genetic basis of cancer

mendels overview

one trait → one gene → 2 variants (alleles)

in menders work what kind of dominance

complete

genome can be described as

• specific constitution of an organism

• the complete genetic information of an organism

• full complement of genetic information of a species in the form of DNA sequence

chromosome can be described as

discrete linear DNA molecules present in the nuclei of eukaryotic cells

heritable phenotypes that do not involve alterations in the DNA sequence

most human traits are polygenic meaning

• determined by interactions between multiple genes and the environment

genes overview

• genes determine phenotupe

• located on chromosomes

human chromosome 1 has around ____

2000 genes

homologous chromosomes

• two copies of each chromosome

• one from each parent

• same genes in the same order

alleles

a variation of the gene

the functional region of a chromosome

gene that codes for regions or functional mrna or proteins

gene regions

• direction of transcription

• can overlap with each other

• can go in the same or opposite strand.

homologous chromosomes

• two copies of each chromosome, one from each parent

gene sequences account for ______ of the genome

less than 5%

along the chromosome if it isn’t part of a gene

noncoding, junk intergenic regions

mb

• megabases

• a unit that measures in 1 million nucleotides

selected mutation

• mutation on coding sequence

• defective phenotyoe

• inability of organism carrying mutant allele to compete

• loss of allele from gene pool

neutral mutation

• mutation in the junk dna

• no effect on phenotype

• no reduction in ability to compete

• retention in gene pool

mutant alleles tend to be selected against or for?

against!

genetic polymorphisms

changes in non functional regions

• retained

mutant allele

• affect in protein product

• in coding region, in regulatory region

23 and me type of dna sequencing will pick up in

genetic polymorphisms based off of ancestry

23 and me like dna companies are or aren’t sequencing your whole dna

aren’t

• only at certain genes

give an example of conservation of gene sequence

• human protein sequence aligned with a corresponding protein produced by two yeast species

• last common ancestor over 2000 years ago

how do we number chromosomes on karyotypes

1 is the longest 22 is the shortest

centromeres in chromsomes via karotypes

• centromere is not in the exact middle

• shorter at the top

• longer at the bottom

karyotype in pancreatic cell example

mutations of chromosomes translocated to other areas

• changes at the genomic level are greater than those at oncogenes etc

• as cancer progresses the cancer cells undergo further mutations

different ways to visualize the human karyotype

• FISH

• scanning electromicroscope

• gene mapping

genes encode proteins and

proteins carry out specialized functions

where is the regulatory region

between 5’ start and promotor

where does the coding region start and end

transcription initiation region and termination region

what is added after transcription

a 5’ cap and a 3’ poly-A tail

after transcription what happens in processing before translation

intron splicing

from genotype to phenotype starts

• transcription bt RNA polymerase II

• Dna become hnRNA (pre mrna)

genotype to phenotype mrna processing

introns are spliced and discarded

from genotype to phenotype: translation

mature mrna is exported to the cytoplasm

• associates with ribosomes and then synthesizes protein into the cytoplasm

alternative splicing results in

• multiple protein products with slightly different functions from the same gene

transcription factors do what

• regulation of gene expression

give an example of transcription factors

• tata binding protein

• TFIIA, TFIIB, TFIIE, TFIIF, TFIIH

Chromatin modification via epigenetics

alters how tightly the DNA is packaged and regulates access to the promoter

DNA methylation

• mostly on cytosine sometimes on A

5- methylcytosine

leads to transcriptional repression

cpg-islands

• Short DNA regions with a high concentration of cytosine (next to guanine) nucleotides that regulate gene expression

where are CpG islands mostly found

promoters

• both C’s in the 5’3 and the 3’5 will be methylated

aneuploidy

• abnormal number of chromosomes in a cell

• in 90% of cancer cells

mutations that occur from one generation to the next

germ line mutations

• mutation must strike a gene carried in the genome of sperm or egg or precursor to the gametes

mutations that effect the genome of cells outside of the gametes

• called somatic mutations

• can affect the behavior of the cell

• starts as a progenitor cell and through division forms a “clone” of millions/billions of mutated cells within a tissue

RNA polymerase II

• responsible for going from DNA to mRNA

• first creates heterogeneous nuclear RNA (pre mrna)

