Topics A58-62. Neoplasm 2: Oncogenes, Tumor Suppressor Genes, DNA Repair, Telomeres, Epigenetics, Genetic Cancers Flashcards
What are the 4 things that can be genetically altered which relate to cancer development?
- Oncogenes
- Tumor suppressor genes
- DNA repair genes
- Telomer and telomerase
What is the difference between a protooncogene and an oncogene?
Protooncogene: normal gene that produces proliferatory signaling molecules to help the cell grow. The production is coordinated, can turn on and off
Oncogene: mutated form of a protooncogene that functions autonomously, overproducing the normal growth-promoting signals
What are the 4 types of mutations to know related to oncogenes?
- Point mutation / Deletion / Insertion
- Translocation: Promoter Exchange
- Translocation: Fusion gene. (Breaking in the exons -> fusion of 2 genes -> new hybrid gene -> new protein)
- Gene amplification: Everything is fine, but just coding unusually high amount
What is an example of point mutation creating an oncogene?
EGFR: Epidermal Growth Factor Receptor. Importantly controls cell growth and proliferation, allows MAPK, STAT, and AKT.
With oncogenic mutation, the intracytoplasmic domain mutates -> continuous cell prolferation, transcription, and cell cycle progression
What is an example of promoter exchange in oncogene formation?
BCL2 protooncogene: BCL2 is normally an anti-apoptotic protein. BCL2 protein blocks apoptosis by forming heterodimer with BAX/BAK
Chromosome 18 is Ig heavy chain gene, and chromosome 14 where BCL2 is coded.. they break and form a hybrid where BCL2 is coordinated by enhancer/promoter of Ig heavy chain gene.
What is an example of gene fusion in oncogene formation?
t(9:22) translocation: “Philadelphia chromosome” - Breakpoint Cluster Region (BCR) is on chromosome 22, fuses with 9 -> chronic myeloid leukemia
Fusion gene activates JAK-STAT, SRC, RAS etc all cell proliferation, plus suspends BCL2 activity in blocking apoptosis
What is an example of gene amplification?
What are 2 ways that gene amplification may appear / be physically manifested?
HER2 is amplified in 30% of breast cancers. HER2 is an epidermal growth factor-like receptor (EGFR)
May see extended chromosome regions, or see small aggregates of extrachromosomal DNA called “double minutes”
What is the double-hit theory (of Knudson)?
Because we have two alleles, just one mutating is not usually enough to be a problem. Have to have a “double hit” - both alleles mutated. Usually one allele is inactive from hereditary cause, and then the other one is mutated sporadically (point mutation etc). First mentioned for retinoblastoma.
Doesn’t apply to oncogenes, but it does apply to tumor suppressor genes
What are tumor suppressor genes?
Genes that encode proteins that inhibit cellular proliferation, for example by regulating the cell cycle
What are the 5 ways that tumor suppressor genes can be mutated/inactivated?
- Loss of Heterozygosity (LOH): both alleles inactivated
- Point mutation/deletion: causes stop codon, missense etc
- Hypermethylation: epigenetic inactivation of promoter region
- Transdominant gene: mutant gene complexes with non-mutant one, but silences the protein
- Haplo-insufficiency: one allele is silenced, and the other is too weak / insufficient. Need product of both alleles to work.
How does the retinoblastoma (RB) tumor suppressor gene work?
Which tumors is RB silencing implicated in?
RB binds to E2F nuclear transcription factor when it’s unphosphorylated, preventing transcription. If RB is deleted, then E2F is free to transcribe uncontrolled.
(This is in G1/S checkpoint regulation. CDK4,6 binds to cyclin D, the complex phosphorylates RB and frees E2F to promote transcription)
Retinoblastoma, osteosarcoma from hereditary neoplasms, but RB sporadic mutation involved in breast, colon, and lung cancer (remember additional mutations must also be present)
What is p53 normally linked to?
What happens to p53 if there is a mutation detected in the cell? (3 things)
Normally linked to MDM2, without that it’s degraded quickly.
If there is a detected mutogenic effect, p53 is activated and then activates other genes:
- Genes for DNA repair
- Genes that stop cell cycle (like RB)
- If it can’t be repaired, activates genes that initiate apoptosis (BAX, APAF1)
Hereditary mutation of the APC gene is involved in which cancer?
What is the mechanism?
Adenomatosus polyposis coli
β-Catenin Pathway: APC and β-Catenin are together in the “destruction complex” - blocks the activation of cell proliferation signal transcription. If there is WNT signal, β-Catenin separates and forms new complex that promotes transcription.
Mutation of APC in adenomatosus polyposis coli: there is then no downregulation of β-Catenin, so it continues to promote transcription that activates the cell cycle -> colon cancer
What are 3 types of DNA repair from lecture? (There are others though)
- Mismatch repair: if opposing nucleotide is incorrect (not A-T, C-G)
- Nucleotide Excision Repair: usually repair of thymidine dimers
- Double-break DNA Repair
What are the proteins that perform mismatch repair?
