L1-2 cancer genetics flashcards

This set of flashcards covers essential vocabulary related to cancer biology and treatment, focusing on key concepts and definitions for exam preparation.

Heterogeneous Tumor

A tumor composed of a diverse mixture of cell types, leading to variations in genetic and phenotypic characteristics.

Oncogenes

Genes that promote cell growth and division, which can lead to cancer when mutated or overexpressed.

• mutations lead to dominant gain of function - promotes cell growth/division.

• not usually inherited

• dominant when inherited

Tumor Suppressor Genes

Genes that inhibit cell division and survival; mutations in these genes can result in uncontrolled cellular proliferation.

can be inherited - recessive

Selective Pressure

For cancer treatment, it refers to the application of therapies that eliminate certain cancer cells while allowing others to survive and potentially develop resistance.

Anaplasia

A condition of undifferentiated cells often seen in tumors, signifying a loss of normal cell features.

Angiogenesis

The formation of new blood vessels, which tumors stimulate to secure a blood supply for growth.

Intratumoral Heterogeneity

Variability within a single tumor mass, involving different cell subtypes and their unique genetic profiles.

Tumour Microenvironment

The surrounding cellular environment that influences tumor behavior and growth, including interactions with immune and stromal cells.

Genomic Instability

An increased tendency of the genome to acquire mutations, often contributing to cancer progression.

Four Main Stages of Cancer Progression

1. Initiation (abnormal cell proliferation)

2. Angiogenesis (developing a blood supply)

3. Invasion and Intravasation (entering the circulatory system)

4. Metastasis (spreading to distant sites and forming secondary tumors).

what are the intrinsic factors promoting cancer?

dysfunction in:

1. tumour suppressor + oncogenes

2. cell-cycle proteins

3. signalling pathways

4. chromosomal instability (2-hit)

what are extrinsic factors promoting cancer (Tumour microenvironment)

• soluble (growth) factors

• altered environment

• infiltration of immune cells

• ECM

• angiogenesis

what is the evidence supporting cancer as a genetic disease

• most carcinogens are mutagens

• cancer is not a contagious disease

• cancer incidence increases with age - accumulated DNA damage

• chromosomal instability common in cancer

• defects in DNA repair increases chances of developing cancer

what are the types of cancer genetic mutations

• germine vs sporadic

• mutations of tumour suppressor or oncogenes

• mutations of caretaker, gatekeeper, or landscaper genes

what are germline mutations?

mutations inherited from parent-offspring - present in all cells

what are somatic mutations

mutations acquired from cumulative damage to genes (sporadic) - in non-germline cells

proto-oncogene

normal functioning oncogene - promotes controlled growth/proliferation

what tumour suppressor gene causes retinoblastoma

RB1

what tumour suppressor gene causes familial adenomatous polyposis

APC gene

what tumour suppressor gene causes Li-fraumeni Syndrome

TP53 gene

what type of mutation causes the fusion of BCR-ABL gene in chronic myeloid leukaemia (CML)

translocation (of the Philadelphia (Ph) chromosome

(exception) family cancers linked to oncogenes

RET - causes multiple endocrine neoplasia type 2 (MEN2)

MET causes isolated hereditary papillary real cell cancer (HPRCC)

how are oncogenes activatied?

point mutations (Ras family genes) (usually missense)

amplification (Myc oncogene)

translocation (fusion protein BCR-ABL)

what type of genetic mutation is responsible for activating the oncogene H-ras in bladder carcinoma

missense point mutation (gly→val)

how are tumour suppressor genes mutations distributed on the gene?

usually spread across gene

evenly missense and premature termination codons (nonsense) point mutations

how are oncogene mutations distributed on the gene?

focused in particular regions/domains (Kinase)

biased towards missense point mutation

what are gatekeeper genes

genes that act directly on the cell-cycle to inhibit cell proliferation (tumour suppressor genes, some oncogenes)

what are caretaker genes>?

genes that act indirectly on the cell-cycle or proliferation that maintain genome integrity (health) (DNA repair genes)

disruption leads to genomic instability

what are landscaper genes?

genes that regulate the microenvironment and promotes the growth of cancerous cells (extracellular matrix genes)

what is genomic instability?

what is the role of DNA repair genes?

acts indirectly as ‘caretakers’ of genome integrity

what happens if DNA repair genes are inactivated by mutation?

• DNA damage going unrepaired

• accumulation of mutations in other cellular genes

• increases likelihood of damaging mutations other critical genes

why does inherited retinoblastoma occur earlier?

inherited RB only requires 1 occurrence of somatic mutation as there is already a pre-existing germline mutation present, whereas sporadic RB would require a SECOND somatic mutation.

difference between sporadic and inherited blastoma

inherited retinoblastoma

• autosomal dominant transmission

• RB1 gene localised on chromosome13

• Rb protein negatively regulates cell cycle

• 1 germline mutation, 1 somatic mutation

two-hit hypothesis

suggests that two genetic mutations are required for tumorigenesis.

1st hit is a germline mutation (point mutation)

2nd hit is a somatic mutation (LOH through mitotic recombination)

how does two-hit hypothesis explain sporadic retinoblastoma?

• sporadic RB requires two independent mutations

• rb1 allele is recessively acting

• following a single mutation, cell is left heterozygous (Rb+/-) and would exhibit wild-type phenotype

• therefore the other allele must be deleted for tumour development

sporadic retinoblastoma

Occurs when both RB1 alleles are mutated in somatic cells, leading to tumor development without inherited predisposition.

2 somatic mutations

why is sporadic retinoblastoma very likely?

retinal cells grow very rapidly in early life. the likelihood of a second somatic mutation is high when one gene is already out of action.

dominant inheritance of retinoblastoma

if you have 1 inherited copy of allele = 90% penetrance of RB

rb1 is a recessive allele

the rb1 allele must be mutated in both copies for retinoblastoma to develop; only one functioning allele is necessary for normal cell function.

allelic deletion (loss of heterozygosity)

mitotic recombination leading to loss of wild-type allele

haploinsufficiency (in tumour suppressors)

a condition where one functional copy of a gene is insufficient to maintain normal function, leading to tumorigenesis. (gene does not act recessively)

TP53 gene

encodes for p53 tumour suppressor protein

when DNA damage: p53 induces cell-cycle arrest for DNA repair to happen or induces apoptosis

multistep tumourigenesis

in sporadic cancers:

(aging, lifestyle, environment)

dominant negative effect exhibited by p53 inactivation

• p53 subunits form tetramer

• mutated p53 allele cancels out the normal function of p53

• only 1 mutated subunit is required for an inactive p53 protein

define multi-step model (tumourigenesis) of sporadic cancer

acquisition of multiple mutations that lead to cancer

example of multistep tumourigenesis

sporadic colorectal cancer:

• colon epithelial cells have high turnover (stem cells) - 15-20% cells die & replaced each day - HIGH RISK OF MUTATION

• mutations only required in ~5 critical genes for cancerous adenomas to develop

• requires screening every 5 years

BRCA1 and BRCA2

Genes associated with increased risk of breast and ovarian cancer when mutated; important for DNA repair.

anaplasia

A condition of undifferentiated cells often seen in tumors, signifying a loss of normal cell features.