• progressive splicing will lead to exons only - mrna

epigenetics

• regulation of gene expression

• changes that affect gene expression without altering DNA sequence

example of epigenetics

• affect dna packaging

  • chromatin histone modification

    • acetylation, methylation, phosphorylation

  • dna - methylation

  • regulates access to the promoter

epigenetic of histone mod and dna mod

• called transgenerational

histological sections in tumors

• thin slices of tissue stained with different dyes or other reagents to reveal tissue architecture and components

histology is described as

microscopic analysis of sectioned tissues

histology can reveal

• overall tissue type

• types of cells present within the tissue

• surrounding supportive structures (stroma)

what defines the tumor type?

tissue of origin and cell type of origin

histopathology

• comparing diseased tissue to normal tissue

found in histopathology how can metastases be ID’d

• histological hallmarks of their original tissue of origin

why do epithelial tumors end up being 80% of cancer related deaths

more exposure to the elements and be influenced

benign tumor

grows locally does not invade adjacent tissues

malignant tumor

invades nearby tissues, spawns metastases

epithelial cell structure

• lumen (cavity)

• epithelium

• basement membrane (ECM)

• stroma

• (sometimes stem cells if in lining of stomach)

epithelia is described as

sheets of cells that line the walls, cavities and channels of our body as well as outside covering

epithelia have two major functions

• cells that serve to seal the cavity or channel they line

• cells that secrete substances into the ducts or cavities they line

squamous cell carcinoma

• come from epithelial cells that seal the cavity of channel they line

adenocarcinomas

• come from cells that secret substances into the ducts or cavities they line

epithelial tumors

• carcinomas

• 80% of cancer related deaths in the western world

• adenomas, squamous cell carcinomas

connective tissue tumors

• called sarcomas

• 1% of tumors encountered

types of sarcoma

• osteosarcomas

• liposarcoma

• rhabdomyosarcoma

hematopoietic tissue tumors

7% of tumor associated mortality in the US

• lymphomas (solid tumor masses)

• leukemias (dispersed in circulation)

tumors of the nervous system

• 2.5% of tumor related deaths

• ex gliomas, blastomas, neuroblastomas

atypical cancers

• dont fit into classifications and cells of origin are unknown

• ex: melanoma, small lung carcinoma, teratoma

monoclonal tumors

• arise from one parent cell

• subsequent mutations create a heterogeneous tumor (subclonal)

a-typical tumors

• dont fit into other classifications/cells of origin unknown

types of a typical tumors

melanoma, small cell lung carcinoma, teratoma

monoclonal growths

• descended from a single cell

• as tumors grow, they get more mutations and become unstable

tumors and sub clonal growths

• as tumor cells accumulate mutations in different genes, tumors become heterogeneous

epidemiology and cancer

• incidence of specific cancers differs in different regions and genetic populations

tumor phenotype

• associated with alterations in genes

• usually more than one

the Philadelphia chromosome

• recirprocal translocation between chromosome 9 and 22

• often responsible for chronic myelogenous leukemia

cancer types and diff populations

some populations are more likely to have diff TYPES of cancer. no one population is susceptible to all

cancers and different frequency across human populations can potentially be explained by

• genetic differences between diff populations

• environmental factors

exposure to carcinogens

• the more likely that there is mutation that causes cancer

carcinogens are mutagenic explain

• mutations do not have a preference for causing cancer (random)

• however the more exposure, the more mutations and likely they will

examples of chemical carcinogens

• polycyclic aromatic hydrocarbons (combustion, cigarette smoke)

• arsenic, asbestos, benzene, radium

• alkylating agents (things that damage DNA)

ionizing radiation as carcinogenic exposure

x rays, gamma rays

types of viruses that cause cancer

Eipstein-Barr virus, hepatitis B virus, hepatitis C virus, HPV

how many base pairs in a diploid cell

6.4 billion

dna polymerase error rate

1-10k to 1-1000k bases

chance of an uncorrected mutation per cell division

1 in 10B

what percent of our genome codes for proteins

1.2%

genes and their regulatory elements make up for how much of our genome

25%

the average human adult stem cell accumulates how many mutations each year

about 40

the number of stem cells in the colon and how often they divide

200k, once a week

viruses and cancer

• are not random mutations

• can disrupt genomic DNA by insertion

• more common that a virus carries an oncogenic version of a gene

mutagens can include dna damage but can also

cause tissue damage and increase stem cell proliferation rates

carcinogens causing cancer is not a good way to describe it explain

• it increases likelihood of mutations not necessarily directly causing cancer

the four types of tumors

epithelial, mesenchymal, hematopoietic, neuroectodermal

true or false cancer can develop progressively from benign to metastatic

true

hyperplasia and dyplasia

hyperplasia = lots of normal cells

dysplasia = abnormal cells

true or false benign tumors are only hyperplastic

false, can be dysplastic (precancerous)