Pathology 5 - Genetics

Front 1

(1) what is cancer due to? (2) what does this lead to?

Back 1

heritable changes in DNA

Hint 1

increased expression of normal proteins, decreased or absent expression of normal protein, expression of abnormal protein

Front 2

(1) what is the package of normal/abnormal proteins called? (2) what can this be used for treatment wise?

Back 2

phenotype

Hint 2

sophisticated chemotherapy

Front 3

(1) what are the molecular mechanisms of cancer? (2) what is a new approach to genetic changes in cancer?

Back 3

genetic disease (heritable change in DNA of tumor cells), increased expression of normal proteins (oncogenes, apoptosis controlling genes), decreased expression of normal proteins (tumor suppressor genes, DNA repair genes), expression of abnormal proteins

Hint 3

DNA micro-array to compare normal cDNA synthsis vs tumor cDNA synthesis

Front 4

(1) what can cause non lethal damage to the genome? (2) why doesn't DNA damage always lead to mutation?

Back 4

chemicals, radiation, viruses and infectious agents

Hint 4

repair enzyme families (proof read and repair) takes 1-2 rounds of DNA replication with an error for repair enzymes to not recognize the error > mutation permenant

Front 5

(1) what types of DNA damaged occur?

Back 5

point mutation, double strand breaks, insertions, DNA amplification

Front 6

(1) what is point mutation? (2) what is a double strand break?

Back 6

single base substitution, location determines affect; an exon or splice site = altered protein

Hint 6

creates an oppurtunity for chromosome abnormalities; cause major gene expression changes

Front 7

(1) what are single or double base insertions/deletions? (2) what is DNA amplification?

Back 7

insertion of single/double base which can lead to a frame shift mutation (entire viral genomes may be inserted as well)

Hint 7

gene copies increased by 100-1000 fold

Front 9

(1) what can be attributed to inherent chromosomal intability in neoplastic cells? (2) what are the consequences?

Back 9

abnormal karyotypes (chromosome content)

Hint 9

duplication, deletion, reciprocal and nonreciprocal translocation

Front 10

(1) what types of genetic alteration are observed in cancer cells?

Back 10

aneuploidy, translocation, mutation, deletion, amplification, microRNAs (miRNA)

Front 11

(1) what in aneuploidy? (2) what are some examples?

Back 11

abnormal chromosome/DNA content in a cell. Affects entire chromosome population or single gene. Arises due to mistakes of chromosome segregation during mitosis

Hint 11

duplication of chromosome 13, a trisomy, is found in 25% of canine lymphomas

Front 12

(1) what does translocation result from? (2) what can occur with point mutation?

Back 12

abnormal response to DNA damage; cell goes through cycle leading to chromosomal instability due to failure of normal repair mechanisms (p53 fails to arrest cell cycle for repair or apoptosis). Includes telomere dysfunction

Hint 12

a single point mutation can create an activated protein leading to transformation (ie RAS in human transitional cell carcinoma of urinary bladder and hereditary renal cystadenocarcinoma/dermatofibrosis in GSD)

Front 13

(1) what is deletion? (2) how does amplification occur?

Back 13

loss of 1-2 bases > frame shift muation. Can lead to premature termination of transcription > abnormal proteins

Hint 13

duplication of local areas of DNA sequences but unclear mechanism (internal tandem repeat, ITR, in c-kit gene in some dogs with mast cell tumors, helps ID tumor type)

Front 14

(1) what are microRNAs (miRNA)? (2) what may result?

Back 14

small RNA chains (21-25 NTs) bind to RNA transcripts (including oncogenes) altering gene expression

Hint 14

disordered miRNA expression found in some tumor types

Front 15

(1) what are examples of translocations?

Back 15

active promoter moved to highly regulated oncogene or immunoglobulin promoter moved next to c-myc

Front 16

(1) how does epigenetics affect tumors? (2) what are epigenetic mechanisms?

Back 16

heritable changes that lead to altered gene expression in somatic cells through something other than DNA alteration

Hint 16

DNA methylation, imprinting, histone modification,

Front 17

(1) what is DNA methylation? (2) how do tumors affect DNA methylation?

Back 17

adding methyl groups to DNA > limits transcription. Typically at cytosines upstrea of a guanine base and regulated by cellular enzymes

Hint 17

reduced globally, but focal areas of increased methylation in promoter regions (in virtually all human tumors)

Front 18

(1) what is imprinting? (2) how can it contribute to tumors?

Back 18

silencing of one (maternal or paternal) gene (via methylation) so that only one allele is normally functional

Hint 18

loss of impriting results in a double dose of a particular gene, which can result in tumor formation if the gene is a growth factore (ie insulin-like growth factor II; IGF-II)

Front 19

(1) what is histone modification?

Back 19

methylation, acetylation or other changes affect how tightly DNA binds histones, which affects DNA transcription (or silencing)

Front 20

what determines the neoplastic phenotype?

Back 20

DNA mutations, Epigenetic Changes, chromosomal alterations

Front 21

(1) what are germ line mutations? (2) give examples of germ line mutations?

Back 21

specific molecular abnormalities that are inherited in families through the germ line (inherit one abnormal allele at birth). Most are abnormaltities in tumor suppressor genes

Hint 21

retinoblastoma (ttumor suppressor gene RB). Aggressive ocular neoplasms of retina primitive cells. Retinoblastoma as infants and osteosarcoma as adults. P53 (Li Freemen syndrome), NF1&2 (neurofibromatosis - elephant man), BRCA 1&2 (breast and ovarian cancer risk), Men1 (multiple endocrine neoplasia), hereditary multifocal renal cystadenomas and nodular dermatofibrosis (GSD's)

Front 22

(1) what are acquired somatic mutations? (2) how do somatic mutations occur?

