Genetics - Cancer

Front 1

Cancer risk factors

Back 1

- Genes
- Viral infection
- Radiation
- Carcinogens
- Immunological defects

Front 2

Cancer development

Back 2

Multi-step process
- Usually 1st hit is non-malignant - possible growth increase
- 2nd, subsequent hits increase malignancy, aneuploidy, polyploidy

Front 3

Features suggesting an inherited predisposition to cancer

Back 3

Two or more close relatives affected
- Early age of onset.
- Specific cancers occurring together (e.g., breast and ovary).
- Multiple/bilateral cancers occurring in one person

Front 4

Oncogenes

Back 4

- Proto-onco genes that have gone awry
- Involved in upregulating growth and prolifieration
- Dominant at the cellular level
- Identified because of their ability to cause transformation

Front 5

Oncogene activation

Back 5

Gain of function mutation on road to malignancy
- Change in protein structure (Ras always on, hybrid CML protein, etc.)
- Change in expression (levels or location)

Front 6

Ras mutation

Back 6

Mutation blocks inactivation
-Constant signalling, proliferation

Front 7

CML pathogenesis

Back 7

Philidelphia chromosome - 9:22 hybrid
- Growth factors always on, contstant proliferation

Front 8

Burkitt Lymphoma

Back 8

- Common in Africa, rare elsewhere
- B-cell tumor of jaw

Front 9

Burkitt lymphoma pathogenesis

Back 9

C-myc gene on chromosome 8 normally regulated by neighbors
- Moved elsewhere, regulation disappears, induces proliferation

Front 10

Inherited mutations of oncogenes

Back 10

Rare, but do happen (RET & MET)
- Protein kinase receptors - kinase activity w/o ligand

Front 11

Tumor suppressor genes

Back 11

Usually 2 copies, need 2 hits to KO functionality

Front 12

Loss of heterozygosity

Back 12

2nd hit destroys remaining wild type allele, both b/c mutant

Front 13

Loss of regulation types

Back 13

- Proliferation
- Tumor suppression
- Apoptotic
- Anti-apoptotic

Front 14

Retinoblastoma inheritance

Back 14

Can be autosomal dominant
- Inherited from carrier parent or germline mutation
- Bilateral = probably inherited, small chance of randomly getting in both eyes

Front 15

Retinoblastoma pathogenesis

Back 15

Tumor supressor gene RB1 on Chr. 13
- RB1 in nucleus, controls transcription
- Loss of function, over-phosphorylated (inactivated)

Front 16

Mendelian vs. Sporadic cancer

Back 16

- Mendelian = already have 1 mutant copy, only need 2nd hit
Bilateral, early onset, multiple tumors
- Sporadic = need 2 hits, each independent somatic events

Front 17

Breast cancer

Back 17

Mutations in BRCA1 & BRCA2 are "1st hit"
- Presence of mutations = higher likelihood of cancer development
- BRCA2 = risk to male carriers also

Front 18

Familial adenamatous polyposis (FAP) Inheritance

Back 18

Autosomal dominant

Front 19

Familial adenamatous polyposis (FAP) pathogenesis

Back 19

APC gene usually helps degrade β-catenin (cell proliferation)
- Loss of APC = more β-catenin, uncontrolled proliferation

Front 20

FAP symptoms

Back 20

Heterozygotes dev benign tumors early in life - usually get 2nd hit, become malignant

Front 21

FAP treatment

Back 21

Surgical removal of colon
- Frequent colonoscopies (family also)

Front 22

Hereditary Non-polyposis Colon Cancer (HNPCC) inheritance

Back 22

Autosomal dominant

Front 23

HNPCC pathogenesis

Back 23

Mutations in MMR genes
- Defective/absent DNA repair
- High microsatellite instability - only present in tumor cells

Front 24

Cancer cell epigenetic markers

Back 24

- Hypomethylation - activates genes that are normally tightly controlled
- Hypermethylation - suppresses control mechanisms

Front 25

Sporadic vs. Inherited Cancer

Back 25

Sporadic cancer requires 2 random "hit" events
- Inherited cancer = already inherit 1 "hit", much more likely to get the 2nd...

