Genetics Ch 19 – Flashcards

Single nucleotide substitutions Chromosomal rearrangements Amplifications Deletions

Somatic cells Only 5% associated w/ germ line

Genetic, somatic

Mutated gene products or abnormally expressed genes

Unregulated cell proliferation Metastatic spread

Unregulated cell growth that forms a multicellular mass - removed by surgery and causes no serious harm

Metastasized cells invading other tissue -life-threatening

Common ancestral origin cell in tumors

Reciprocal translocations (same translocations) and X-inactivation (same inactivated X)

Lymphoma cells have identical translocation breakpoints

1/3

That cancer develops from accumulation of sever mutagenic events in a single cell

Both independent and random mutations

Cancer is a multi-step process Ex: Leukemia from Hiroshima incubated 5-8 years

Development of a malignant tumor resulting from 2 or more genetic alterations

Tumor-suppressor gene that encodes protein involved in differentiation of intestinal cells - controls cell-cell contact and growth inhibition

Inactivating mutations in the APC gene

Driver Mutations - Give growth advantage to tumor cells Passenger Mutations - Have no direct contribution to cancer phenotype

Mutation Genomic Instability Chromosomal Abnormalities Change in DNA methylation patterns Change in chromatin modifications

Translocations Aneupoloidy DNA Amplification Chromosome loss Chromosomal deletions

DNA amplification of two cancer genes (MYCN and MYDM2) - amplified as small DNA fragments separate from DNA Neuroblastoma Cells

Multiple copies of the MYCN gene are amplified within one large region called a heterogeneous staining region Neuroblastoma Cells

Defects in genes that control DNA repair Xeroderma pigmentosum CML (Leukemia) HNPCC (Colorectal cancer)

Translocation b/w chromosomes 9 and 22 which creates a chimeric protein - Caused by defect in DNA repair Constantly stimulates proliferation

Autosomal Dominant - Mutations to 6 DNA mismatch repair genes Increases chances of developing colon, ovary, uterine, and kidney cancers

Study of factors that affect gene expression but do not alter sequence of DNA - may be somatic or germ cells Histone acetylation and phosphorylation in DNA

Gene silencing Heterochromatin gene expression X chromosome inactivation

Histones disrupted in cancer cells Genes that encode histone acetylases, deacetylases, methyltransferases, and demethylases are often mutated or aberrantly expressed in cancer cells

Location or Promoter mutations Repair genes hypermethylated Transcriptionally silenced areas Mutated acetylation genes

To replace dead/damaged tissue Checkpoints (G1/S, G2/M, and M) Mutations lead to uncontrolled proliferation

The process of transmitting growth signals from the external environment to the cell nucleus. Cancer cells have defective pathways

Responsible for cell cycle control Complex phosphorylates proteins to advance cell cycle. CDK breaks down Cyclins.

Programmed cell death - occurs when DNA or chromosomal damage is too severe to repair and prevents cancer

Proteases that initiate apoptosis and digest intracellular components

Heterodimers w/ BAX and Bcl2 BAX-BAX promotes apoptosis, BAX-Bcl2 is inactive, and Bcl2-Bcl2 blocks apoptosis

Genes promoting cell growth and division Cyclins, c-kit

TFs that stimulate expression of other genes Signal transduction to stimulate cell division Cell-cycle regulators

Mutated proto-oncogene that contributes to cancer - stimulates cell division

Gain-of-Function

Regulate cell cycle checkpoints Initiation of apoptosis Mutations to these lead to cancer

ras family genes

Encode signal transduction - regulate cell growth/division

Prevention of ras to hydrolyze GTP which leads to constant cell proliferation (GDP inactive, GTP active)

p53 Tumor-Suppressor Gene

Encodes TF that represses/stimulates transcription of genes

Bound to Mdm2 and is activated by ds breaks or chemical DNA damage so Mdm2 dissociates Will either arrest cell cycle or initiate apoptosis

G1/S - stimulates p21 which prevents cyclin activation S phase - activates proteins that slow DNA replication, giving it time to repair Apoptosis - Increases BAX gene, represses Bcl2 gene

p53 TSG

Cannot arrest cell cycle or enter apoptosis No p21 stimulation and No BAX gene activation

Mutation to both alleles causes cancer (RB1/RB1 instead of +/+)

Mutated RB1 inherited so only 1 independent mutation is necessary Requires 2 independent mutation events in the same cell

G1/S

Extracellular matrix and basal lamina

0.01%

Cell adhesion and Proteolytic enzymes

Present at higher than normal levels in highly malignant tumors - not susceptible to normal controls and regulatory molecules Metalloproteinases