Back 22

acquired during life through intrinsic or extrinsic means rather than inheritance

Hint 22

mutations in individual cells, random, intrinsic factors (oxidative processes, DNA replication error rates, errors in other enzyme systems), extrinsic factors (chemicals, radiation, viruses, infectious agents)

Front 23

(1) what are intrinsic factors? (2) what are extrinsic factors?

Back 23

reactive oxygen speces that damage DNA/DNA repair from normal metabolism, age via accumulated DNA damage

Hint 23

factors from the environment; chemicals, radiation, infectious agents

Front 24

(1) what are the molecular determinants of cancer? (2) what type of process is it?

Back 24

alterations of DNA, usually coding region, but also to promoters and enhancers, and stability of mRNA transcripts

Hint 24

multistep; arise from a series of genetic injuries; multiple mutations must occur. No clear order to changes.

Front 25

(1) what is a possible process of genetic changes leading to tumors? (2) what do molecular changes leading to cancer affect?

Back 25

loss/mutation of APC locus on chromosome 5q > mutation of RAS gene on chromsome 18q > loss of tumor suppressor on chromosome 18q > loss of p53 gene on chromosome 17p

Hint 25

regulation of cell proliferation, differentiation, death, particularly tumor suppressor genes and oncogenes

Front 26

(1) what is the role of tumor suppressor genes in tumor development? (2) what is the role of oncogenes in tumor development?

Back 26

lose their normal function due to mutation or other means

Hint 26

activation causes gain of function due to mutations

Front 27

(1) what do tumor-suppressor genes regulate cell proliferation by governing cell cycle?

Back 27

pRB, p53

Front 28

(1) what is pRB? (2) what does loss of pRB lead to?

Back 28

nuclear phosphoprotein with key role in regulating cell cycle in all cell types; normally nonphosphorylated state binding E2F transcription factor in the RB pocket in cells in G1/GO, phosphorylation of pRB by cyclins causes entry into S phase and frees E2F to stimulate cell replication

Hint 28

uncontrolled cell replication

Front 29

(1) what is p53? (2) what does mutated p53 genes lead to?

Back 29

tumor-suppressor gene that encodes nuclear phosphoprotein that regulates transcricption; regulate entry into S and induction of apoptosis, normally short-lived protein but genetic damage causes longer half-life and nuclear accumulation > arrest at G1 for repair of DNA damage or apoptosis

Hint 29

cell doesn't arrest before entering S, less likely to undergo apoptosis; replicate w/damaged DNA and if genetic changes aren't lethal, can acquire additional genetic damage > neoplastic transformation

Front 30

(1) what is the general role of Rb on the cell cycle? (2) what is the general role of p53 on cell transformation?

Back 30

normal function of binding E2F, mutation causes overexpression of cyclin D, can be caused by some DNA viruses (papilloma viruses and adenoviruses)

Hint 30

cellular policeman; regulates entry into cell cycle and apoptosis, loss of function leads to risk of transformation (only one bad copy of p53 needed): 50% human neoplasms contain mutation, human inheritantce of mutant gene have 25s greater risk by age 50

Front 31

(1) what are the general features of p53? (2) what are the mechanisms of p53?

Back 31

localized in nucleus, short half life, during DNA damage increased amount and life-span, not involved in normal cell cycle regulation

Hint 31

transcription factro must bind DNA (mutations in binding region), which regulates expression of genes that arrest cell cycle late in G1, stimulates expression of cdk inhibitor and DNA repair genes (severe DNA damage = apoptosis via bax or in hopoxia)

Front 32

what causes p53 inactivation?

Back 32

mutations, viral proteins (papilloma virus), mdm2 overexpression

Front 33

(1) when were oncogenes described? (2) How are the names of oncogenes derived?

Back 33

Rous in the 1900's, Varmus and Bishpo, the origin of oncogenes from protooncogenes

Hint 33

three letter code from the name of the neoplasm or virus associated with the gene; myc (avian MYeloCytomatosis virus), sis (SImian Sarcoma varius)

Front 34

(1) what do oncogenes do? (2) what are the features (general) of growth factor receptors?

Back 34

encode oncoproteins; abnormal proteins are responsible for abnormal function that leads to cellular transformation

Hint 34

extraceullular, intramembranous, cytoplasmic

Front 35

what type of drugs are being used in clinics from neoplasia research?

Back 35

tyrosine kinase receptor-related drugs

Front 36

(1) what, specifically, leads to cell transformation?

Back 36

oncoproteins, the product encoded by oncogenes, NOT oncogenes

Front 37

(1) what do defects in DNA repair cause? (2) what are some associated genes?

Back 37

abnormalities of DNA repair mechanisms with a hig hrisk of cancer

Hint 37

BRCA-1 & BRCA-2 (increased risk of breast and ovarian tumors) possibly involved in double stranded DNA breaks

Front 38

(1) what does identifying the phonotype of a cancer allow? (2) examples?

Back 38

targeted therapies

Hint 38

extrogen dependent tumors = estrogen blockers, chromosomal translocation protein (BCR/ABL) in tumor cells = Gleevac, epidermal grwoth factor receptors (EGF-R) in epithelial tumors = Iressa