Cancer & Population Genetics

how does cancer arise

mutations is somatic cells, when it occurs in cell division

• mutation is transmitted to progeny cells

• individual is mosaic for mutation

what are some of the abnormalities of cancer

1. uncontrolled growth

2. the ability to spread/metastasize

what are some main reasons for cancer abnormalities

• insensitivity to anti-growth signals

• evasion of apoptosis

• self sufficiency in growth signals

• sustained angiogenesis

what are 4 classifications of cancer types

carcinomas - epithelial cells

sarcomas - connective/muscle tissue

leukemia - hematopoietic/white blood cells

gliomas - nervous system

describe the development of cancer

1. abnormal cells, no proliferate = no cancer

2. abnormal cells, proliferates uncontrollably = tumour

3. clustered cells, no invasion = benign

4. neoplastic cells invade other tissue = malignant

what are different primary tumors

basal cell carcinoma

• origin = basal cells of epidermis

• only locally invasive

melanoma

• origin = melanocytes

• aggressive invasion

what are some genetic causes of cancer

1. single nucleotide substitutions (SNPs)

2. chromosome arrangements (gains/loses, translocations)

3. integration of virus into chromosome

4. inappropriate DNA de(methylation) - epigenetic changes

why is cancer infrequent despite many daily mutations

cancer development requires several independent mutations in a single cell

• many cancer cells have mutations in genes controlling growth, division, apoptosis

what are proto-oncogenes

gene regulatory proteins, promote

• cell division

• cell survival

• can be involved in cell-cell signaling

• produce signaling proteins

what are the 4 main ways to convert proto → oncogene

1. recombination with retroviral DNA

2. deletion or point mutation

3. gene amplification

4. chromosome rearrangement

where can changes occur in proto-oncogenes

1. protein coding region - hyperactive protein

2. regulatory regions - over expression

what is chronic myelogenous leukemia

non-lethal overproduction of white blood cells, these have an abnormality - Philadelphia chromosome

• translocation between long arms of Chr 9 & Chr 22

• fusion protein Bcr-Abl has hyperactive kinase activity

continues for several years between rapidly deteriorating 

• early stage = cells show translocation

• late stage = several abnormalities, further mutations

what is Burkitt’s lymphoma

B-cell (antibody-producing cells) malignancy

• translocation = 8q11 to 14q32, or 2p11 to 22q11

what is some info on Bcl-2 gene

located on chromosome 18q21 - translocation may convert it to an oncogene

• inde

how does retinoblastoma form

Rb gene (-ve regulator of transcription)

• patients with hereditary form inherit loss or mutation in one gene copy and are predisposed to developing cancer

• sporadic event requires 2 independent mutations

what is loss of heterozygosity in retinoblastoma

initial mutation = chromosomal deletion / point mutation

• second copy of gene is lost/replaced by first defective gene

• can result in loh – daughter cell is now homozygous for the mutation

what is some info on the p53 gene

tumor suppressor gene with features of an oncogene

• mutant protein binds to wildtype blocking function

• dominant negative

normally low levels of p53 in cells but induced after DNA damage

• functions as a control to recognize DNA damage

what are some common treatments for cancer

• surgery

• radiation - solid tumors

• chemotherapy - targets rapidly dividing cells

• targeted therapy - monoclonal antibodies, inhibitors, etc

what is evolution

encompasses all changes in the genetic composition of a population over time

• not just adaptions but also genetic drift, gene flow and random mutation events

what is adaption

a subset of evolution, focusing especially on heritable, genetic changes that improve a populations ability to survive and reproduce

• cannot happen without a mutation

what is the hierarchy of impacts for mutations

• mutations that change protein sequence

• protein changes that cause changes in the cell phenotype

• phenotypes changes that change the fitness of organisms

what are some assumptions for the Hardy-Weinberg Equilibrium

• equal number of M/F

• random mating

• no selection

• no migration

• very large population size (no drift)

• discrete generation

what is the Hardy-Weinberg equilibrium

A² + 2Aa + a² = 1

allows comparison of the genotype frequencies predicted under the HWE to the actual genotype frequencies

what are the 4 steps for using the HWE

1. count genotype frequencies from a sample of population

2. calculate allele frequencies

3. calculate HWE genotype frequencies

4. compare expected & observed

when might there be a deviation from HWE

1. natural selection could affect the individual & genotypes

2. population structure - e.g. 2 islands, one is homozygous for allele a, the other for allele A. If you summed the allele frequencies without know about the islands you would predict the existence of heterozygotes.

3. assortative mating - individual might breed with individuals of similar genotype

4. inbreeding between individuals affects genotype of population

why are chi-squares used

compares the observed genotype counts with those expected under HWE