Cancer – a disease of many mutations No two tumors are identical (or homogeneous), but are there common mutations that could help guide drug design?

Bert Vogelstein discusses the biology of cancer Clips 5-13 13 minutes

Let’s look at the stages in an epithelium An epithelium is a layer of single cells surrounding a tissue Normal epithelium Cells adhere to each other and a matrix in an organized manner Benign (in situ) tumors Cells lose orderly geometry and associate improperly Cells are still contained within the tissue boundary (blue) Benign tumors can be VERY LARGE! Majority of cancers originate in epithelia

Benign tumor is contained within the tissue boundary Malignant tumors break through the tissue boundaries Many secrete proteases that digest the matrix surrounding the tissue Metastatic tumors move to new sites in the body (meta-statis = “new place”)

Pathologists can identify cancers by their appearance Pap smears are used to detect cervical cancer Normal Malignant Metastatic Cervical cancer detected with a Pap smear 2

Hallmarks of cancer The challenge: to identify genes responsible for each of these characteristics Cell 100:57-70 (2000)

Many of the genes commonly mutated in cancer are often classified as: Oncogenes: drive growth mutation generates super-active protein Tumor suppressor genes: arrest growth, signal suicide mutations inactivate these include many checkpoint genes DNA repair genes: repair DNA damage mutations inactivate these

Bert Vogelstein discusses the genetics of cancer Clips 18-22 ( 10 minutes) 10 minutes

Random mutations accumulate throughout life Repair processes are not 100% efficient Intrinsic mutation includes errors in DNA replication and repair Environmental factors may increase the mutation rate

Vast majority of tumors appear in adult life Frequency increases with age Intrinsic processes Environment and lifestyle Mutations in growth promoting/suppressing genes are present in cancer cells Research challenge: distinguish passenger (circles) and driver (stars) mutations As tumors develop, the cell may become unstable, causing mutations to accumulate at a higher rate - mutator phenotype

In later (more lethal) stages of cancer, transformed cells break through the normal tissue barriers and move to new locations Intrinsic processes Environment and lifestyle Mutator phenotype

The timelines for acquiring mutations vary in each tumor Oncogene mutations usually occur early in the sequence Most tumors have an oncogene mutation Genes implicated in metastasis typically acquire mutations late in cancer progression

Why sequence cancer genomes? The hope: Chemists may be able to design highly targeted drugs that inhibit proteins implicated in tumorigenesis with minimal damage to normal cells

Challenge of drug design – identifying target proteins that drive cancer This growth-promoting pathways involves several proteins that are frequently over-produced or mutated in cancers.

Much data has been collected!

Mutations in the EGFR gene show tumor-specific patterns MS Lawrence et al. Nature 505, 495-501 (2014) doi:10.1038/nature12912

Some genes are frequently mutated in a particular kind of cancer Very few genes are mutated with >20% frequency Most genes are mutated at intermediate frequencies (2-20%)