאות מוטציות מורשות ב-BRCA1 and BRCA2 ליתר ה-95% לא ידוע על רקע גנטי סרטן והמערכת האימונית

99. מפה חלקית של גנים שמוטציות בהם מעורבות במחלת הסרטן

101. מוטציות בגנים ממשפחת הפרוטו-אונקוגנים או ב-tumor sup. Genes יכולה להוביל לסרטן. נדרשת יותר ממוטציה בגן אחד ע"מ שהמחלה תופיע. בגן לBRCA1 זוהו כ-200 מוטציות נקודתיות. הסיכוי לחלות בסרטן שד שונה ממוטציה למוטציה ולא כולן גורמות לסרטן

103. דרכי טיפול בחולי סרטן הקרנות כימוטרפיה ניתוח להסרת הגידול

104. אנטומיה של בלוטת הפרוסטטה

105. סרטן הפרוסטטה

106. Androgen dependent prostate cell

107. Androgen independent prostate cancer

108. התפתחות סרטן הפרוסטטה

110. טכניקות ריפוי חדשות שנבדקות במעבדות מחקר Gene Therapy Site-Specific Activation of Prodrugs

111. Retrovirus Gene expression of virus RT ENV

112. Learning objectives understand the concept of “multistep carcinogenesis” and what kinds of genes are mutated during this process understand the differences between “oncogenes” and “tumor suppressor genes” understand the relationships between viral oncogenes and host cell oncogenes (proto-oncogenes) understand the concept that oncogenes function in signal transduction understand the mechanisms by which oncogenes are “activated” during carcinogenesis understand the concept that tumor suppressor genes are lost or inactivated during carcinogenesis understand the concept that a “loss of function” mutation can be expressed as a dominant disease (Knudson’s two-hit hypothesis) understand the functions of Rb and p53

113. Hereditary Risk: Genes Involved in Restraining Cell Proliferation Hereditary Risk: Genes Affecting DNA Repair and Genetic Stability Hereditary Risk: Other Genes and Issues Contents Chapter 8 Heredity and Cancer

114. Hereditary Risk: Genes Involved in Restraining Cell Proliferation ► It does not mean that people inherit cancer from their parents ► Susceptibility of developing cancer  Familial cancers  Hereditary cancers ► Non-inherited cancer  Sporadic cancers  Nonhereditary cancers

115. Cancer Risk Is Influenced by The Inheritance of Dominant or Recessive Mutation of Varying Penetrance ► F 8-1 ► Penetrance: a population of excepted trait

116. Hereditary Risk : Genes Involved in Restraining Cell Proliferation

117. Retinoblastoma is a rare childhood cancer of the eye that occurs in hereditary and nonhereditary forms ► Light-absorbing retinal cells ► 1/20,000 of chance of developing retinoblastoma (RB) ► Families of retinoblastoma: 50% of chance ► F. 8-2 ► 40% RB are familial ► 60% are sporadic

118. Hereditary Risk : Genes Involved in Restraining Cell Proliferation

119. The two-hit model predicts that two mutations needed to trigger the development of retinoblastoma ► Mechanism: in 1971, two-hit model ► F. 8-3 ► Deletion region located on chromosome 13  Association with both the hereditary and nonhereditary form of RB  RB gene ► Both alleles must be mutant (or deleted) for cancer development ► But the penetrance of retinoblastoma in children who inherit a single defective RB gene is 90% ►

120. Hereditary Risk : Genes Involved in Restraining Cell Proliferation

121. The RB gene is a suppressor of cell proliferation ► RB protein ► Tumor suppressor gene

122. Familial Adenomatosis Polyposis is a colon cancer syndrome caused by inherited mutations in the APC gene ► 5% colon cancer cases are inherited-mutation (7500/year in USA) ► F. 8-4 ► At least one of the polyps is likely to turn malignant by the time of 40 y/o ► APC gene is responsible for familial adenomatous polyposis (a tumor suppressor gene) ► APC protein can inhibit the Wnt signaling pathway ► Wnt signaling pathway palys a prominent role in regulating cell proliferation and differentiation in embryonic development ► Loss of functional APC protein: enhancing cell proliferation ► F. 10-8

