Chapter 2 Genetics and Cancer

Figure 24.1 Estimated number of new cases and deaths from specific types of cancer in the United States in 1997.

2006 年台灣十大死因

2006 年台灣主要癌症死亡率

順位 癌症死亡原因1 肝 癌2 肺 癌3 結腸直腸癌4 口腔癌 (含口咽及下咽 )5 胃 癌6 食道癌7 攝護腺癌8 胰臟癌9 非何杰金淋巴癌10 鼻咽癌

男性順位 癌症死亡原因1 肺 癌2 肝 癌3 結腸直腸癌4 女性乳癌5 胃 癌6 子宮頸癌7 胰臟癌8 非何杰金淋巴癌9 膽囊癌10 卵巢癌

女性

資料來源 :行政院衛生署

2006 年台灣地區主要癌症死亡原因

Benign tumor: Tumor cells do not invade the surrounding tissues.

Malignant tumor: Cells detach from a tumor and invade the surrounding tissues, i.e. metastasis.

Carcinogens: Agents such as radiation, mutagenic chemicals, and certain types of viruses can transform normal cells into cancerous cells.

Figure 24.2 A schematic view of the START checkpoint in the mammalian cell cycle. Passage through the checkpoint depends on the activity of the cyclinD/CDK4 protein complex.

CDK: cyclin-dependent kinase

Checkpoint: A mechanism that halts progression through the cycle until a critical process such as DNA synthesis is completed, or until damaged DNA is repaired.

In tumor cells, checkpoints in the cell cycle are typically deregulated.

Mid-G1 phase

Cancer is caused by genetic malfunctions 1. The cancerous state is clonally inherited. The cance

rous condition is transmitted from each cell to its daughters at the time of cell division.

2. Certain types of viruses can induce the formation of tumors in experimental animal, indicating that viral genes are involved in the transformation process.

3. Cancers can be induced by mutagenic agents that cause mutations of genes.

4. Certain types of cancer tend to run in families, e.g. retinoblastoma and colon cancers.

5. Certain type of leukemias and lymphomas are associated with particular chromosomal aberrations.

Tumor-Inducing Retroviruses and Viral Oncogenes

Rous sarcoma virus-The first tumor-Inducing retroviruses

-Discovered in 1910 by Dr. Peyton Rous

-Caused sarcoma in the connective tissue of chicken

-Encode four gene, gag (capsid protein), pol (reverse transcriptase), env (envelope), and v-src (protein kinase)

-V-src is a oncogene that responsible for the virus’s ability to form tumors

Oncogene: Gene that causes cancer is called oncogene

Viral oncogene (v-onc)

Figure 24.3 Structures of the v-src and c-src genes

Cellular homologues of viral oncogenes: The proto-oncogenes (c-onc)

Single exon

Why do v-oncs induce tumors, whereas normal c-oncs do not?

- v-onc produces much more protein - v-onc genes express at inappropriate times

- v-onc genes express mutant forms of the proteins

p707

Figure 24.4 The transfection test to identify DNA sequences capable of transforming normal cells into cancer cells.

Dr. Robert Weinberg

c-H-ras oncogene

Figure 24.5 Ras protein signaling and cancer

Dominant activator

(a) Normal Ras protein signaling

(b) Oncogenic Ras protein signaling

Figure 24.6 The reciprocal translocation involved in the Philadelphia chromosome associated with chronic myelogenous leukemia (CML).

bcr/c-abl fusion protein: constitutively activated c-abl tyrosine kinase function

Figure 24.7 A reciprocal translocation involved in Burkitt’s lymphoma. Immunoglobulins in B cell: H (chromo. 14), (chromo. 22), (chromo. 2)

Tumor Suppressor Genes

Figure 24.8 Knudson’s two-hit hypothesis to explain the occurrence of inherited and sporadic cases of retinoblastoma. Two inactivating mutations are required to eliminate the function of the RB gene.

Knudson’s Two-Hit HypothesisNon-inherited

The Retinoblastoma Tumor-Suppressor Gene

Somatic divisions

Homozygous or hemizygous for the RB- alleles (recessive mutation)

Dominantinheritance

Inherited Cancer Syndromes

Figure 24.9 Role of pRB in progression of the cell cycle.

Early G1

Late G1

S

M

recessive

dominant

ODDBDTAD

Cell-cycle Arrest Pathway Apoptotic Pathway

Damage to the DNA induces an increase in the abundance of p53

Cell-cycle arrest

Cell death

Figure 24.10 (a) Principal domains within p53. (b) Role of p53 in cellular response to DNA damage.

TAD, transcription activation domain

DBD, DNA binding domain

OD, homo-oligomerization domain

Figure 24.11 (a) Principal domains within pAPC. (b) Role of pAPC in cell-cycle control.

Autosomal dominant disease, familial adenomatous polyposis (FAP)

APC adenomatous polyposis coli

Figure 24.12 Genetic pathways to cancer.

Androgen- independent prostate cancer

Metastatic colorectal cancer

Glioblastoma

Six hallmarks of the pathways leading to malignant cancer

1. Cancer cells acquire self-sufficiency in the signaling processes that stimulate division and growth.

2. Cancer cells are abnormally insensitive to signals that inhibit growth.

3. Cancer cells can evade programmed cell death.

4. Cancer cells acquire limitless replicative potential.

5. Cancer cells develop ways to nourish themselves.

6. Cancer cells acquire the ability to invade other tissues and colonize them.

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