Introduction of Cancer

What is Cancer?

Uncontrollable growth.

Cancer Classification

  1. Carcinoma: arise in epithelial tissue that is found in the internal and external lining of the body
  • Adenocarcinomas develop in an organ or gland
  • Squamous cell carcinomas develop in the squamous epithelium of organs, including the skin, bladder, esophagus and lung
  1. Sarcoma: arise from connective tissue that is found in bones, tendons, cartilage, muscle and fat
  2. Leukemia: cancers of the blood that originate in bone marrow
  3. Lymophoma: cancers of the lymph system

Cancer Incidence

Diagnosed <-> Death -> Population

  1. Lung cancer: hard to find out in early stage, thus death rate is high
  2. Colon cancer: screening has high accuracy, cancer could be removed if found
  3. Breast cancer: curable if found early. adenocarcinomas is the most commonplace type. no known proven strategies for prevention. BRAC1/2 mutation.
  4. The Prostate: curable if found early. ethnicity and family history is clear risk factor. no known prevention strategies.
  5. The Liver: no proven strategy for screening. diagnosed = death -> not detectable in early stage. Hepatitis B/C or alcohol -> chronic damage (cirrhosis) -> genetic damage -> cancer. Hep B/C is endemic in Asia.
  6. The Stomach: no proven strategy in screening. more common in man. H. pylori -> chronic damage -> genetic damage -> cancer

Genetics of Cancer

  1. DNA genes: road
  2. Gene expression: traffic pattern
  3. Epigenetic regulation: traffic light that regulate what genes are transcribed to RNA in each cell
  4. Oncogene: gas, promotes cancer
  5. Tumor suppressor: brake, protects against cancer (high in normal cell, low in cancer)

Genetic Variation and Mutation

A single mutation is not sufficient to induce cancer formation.

Most genetic variation is benign. Small variations in one or a few bases of the DNA in particular place is what makes us different——polymorphisms (SNPs).

Cancer is caused by an accumulation of detrimental variation in the genome.

Types of Mutation

  1. Activating: causes the gene to be expressed at the wrong time, wrong level or with a new function

Activating mutations in oncogenes are tumorigenic

  1. Inactivating: causes reduced functinon of a gene (less RNA or protein is made)

Inactivating mutations in tumor suppressors are tumorigenic

Two-Hit Hypothesis and Genomic Instability

Where do mutations come from

  1. somatic mutations: acquired by a somatic cell (all cells except eggs or sperm) that are passed on to daughter cells during cell proliferation. these mutations can't be inherited by offspring.
  • everytime a cell divides, it must replicate its DNA -> errors get made by chance, about 1 mutation every 10 billion base pairs
  • increased DNA damage and replication error can be due to environmental carcinogens. such as UV damage to skin cells, chemical damage to lung cells (smoking), hepatitis leading to damaging cirrhosis of liver cells.
  1. germline mutations: present in a germ cell (egg or sperm) and inherited by offspring
  • however, as cancer is caused by an accumulation of detrimental variation in the genome, thus, for example, not all women who inherit a BRCA1/2 mutation develop breast cancer

The biggest risk factor for developing cancer is aging-over time, we accumulate mutations that arise by random replication error or by exposure to carcinogens that increase DNA damage

Two-Hit Hypothesis

Humans have two copies of every gene ("diploid")- one maternal, one paternal

Even if one copy (allele) of the gene is mutated, the other copy allows the protein to operate normally.

For a gene to be cancer inducing, both copies of the gene must be affected. The second "hit" may alter the DNA (mutation) or alter the expression of the DNA (epigenetic).

Most Cancer Requires Mutations in Multiple Different Genes

To survive, a cancer cell must overcome normal regulation of:

  • cell proliferation
  • cell survival
  • cellular communication

Each of these processes is tightly regulated in normal cells by redundant pathways.

To become cancerous, a cell must accumulate mutation (minimum 6-7) in multiple different genes.

Cancer Cells Show Genomic Instability

  • Genomic instability: can survive and divide with higher rates of mutation than normal cells
  • Normal cell: DNA replication error -> programmed cell death
  • Cancer cell: DNA replication error -> cell continues to divide and passes mutation As mutations in these repair pathways accumulate, the frequency of mutations in the cancer cell genome increases