麻省理工大学：遗传学（Genetics）讲稿_lecture33_1

Most environmental causes of cancer are mutagens mutagenic compounds, X-rays, uv Enzymatic conversion HC to reactive epoxide Spontaneous reaction with N7 of guanosine Aflatoxin B H G H2 3, benzpyrene DNA

Most environmental causes of cancer are mutagens: mutagenic compounds, X-rays, uv Enzymatic conversion ve epoxide Spontaneous reaction with N7 of guanosine H i 3C O O O O O O to react H3C O O Aflatoxin B O O O HO O O N+ HN G H2N N 3,4-benzpyrene N DNA

Cancer tends to arise in actively dividing cells Epithelial cells(lining of intestine, lungs etc. )=carcinoma Blood and lymphatic cells= lukemia, meyloma, lymphoma Connective tissue(bones tendons muscle =sarcoma

Cancer tends to arise in actively dividing cells • Epithelial cells (lining of intestine, lungs etc.) = carcinoma • Blood and lymphatic cells = lukemia, meyloma, lymphoma • Connective tissue (bones, tendons muscle) = sarcoma

Cancer is a genetic disease of somatic cells The underlying cause is mutations that release cells from the normal constraints that exist in well organized tissues allowing uncontrolled growth Which are the key genes that are mutated

Cancer is a genetic disease of somatic cells The underlying cause is mutations that release cells from the normal constraints that exist in well organized tissues allowing uncontrolled growth Which are the key genes that are mutated ?

Incidence of stomach cancer as a function of age Stomach Cancer Maes(1975) 8 Females(1975) A Incidence of stomach cancer as a function of age. Figure by MIT OCW

Incidence of stomach cancer as a function of age 0 100 200 300 400 500 600 700 800 0 5 10 3020 2515 35 5545 5040 60 80 85 70 7565 Age (1992) Stomach Cancer Rate per 100,000 Females Females (1975) Males (1992) Males (1975) Incidence of stomach cancer as a function of age. Figure by MIT OCW

Major complications in understanding the genetic basis of cancer Multiple mutations are necessary to produce a tumor cell Different types of tumor have different genes mutated Early initiating events occur rarely in complex tissues and are therefore extremely difficult to detect The key initiating event often leads to an increase in mutation rate thus tumor cells often bear many fortuitous mutations Important aspects of the disease we wont discuss relate to the spread of cancer cells and the formation of large tumors (metastasis and angiogenesis)

Major complications in understanding the genetic basis of cancer • Multiple mutations are necessary to produce a tumor cell • Different types of tumor have different genes mutated • Early initiating events occur rarely in complex tissues and are therefore extremely difficult to detect • The key initiating event often leads to an increase in mutation rate thus tumor cells often bear many fortuitous mutations Important aspects of the disease we won't discuss relate to the spread of cancer cells and the formation of large tumors (metastasis and angiogenesis)

3t3 cells in culture Transformed 3t3 cells Images removed due to copyright reasons

3T3 cells in culture Transformed 3T3 cells Images removed due to copyright reasons

DNA from human tumor cells Isolation of the ras Transfect mouse 3T3 cells oncogene from human tumor cells Culture for 2 weeks Focus of transformed 3T3 cells growing among untransformed cells Extract DNA, transform new mouse cells Second cycle Extract genomic dNA Introduce into phage vector Surviving human dna Phage library 7S2S@GQQ@3 Plate phage on Alu probe igure by MIT OCW Replic filter paper Oncogene

Isolation of the Ras oncogene from human tumor cells Figure by MIT OCW

Synergistic effect of oncogenic forms of myc and ras myc 100 80 ras 60 40 myc t ras 20 50100150200 Age(days)

Synergistic effect of oncogenic forms of myc and ras 100 80 60 40 20 0 i D D Tumor-free m ce (%) myc ras myc + ras 0 50 100 150 200 Age (days)