123. Hereditary Risk : Genes Involved in Restraining Cell Proliferation

124. The Li-Fraumeni Syndrome is caused by inherited defects in the p53 gene ► Li-Fraumeni Syndrome ► F. 8-5 ► Li-Fraumeni Syndrome confers 90% of developing cancer but no single cancer predominants ► Osteosarcomas, breast cancers, leukemia's, adrenal carcinomas, brain tumors …… ► Defection of p53 gene (a tumor suppressor gene) ► F. 10-5

125. Hereditary Risk : Genes Involved in Restraining Cell Proliferation

126. Hereditary cancer syndromes arising from defects in genes that restrain cell proliferation share several features in common ► Common features  By a single tumor suppressor gene  A dominant trait  Two-fit model  50% chance of inheriting the gene defect  Inactivation or loss of tumor suppressor gene  Have non-hereditary cancers ► Other tumor suppressor genes (T. 8-1)

127. Hereditary Risk : Genes Involved in Restraining Cell Proliferation

128. Hereditary Risk: genes affecting DNA repair and genetic stability ► Gatekeepers ► Caretakers

129. Xeroderma pigmentosum is an inherited sensitivity to sunlight-induced skin cancer ► Xeroderma pigmentosum is a first report of DNA repair and cancer ► Sensitive to UV radiation ► F. 8-6 ► Involving two mutant copies of the same gene inherited from mother and father ► A recessive trait ► F. 8-7 ► F. 8-8

130. Hereditary Risk : Genes Affecting DNA repair and Genetic Stability

133. Xeroderma pigmentosum is caused by inherited defects in excision repair ► Mutations in seven different genes about excision repair  Code for enzymes for excision repair pathway  Inheriting two defective copies of any one of these seven genes halts excision repair and creates the cancer predisposition syndrome ► XPV gene, the eighth gene, is a gene for DNA polymerase eta which catalyzes translesion stnthesis

134. Hereditary Nonpolyposis Colon Cancer (HNPCC) is caused by inherited defects in mismatch repair ► At least 8 repair genes involving (~75%)

135. Mutations is the BRCA1 and BRAC2 genes are linked to inherited risk for breast and ovarian cancer ► 1/8 women in USA will develop breast cancer ► 10% breast cancer cases are hereditary ► Mutation (or defection) either the BRCA1 or BRCA2 gene ► F. 8-9 ► Non-genetic factors also significantly affect the risk of developing breast cancer ► BRAC1 and 2 genes are involved in DNA repair

136. Hereditary Risk : Genes Affecting DNA repair and Genetic Stability

137. Inherited defects in DNA repair underlie ataxia telangiectasia, Bloom syndrome, and Fanconi Anemia ► ATM gene code a protein involved in the DNA damage response  For detecting of DNA damage (especially ds DNA break)  F. 10-5 and 10-13 ► BLM gene code for DNA helicase ► Fanconi anemia is a recessive pattern of inheritance  Mutation of at least one of 11 genes which involved in DNA damage responsible pathway

138. Hereditary Risk: other genes and issues

139. Multiple endocrine neoplasia type II is caused by an inherited mutation in a proto-oncogene ► Multiple endocrine neoplasia type II is caused by a mutant RET gene which codes for Ret receptor protein (binding with GF) ► Mutant RET gene produces a constitutively active Ret receptor ► Gain-of-function mutation ► An oncogene ► F. 8-10

140. Hereditary Risk : Other Genes and Issues

141. Inherited variations in immune function and metabolic enzymes can influence cancer risk ► Primary immunodeficiency disease  Caused by inherited mutation  Immune system dysfunction  Associated with Lymphoma (often by EBV infection) ► Inhereditary mutation on liver enzymes or proteins  Cytochrome P450 enzymes

142. Cancer susceptibility is influenced by inheritance of small-risk as well as high-risk genes ► Small-risk genes affect cancer susceptibility can be significant  Difficult to identify  Not for cancer inheritance ► F. 8-11

143. Hereditary Risk : Other Genes and Issues

144. Genetic testing for cancer predisposition has benefits as well as risks ► A cancer is likely to be hereditary?  Without an obvious environmental or lifestyle explanation (such as smoking)  Developing cancer during childhood or earlier than typical  Developing multiple cancers or different types of cancer in succession ► Genetic testing ► T. 8-2

145. Hereditary Risk : Other Genes and Issues