Front 26

Cancer risk factors

Back 26

- Genes
- Viral infection
- Radiation
- Carcinogens
- Immunological defects

Front 27

Cancer development

Back 27

Multi-step process
- Usually 1st hit is non-malignant - possible growth increase
- 2nd, subsequent hits increase malignancy, aneuploidy, polyploidy

Front 28

Features suggesting an inherited predisposition to cancer

Back 28

Two or more close relatives affected
- Early age of onset.
- Specific cancers occurring together (e.g., breast and ovary).
- Multiple/bilateral cancers occurring in one person

Front 29

Oncogenes

Back 29

- Proto-onco genes that have gone awry
- Involved in upregulating growth and prolifieration
- Dominant at the cellular level
- Identified because of their ability to cause transformation

Front 30

Oncogene activation

Back 30

Gain of function mutation on road to malignancy
- Change in protein structure (Ras always on, hybrid CML protein, etc.)
- Change in expression (levels or location)

Front 31

Ras mutation

Back 31

Mutation blocks inactivation
-Constant signalling, proliferation

Front 32

CML pathogenesis

Back 32

Philidelphia chromosome - 9:22 hybrid
- Growth factors always on, contstant proliferation

Front 33

Burkitt Lymphoma

Back 33

- Common in Africa, rare elsewhere
- B-cell tumor of jaw

Front 34

Burkitt lymphoma pathogenesis

Back 34

C-myc gene on chromosome 8 normally regulated by neighbors
- Moved elsewhere, regulation disappears, induces proliferation

Front 35

Inherited mutations of oncogenes

Back 35

Rare, but do happen (RET & MET)
- Protein kinase receptors - kinase activity w/o ligand

Front 36

Tumor suppressor genes

Back 36

Usually 2 copies, need 2 hits to KO functionality

Front 37

Loss of heterozygosity

Back 37

2nd hit destroys remaining wild type allele, both b/c mutant

Front 38

Loss of regulation types

Back 38

- Proliferation
- Tumor suppression
- Apoptotic
- Anti-apoptotic

Front 39

Retinoblastoma inheritance

Back 39

Can be autosomal dominant
- Inherited from carrier parent or germline mutation
- Bilateral = probably inherited, small chance of randomly getting in both eyes

Front 40

Retinoblastoma pathogenesis

Back 40

Tumor supressor gene RB1 on Chr. 13
- RB1 in nucleus, controls transcription
- Loss of function, over-phosphorylated (inactivated)

Front 41

Mendelian vs. Sporadic cancer

Back 41

- Mendelian = already have 1 mutant copy, only need 2nd hit
Bilateral, early onset, multiple tumors
- Sporadic = need 2 hits, each independent somatic events
Unilateral, later onset, single tumors

Front 42

Breast cancer

Back 42

Mutations in BRCA1 & BRCA2 are "1st hit"
- Presence of mutations = higher likelihood of cancer development
- BRCA2 = risk to male carriers also

Front 43

Familial adenamatous polyposis (FAP) Inheritance

Back 43

Autosomal dominant

Front 44

Familial adenamatous polyposis (FAP) pathogenesis

Back 44

APC gene usually helps degrade β-catenin (cell proliferation)
- Loss of APC = more β-catenin, uncontrolled proliferation

Front 45

FAP symptoms

Back 45

Heterozygotes dev benign tumors early in life - usually get 2nd hit, become malignant

Front 46

FAP treatment

Back 46

Surgical removal of colon
- Frequent colonoscopies (family also)

Front 47

Hereditary Non-polyposis Colon Cancer (HNPCC) inheritance

Back 47

Autosomal dominant

Front 48

HNPCC pathogenesis

Back 48

Mutations in MMR genes
- Defective/absent DNA repair
- High microsatellite instability - only present in tumor cells

Front 49

Cancer cell epigenetic markers

Back 49

- Hypomethylation - activates genes that are normally tightly controlled
- Hypermethylation - suppresses control mechanisms

Front 50

Sporadic vs. Inherited Cancer

Back 50

Sporadic cancer requires 2 random "hit" events
- Inherited cancer = already inherit 1 "hit", much more likely to get the 2nd...