Law: Cancer Genetics

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Cancer

accumulation of alteration in somatic cell genes lead to development of cancer

Characteristics of p53 gene

1. located on 17p13.1
2. 20 kb genomic DNA
3. 11 exons/10 introns
4. 393 amino acids

functions of p53 protein

1. DNA binding protein that activates regulators of cell proliferation - transcription factors
2. helps maintain the G1/S checkpoint - pauses cell cycle to repair DNA
3. induces apoptosis at two pathways

Li Fraumeni Syndrome

1. autosomal dominant mode of inheritance
2. increases susceptibility of cancer
3. neoplasms are diverse in origin
4. early age of onset
5. multiple primary tumors

How are cancers named?

1. cell type
2. tissue type
3. site of origin

What do all cancer cells have in common?

1. all have an underlying alteration in the regulation of cell proliferation

Why do all cancers have different prognoses?

1. aggressive nature of cancer
2. amendable to early detection
3. adequate therapeutic treatments

Why does risk of cancer increase with age?

1. longer life = ↑probability of mutations in cells
2. longer exposure period to mutagens/carcinogens
3. immune system decline

Characteristics of Cancer Cells

1. growth factor independence - do not require GF to divide
2. growth density insensitivity - continuous growth regardless of space
3. anchorage independence - does not need to anchor to a basement membrane
4. immortal - can multiple inifinitely

Tumorigenesis

1. multi-step process
2. each step brings the cell closer to cancer
3. clonal expansion of original cell line

2 hit hypothesis

1. must inactivate both alleles in order to contract cancer
2. familial cancers already have individuals with 1 inactivated allele which makes it easier to inactivate 2nd allele.

Why are cancers sporadic?

1. no germ line mutations
2. no inherited predisposition
3. inherited familial cancer (5-10%)

Clases of cancer genes

1. oncogenes
2. tumor suppressor genes
3. DNA repair genes (mutator genes)

Oncogenes

1. first identified cancer gene
2. discovered by Peyton Rous in 1911
3. Discovered the Rous sarcoma virus - v-onc

Proto-oncogenes

1. normal cellular genes that promote cell proliferation
2. high homology with v-oncs
3. occur in cells without viral infections

Cellular Oncogenes

1. mutated proto-oncogenes
2. mutations occur in amplification and translocation

How do oncogenes cause cancer?

1. positive growth effectors - promotes cell proliferation without regulation
2. onco-proteins are needed for initiation and maintenance of cancer
3. gas pedal of cell proliferation
4. not associated with inherited predisposition

Functions of Oncogenes

1. growth factors - continued synthesis and activation of GF
2. growth factor receptors - tells cells to grow with or without GF
3. inter-cellular messengers (signal transduction) - sends cell signally directly to nucleus rather than through the typical pathway
4. nuclear effectors (transcription factors) - turns on genes without signal from GF

abl

1. oncogene that causes problems in signal transduction
2. leads to sarcomas

scr

1. oncogene that causes problems in signal transduction
2. leads to lymphomas

erb-b

1. oncogene that makes growth factors
2. leads to leukemia

myc

1. oncogene that affects nuclear effectors
2. leads to carcinomas and sarcoma

ras

1. most common mutated proto-oncogene in human cancer
2. GTP binding (on/off switch) in genes

Tumor Suppressor genes

1. inhibits cell proliferation - 12-15 identified
2. tumor suppressor protein is needed for normal cell growth
3. brakes of cell proliferation
4. mutations associated with familial cancer syndromes - germ line mutations

DCC

1. deleted in colon cancer

BRCA 1 and BRCA 2

1. familial breast cancer, breast and ovarian cancer

APC

1. Familial adenomatous polyposis (1%) - FAP

Rb (retinoblastoma gene)

1. 2nd most important gene
2. familial retinalblastoma (sarcoma)
3. G1/S check point role - losses its ability to hold onto E2F which does not allow G1/S checkpoint to occur

Mutator Genes

1. DNA repair genes - that allow mutations to accumulate quickly when mutated themselves
2. tumorigenesis occurs more rapidly
3. mut genes in excision repair (SLH) - causes hereditary nonpolyposis colon cancer (HNPCC) - cancer in lining of colon

Translocation mutation related to CML

1. translocation on t 9:22
2. chromosome 9 breaks @ abl proto-oncogene
3. chromosome 22 breaks @ bcr proto-oncogene
4. results in Philadelphia chromosome - hybrid gene of (brc/c-abl) that produces a fusion protein that causes CML

Gleevec

designer drug that inactivates fusion protein

4 most common sites of cancer

1. breast
2. prostate
3. lung
4. colon

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