MSH2-MSH6 or MSH2-MSH3 proteins
Colon, GI tract cancers are common from mutations of these proteins
When is nucleotide excision repair usually needed?
How is it performed? What are some important proteins involved in the process that, if mutated, cancer can develop?
Commonly needed after UV radiation that makes thymidine dimers that block transcription of DNA.
XPC-R23 (A xeroderma pigmentosa protein) detects the thymidine dimer. Proteins (complex with XPA, XPG, XPC etc) cut out the DNA of one strand then synthesize normal DNA based on complementary base pairs
Mutation of any of the XP_ proteins can lead to skin cancers.
What usually causes double-break DNA damage?
What are some proteins involved in its repair?
Usually occurs after ionizing radiation
ATM protein recognizes, then a BRCA1/BRCA2 complex that helps repair.
Mutation of BRCA1 or BRCA2 is involved in breast, ovarian and prostate cancers
Mutation of ATM also involved in cancers.
What are telomeres?
Repeating sequences of DNA at the end of the chromosome, which protect the genetic material.
Without telomerase activity (only active in germ, stem, and cancer cells) to renew the telomeres, some part of them is lost with each division. The progressive shortening of telomeres means that cells have a limited capacity to divide - the # of cell cycles is determined by # of telomeres, after which they go into sensecence
If the telomeres of a cell are missing, how does the DNA repair system interpret this?
Loss of telomeres means the chromosome edges are interpreted as a double-stranded DNA break. Attempts homologous recombination, but it makes a decentric chromosome that’s large and fragile, breaks. Cycle will occur with breaking, fusion, breaking, fusion, and so on. Causes heterogenous genetic malformation. Every break can make activation of oncogene or inactivation of a tumor suppressor gene.
This cycle may also reactive telomerase. If cells regain telomerase activity, they will be immortalized neoplastic cells with complex genetic malformations
Epigenetic changes: which enzyme performs DNA methylation? Which nucleotide does it methylate?
What is the effect of DNA methylation?
DNA methyltransferase
Methylates cytidine (technically deoxycytidine -> 5-methyl-cytidine)
DNA hypermethylation silences the genetic region because the DNA coils around histone more tightly
What are some important genes that can be silenced by DNA hypermethylation, thus contributing to cancer development?
Promoters / tumor suppressor genes (RB, APC, ARF, BRCA1, hMLH1, etc)
What are microRNAs (miRNA)?
Small DNA fragments that are non-coding but contribute to regulation by inhibiting gene expression.
A form of epigenetic regulation
How do miRNAs regulate gene silencing?
miRNA bind to RISC: RNA-Induced Silencing Complex
RISC-miRNA complex finds the complementary sequence of messenger RNA (mRNA), then either blocks translation there, or they degrade the mRNA
Can either silence tumor suppressors, or poor expression of miRNA can allow proliferation of oncogenes.
How many different gene mutations are usually necessary in a cascade that leads to cancer?
At least 15-20 mutations
Cancer requires many mistakes to really develop.
What is epigenetic regulation?
card should have been in earlier but got deleted bc brainscape is glitchy
Reversible, heritable change that develops during lifetime, occurs without mutation.
Occurs via DNA methylation, histone acetylation, or miRNAs
What are the 3 most important examples of autosomal dominant mutations associated with cancer?
- Retinoblastoma mutation: RB1 mutation is first hit for retinoblastoma, osteosarcoma risk. Still need double-hit.
- APC mutation: β-catenin etc. First hit. Second hit causes adenomatous polyposis coli
- Li-Fraumenni Syndrome: p53 mutation. 50x risk of cancer by age of 50: many possible cancers (sarcomas, breast cancer, etc)
How do autosomal recessive mutations related to cancer differ from autosomal dominant ones?
Autosomal recessives usually have lower penetrance, and are involved in mutations of repair mechanisms
What are 3 examples of autosomal recessive
- Xeroderma Pigmentosa: defects of XPA-XPD. Poor correction of thymidine dimers -> skin cancer
- Ataxia Teleangiectasia: ATM is defective, homologous recombination repair defective. Related to breast cancer, lymphoma, hepatocellular carcinoma
- Bloom Syndrome: BLM gene is defective, causing mutated DNA helicase and genomic instability. Related to leukemias, lymphomas, carcinomas.
What is meant by “familial cancers?”
Cancer that occurs in families more often than would be expected by chance. These cancers often occur at an early age, and may indicate the presence of a gene mutation that increases the risk of cancer. They may also be a sign of shared environmental or lifestyle factors.
Familiar cancers of uncertain inheritance: no specific marker phenotypes or genes like BRCA1 has been found, yet higher incidence within the family. Virtually all common types of cancers that occur sporadically have also been reported to occur in familiar forms. Siblings have higher relative risk.
What are 3 examples of familial cancers of uncertain inheritance? (from Robbins)
- Breast cancer (not linked to BRCA1 or BRCA2)
- Ovarian cancer
- Pancreatic cancer
