Genetics Of Cancer

The Big Picture A few cells probably escape the controls of the cell cycle in each of us, but are usually silenced by the immune system. In one in three of us, though, such errant cells continue to divide and invade healthy tissue, causing cancer. The many forms of cancer reflect mutations in particular cell types

History of Cancer Egyptian mummies from 3000 B.C. show signs of cancerous tumors By 1600 B.C. Egyptians were attempting to treat cancer by cutting or burning off the growths By 300 B.C. Hippocrates had described several types of tumors and coined the term “cancer” to describe the crab-like shape of a tumor cell.

What is cancer? Overview Collection of diseases that reflect malfunction of the cell cycle that can be set in motion by environmental factors Sequences of mutations in somatic cells and gene expression changes underlie the progression of cancer as it spreads Diagnosis and treatment is becoming more individualized due to genetic and genomic approaches Only about 10% of cases are inherited as single gene disorders where faulty instructions are found in every cell. Cancer is usually a genetic disease at the cellular level, but not the whole body level-as mutations in cancer causing genes generally affect a few somatic cells over a lifetime

The complications of being Specialized Cancers are a complication of our being both multicelluar and specialized… Cells must follow a schedule of mitosis-the cell cycle so that organs and other body parts either: grow appropriately during childhood, Stay a particular size and shape Repair damage by replacing tissue Cell that escapes the normal controls on its division Forms a tumor in solid tissues Divides more frequently and takes over normal cells in non-solid tissues like blood Tumors are Benign if it grows in place but does not spread into or ‘invade’ surrounding tissues Malignant, or cancerous, if it infiltrates surrounding tissue Metastatic if they send parts of them selves into the bloodstream or lymph and are transported as ‘seeds’ to other tissues

Oncogenes and tumor suppressor genes A gene that causes cancer when appropriately activated More than 100 have been discovered by focusing on genes in chromosome regions whose protein products could affect cell cycle control Tumor Suppressor Genes Cause cancer when they are deleted or inactivated More that 30 have been identified Normally function to keep cell cycle running at appropriate rate for a particular cell type under particular conditions

Loss of Cell Cycle Control Timing, rate and number of mitoses a cell undergoes depend on protein growth factors and signaling molecules outside the cell and on transcription factors within These biochemicals are under genetic controls, so is the cell cycle The discovery of the checkpoints reveal how cancer can begin A mutation in a gene that normally halts or slows the cycle can lift the constraint leading to inappropriate mitosis Failure to pause long enough to repair DNA can allow a mutation in an oncogene or tumor suppressor gene to persist

Cancer and Telomere Length Loss of control of telemere length may also contribute to cancer Normally, telemere repeats are lost as the cell matures from 15-40 nucleotides per cell division. The more specialized the cell, the shorter its telemeres; like nerve and muscle. Sperm and oocyte are very long The enzyme telemerase keeps telemers long by adding 6-base repeats(TTAGGG)…in specialized cells enzyme is turned off, signaling a halt to cell division when they reach a certain size In cancer cells, the enzyme is turned back on and releases the normal brake on rapid cell division The longer the telemeres in cancer cells the more advanced the disease

Inherited versus Sporadic Cancer SPORATIC INHERITED Most cancers Found only in cells of affected tissues Somatic mutations May result from single dominant mutation or 2 recessive mutations in the same gene causing loss of cell cycle control Susceptibility is not directly passed to offspring Rare, but, high penetrance, occur earlier in life Cancer susceptibility is directly passed to offspring Germline mutations are in every cell, including gametes Cancer develops when second mutation occurs in the other allele in a somatic cell in the affected body part

Lung Cancer: from both perspectives Germline mutations may explain why some heavy smokers develop lung cancer while others do not; unlucky ones have may have inherited a susceptibility allele in every cell Years of exposure to carcinogens eventually cause a mutation in a tumor suppressor gene or oncogene of a lung cell Without the susceptibility gene, two such somatic mutations are necessary to trigger the cancer This too can be the result of exposure to carcinogens, but, it takes longer for the two events to occur than one

Characteristics of cancer cells

Cancer Cells… Grow alarmingly fast: by time tumor is the size of a pea= billions of cells are actively dividing, eventually grows faster than surrounding tissue because greater proportion if cells are dividing Look different than a normal cell: rounder because membrane is more fluid, contain different antigens on surface Are heritable: when cancer cell divides all daughter cells are cancerous Is transplantable: if injected into healthy tissue of same species it will proliferate Are differentiated: less specialized than normal cells near it, cancer cells pile up and crowd other cells Are invasive: have surface structures that enable them to squeeze into any space, grow irregularly as they invade tissue spaces Metastasize: eventually reach the bloodstream or lymph and are carried to other parts of the body Stimulates angiogenesis the tumor causes nearby capillaries to sprout new branches to provide the tumor with oxygen and nutrients

Breast Cancer: BRCA1 and BRCA2 Inheritance of germline mutation and then having a somatic mutation occur in a breast cell Only 5% of all breast cancers are familial, caused by mutations in any of more than a dozen different genes Mutations in DNA repair genes cause this type of cancer BRCA(breast cancer predisposition gene)1 and 2 are major susceptibility genes; account for 15-20% of familial cases Deletion-frame shift mutations result in shortened proteins, that form a complex that breaks both strands of DNA at same site, cutting chromosome making translocations and deletions possible Inheritance is autosomal dominant with incomplete penetrance

Cancer cells that look alike may be genetically distinct…take leukemia cells

Personalization of cancer Diagnosis and treatment Oldest treatment is surgery to remove the tumor Radiation and chemotherapy which kill all cells that divide rapidly, however, also affect healthy cells: digestive tract, hair follicles, bone marrow Newer treatments target receptors on cancer cells, block telomerase, stimulate differentiation; or attack a tumor’s blood supply

Examples of cancer Genetic vs environmental