Translocation b/w 9 and 22 - causes Leukemia (CML)

p21 - no transcription Bax - apoptosis Mdm2 - prevents conversion to active form

MMP1 MMP1 and MMP2

Levels of proteolytic enzyme activity expressed by the tumor

Are mutated/disrupted in metastatic tumors - less than a dozen identified CD82 - expression lost in metastatic tumors by epigenetic mechanism (not nucleotide mutation)

Somatic cell mutations

50

Loss of Heterozygosity - Phenomenon where second wild-type allele is mutated in tumor

Predisposition to some cancers can be inherited by somatic mutation in the gene, usually other mutations necessary for cancer to be expressed Familial Adenomatous Polyposis (FAP), Breast cancer w/ mutation to BRCA1, Familial Retinoblastoma

Familial Adenomatous Polyposis - genetic disposition to cancer caused by mutant copy of APC gene on long arm of chromosome 5 - may cause deletions/frameshift/point mutations Causes proliferating epithelium of colon leading to cancer

Causes rectal polyps or adenomas in early life - second mutation leads to later stage of cancer

RNA viruses - cause cancer Reverse transcriptase - copies RNA to DNA

Integrates into genome as provirus which is replicated with host DNA during cell cycle

Inhibit reverse transcriptase, prevent binding/entering cell, prevent integration into genome

Retroviruses

Transform cells into cancer cells - carry cell-derived oncogenes and transfer proto-oncogene from host to viral genome

Proviral DNA integrates near proto-oncogenes and stimulates high levels of transcription Acute Transforming Retroviruses Normal retrovirus w/ normal viral gene can stimulate inappropriate cell growth

None have been identified

15% of cancer - 2nd most after tobacco

HIV Human T-cell Leukemia Virus (HTLV-1)

Epstein-Barr virus Hep B/C Human Papilloma viruses Herpesvirus

Causing mutations to proto-oncogenes or tumor-suppressor genes

Tobacco smoke, red meat/animal fat (colon, prostate, breast), and alcohol (liver)

Aflatoxin - mold on bread/corn Nitrosamines - meat preservative Pesticides Asbestos

X-rays and Gamma rays

Responsible for 50% of ionizing radiation exposure to the US population and contributes to lung cancer

The accumulation of several mutations

Inability to repair DNA damage

Cyclin B degraded

RB1 APC p53 BRCA1, BRCA2

Growth factor binds to plasma membrane and causes release of GDP-GTP exchange factor in cytoplasm. Ras exchanges GTP for active or GDP for inactive. GTP leads to cascades of activated proteins ending with Map kinase which activates transcription factors in the nucleus.

RB binds to TFs in its normal state, but when RB is bound to 2 PO4 molecules then it allows activity of TFs. CDK4/Cyclin complex phosphorylates RB

Different cyclins combine with protein kinases at different stages of the cell cycle to affect the cell cycle. Cyclin B combines with CDK1 to move the cell cycle past the G2/M transition. Other cyclins combine with CDK4 (and CDK1?) to move the cell cycle from G1 to S

Signal Transduction

It temporarily arrests the cell cycle in G1 before entering S.

Cancers such as xeroderma pigmentosum and HNPCC

Process such as tumorigenesis and age dependence in cancer - also events like hiroshima

Less in cancer cells Cancer promoters, however, are hypermethylated

Epigenetic

Regulates proteins by phosphorylating them Cyclins bind to kinases switching them on and off (cyclins activate CDKs to phosphorylate M phase proteins at G2/M)

Controls the G1/S checkpoint When it is not phosphorylated, pRB binds to E2F arresting the cell cycle. When phosphorylated, E2F is released and if Cyclins bind to CDK4 then the cycle proceeds to the S phase.

Inheritance is if the genetic circumstance is present, the phenotype will be expressed. Predisposition is a pattern in a phenotype being expressed but it may manifest in different ways or not manifest at all.

0.5 0.05 0.025 0.0225

If the mutated gene was dominant, it would be impossible to be transported to the offspring, since the organism that carries this gene would not survive because of cancer. Loss of function. Gain of function - leads to continuous division.

Activated ras proteins transduce a signal which activates transcription of genes that start cell division. It continually signals cell division.

Repairing DNA damage - often w/ BRCA2 and mRAD51 Does this in S phase arresting w/ p53

ATM or Chk2

Genetic mapping established that certain genes were combined to form a hybrid oncogene ( BCR/ABL ) that encodes a 200kDa protein that has been implicated in the formation of chronic myelogenous leukemia.

Arrests the cell cycle at the G1/S checkpoint by inhibiting the CDK4/Cyclin D! complex.

The concentration of the p53 will be decreased, the process of tumorigenesis will be stimulated.

Breaks activate kinases (Chk2), which phosphorylates BRCA1 and p53. p53 arrests the cell cycle while BRCA1, BRCA2, and mRAD51 repair the DNA.

MSL1, MSH2, MLH3, MSH6 (DNA mismatch repair)