13 - Molecular Mechanisms of Cancer

Based on this figure and your prior knowledge from the course, which of the following do you conclude:

A) The majority of human genomic DNA encodes biologically important information that cannot be disrupted in living cells

B) This cancer is caused by a mutation inherited from the patient’s parent

C) In the pancreatic cancer shown here, gene expression levels could be influenced by chromosome loss, translocation, and duplication

D) Only genetic changes occurring in regions of DNA that encode proteins are relevant to tumor progression

c

is cancer a new disease

Cancer is an ancient disease

The earliest mention of cancer comes from papyri of ancient Egyptians

but an understanding of cancer is recent

Histology

A branch of anatomy that studies the microscopic structure of tissues

A pathologist’s assessment of a tumor provides important information about

tissue of origin, diagnosis, prognosis, and treatment options

cancer stage

tumor size and location

How large is the tumor and has it spread to other tissues?

cancer grade

tumor morphology/structure and growth rate

How abnormal do the cells look and how fast are they growing?

why is determining the cell type of origin (and stage and grade) important when treating a cancer patient.

Cell type of origin reveals what normal cell the tumor came from—this informs drug response, molecular markers, and likely progression.

Stage (size and spread) helps guide treatment aggressiveness (e.g., localized vs metastatic).

Grade reflects how abnormal/dividing the cells are—high-grade tumors are usually more aggressive.

Different cancer types require different therapies, even if mutations are similar (e.g., lung vs colon cancer with same KRas mutation may not respond the same).

Explain what the Philadelphia chromosome is

• Philadelphia chromosome = reciprocal translocation between Chr 9 & 22 → Bcr-Abl fusion.

• Bcr-Abl = hyperactive tyrosine kinase → drives cell proliferation

why Philadelphia chromosome’s discovery supported the theory that cancer is a disease of altered hereditary material. 

• Proved cancer is a disease of altered chromosomes/DNA.
  
  

Describe what Bcr-Abl is and why it was a good drug target for development of Gleevec 

• Bcr -Abl is an in frame fusion of the coding regions of these genes caused by a reciprocal translocation between Chr 9 and Chr 22

• The abl tyrosine kinase domain becomes hyperactive in Bcr -Ab

• Gleevec targets Bcr-Abl kinase → effective especially in early-stage CML.

dominant vs recessive activities of oncogenes and tumor suppressors

• Oncogenes = gain-of-function → dominant (1 mutated copy enough).

• Tumor suppressors = loss-of-function → recessive (both copies must be lost).

Why does the landscape of mutations look so different in an oncogene vs tumor suppressor?

because oncogenes require specific gain of function mutations, often missense clustred in soecific regions, while tumor suppressors undergo widespread los of function mutation, including truncrating mutation to disrupt their function

mechanisms that could lead to activation of an oncogene

Oncogenes: point mutations (e.g., Ras), gene amplification (e.g., Myc), chromosomal rearrangements (e.g., Bcr-Abl).

mechanisms that could lead to suppression/loss of a tumor suppressor

Tumor suppressors: deletions, LOH, promoter methylation, nonsense mutations, dominant negative mutations (e.g., p53).

Explain why most people who inherit a mutation in Rb from a parent eventually develop retinoblastoma in both eyes 

Once one copy of a tumor suppressor is mutated, there is an increased likelihood of loss of the remaining functional copy

Homologous recombination (homology directed repair) uses another chromosome as a template and is more active in mitotic cells. This type of repair can lead to loss-ofheterozygosity (LOH = “gene conversion”)

tumor microenvironment

the surrounding network of extracellular matrix, signaling molecules, and cell types such as immune cells, fibroblasts, blood vessels and resident normal tissue

- This is also referred to as the tumor stroma, which is a term for the supportive connective tissue and blood vessels in an epithelial organ (can make up to 90% of a tumor!)

tumor microenvironment’s role it has in tumor progression

Clonal evolution of cancer:

In the early stages of disease progression, genetic changes promoting cancer (ex. enhancing growth rate) arise and are inherited by daughter cells leading to clonal expansion as these cells outcompete their slower growing neighbors

Clonal expansions are further shaped by additional factors such as therapeutic intervention and metastasis

Heterogeneity

critical part of cancer genome evolution

Tumors are continually evolving

Driver mutations arise that cause expansion of unique subpopulations

Cancer can arise from between 2 and 20 key driver mutation

Genetic instability

promotes tumor progression

Chromosome abnormalities are a widespread feature of cancers

Extent of abnormalities correlates with clinical progression

what pathways are most frquently altered in cancer

Pathways involved in DNA damage response and repair

More cell division =

greater cancer risk

correalation between number of stem cell division and cancer risk

cyclins and cyclin-dependent kinases (Cdks)

control the different phases of the cell cycle

Rb

restricts entry into S phase

Hypophosphorylation of Rb prevents transcription of cyclin that initiates S phase

Hyperphosphorylation of Rb at the R point allows initiation of S phase (DNA replication)

Rb regulates the E2F transcription factor

Hypophosphorylated Rb binds E2F & prevents transcription

Hyperphosphorylated Rb (at the R point), releases E2F.

E2F then drives transcription of a cyclin the initiates S phase (DNA replication)

what does HDAC recruitment do?

they methylate → condense genes

Tumor progression requires loss of both copies of

Rb

MOST commonly mutated gene in cancer

p53 tumor suppressor

Humans who inherit a p53 mutation (Li-Fraumeni syndrome) are at high risk for many types of cancer

p53 in normal cells

Stresses activate p53 in normal cells

regulated primarily through degradation

regulation of p53

In non -stressed cells, the MDM2 ubiquitin ligase targets p53 for rapid degradation

Stress results in phosphorylation of p53 at the MDM2 binding site

Phosphorylated p53 is not degraded and can stimulate transcription of a variety of genes (Ex: for DNA repair, halting cell cycle, or promoting apoptosis)

Apoptosis is an important part of both development and tissue maintenance that becomes impaired in cancer cells

p53 function can be lost by

dominant negative missense mutations

p53 functions as a tetramer Even one mutant subunit in the tetramer makes the whole thing inactive

Mutations in the p53 enable cancer cells to

survive and proliferate despite stress and DNA damag

Hereditary cancers -

Inherited genetic variants have been linked to 5-10% of cancers in the U.S. -

Sporadic cancers

are caused by the accumulation of mutations that were not inherited from an individual’s parents

Carcinogen

An agent that causes cancer

Mutagen

An agent that causes genetic mutation

Chemotherapy and radiation therapy

preferentially target dividing cells and induce DNA damage