The Genetics of Cancer

Newspapers, magazines, radio, and television are reporting discoveries and breakthroughs attributing one form of cancer or another to a specific gene.

Cancer of the breast, colon, prostate, and many other sites in the body are being connected to specific genes... But the meaning of this isn't always clear.

•What does it mean for you if your mother has or had breast cancer... or an aunt and two cousins have colon cancer?

•What does it mean for your children if you've been diagnosed with cancer of the endocrine glands or some other organ?

Cancer in the media

cancer is a disease of the cell cycle

Types of genes which may mutate to cause cancer:

• Tumour suppressor genes

• oncogenes

• DNA repair genes

• telomerase

• p53

The environment:

Some environmental agents associated with cancer are: • Viruses • Tobacco smoke • Food • Radiation • Chemicals

• Pollution

VirusesViruses—mostly in the form of DNA viruses—have been causally linked to cancer.

• human papillomaviruses—primarily types 16 and 18, which are sexually transmitted—have been linked to cervical cancer;

• more than 25 other types of papillomaviruses have been linked to cancer as well

• hepatitis B and C—linked to cancer of the liver

• human immunodeficiency virus (HIV)—linked to Kaposi's sarcoma and lymphoma

• retroviruses—linked to cancers in animals other than humans

Tobacco smoke

• is associated with 50% to 60% of all cancer deaths

• is causally linked to cancers of the lung, upper respiratory tract, oesophagus, bladder, pancreas

• is probably a cause of cancer of the stomach, liver, kidneys, colon, and rectum

Food

• is connected to 50% to 60% of cancer deaths

• is causally linked to cancers of the lung, upper respiratory tract, oesophagus, bladder, pancreas

• is probably a cause of cancers of the stomach, liver, kidneys, colon, and rectum

Radiation• UVB from the sun can damage DNA and is associated

with more than 90% of skin cancers, including melanomas

• radon has been associated with lung cancer among those who work in mines; general levels of radon have not posed a significant cancer threat

• electric and magnetic fields from power lines and household appliances have not been demonstrated contributors to the incidence of cancer or leukaemia

• radio frequency electromagnetic radiation from mobile phones or microwave ovens has not been linked to cancer.

• nuclear radiation is of sufficient energy to ionise molecules and is therefore carcinogenic.

Chemicals

• benzene (myelogenous leukaemia)

• arsenic containing pesticides (lung cancer)

• polychlorinated biphenyls (liver and skin cancers)

• mineral oils (skin cancer)

• mineral fibres (lung cancer and mesothelioma)

Chemicals, many of which have been historically linked to the workplace, have been successfully limited through public health efforts, because they have been associated with a variety of cancers. Examples of common chemicals that fall in this category are:

Pollution

Pollution has been difficult to document as a contributor to human cancer.

However, long-term exposure to high levels of air pollution may increase lung cancer risk by as much as 25%.

Cancer terminology

Classification by tissue type:• carcinoma

epithelial cell90% of all tumoursderived from ectoderm (mostly) or endoderm (some)

• sarcomaconnective tissue2% of all tumoursderived from mesoderm

• leukaemiacirculatory or lymphatic8% of all tumoursderived from mesoderm

Classification by the type of cells:• Adenomatous cells

ductal or glandular cells

• Squamous cellsflat cells

• Myeloidblood cell

• Lymphoidlymphocytes or macrophages

Cancer terminology

Classification by the site of origin of the tumour:

• Breast: carcinoma of ductal, medullary, papillary, etc. cells • Lung: small cell, bronchioloalveolar, squamous, large cell carcinomas

• Bone: osteosarcoma, Ewing's sarcoma

• Eye: retinoblastoma

• Lip, tongue, mouth, nasal cavity: squamous cell carcinoma

• Lymphocytes: acute lymphocytic leukaemia, chronic lymphocytic leukaemia, Hodgkin's lymphoma

• Ovary: adenocarcinoma, choriocarcinoma, teratoma, Brenner tumour

• Testis: seminoma, teratocarcinoma,

Cancer terminologyBenign tumours• are generally slow growing and enclosed in a fibrous capsule

• are relatively innocuous, although their location can make them serious (such as a tumour located in the brain)

• are not considered cancerous (that is, they are not malignant)

• are given names that usually end in "oma" (although a melanoma is a malignant skin cancer)

Malignant tumours• proliferate rapidly, invading neighbouring tissues

• can metastasise, or spread, to other sites of the body

• are named using the conventions of tissue, cell type, and origin

e.g. A tumour of the bone is an osteoma if benign and an osteosarcoma if malignant

Tumour suppressor genes

• The gene’s normal function is to regulate cell division. Both alleles need to be mutated or removed in order to lose the gene activity.

• The first mutation may be inherited or somatic.• The second mutation will often be a gross event

leading to loss of heterozygosity in the surrounding area.

Knudsen’s “two hit” hypothesis

retinoblastoma

retinoblastoma

• Retinoblastoma (RB) is a malignant tumor of the developing retina that occurs in children, usually before the age of five years.

• All forms of retinoblastoma represent a mutation in the gene RB1 located in in the region 13q14.1-q14.2.

• The gene is about 180 kb in length with 27 exons that code for a transcript of only 4.7 kb.

• individual mutations are heterogeneous: 20% are deletions larger than 1kb; 30% are small deletions or insertions; 45% are point mutations.

• mutations have been found in 25 of the 27 coding exons and in promoter elements.

• Genotype-phenotype correlation:most mutant RB1-alleles show premature termination codons and are associated with almost complete penetrance (>95%) and high expressivity (more than 6 individual retinoblastoma foci per individual and, therefore, most often involvement of both eyes);some rare mutant alleles that code for proteins with retention of parts of the functions of the wild-type protein or that result in diminished amounts of wild-type transcript are associated with incomplete penetrance (<75%) and low expressivity (mean of less than 2 tumor foci)

RB1

• Is regulated by phosphorylation by Cdk2

• Hypophosphorylated form binds and sequesters E2F (and viral proteins such as E7 from human papilloma virus-16)

• It also interacts directly with the product of the ABL gene and participates in several regulatory and feed back loops even involving its own transcription.

Breast Cancer

“Why do so many of my relatives have breast cancer...is this just plain bad luck or what?”

breast cancer

• her age, • family history, • age at which she began menstruating, • whether she has given birth and her age at the time of the first birth, and • whether or not a breast biopsy was performed in the past.

Within the general population, there is an 11% chance that any woman will develop breast cancer over her lifetime. For any one individual, this risk may be increased or decreased by a variety of factors:

breast cancer

But its more complicated than that!

oncogenes

• Cellular oncogene c-onc

• Viral oncogene v-onc

• Proto-oncogene, activated by mutation to c-onc

Proto-oncogene activation

Types of proto-oncogene

• Growth factore.g. SIS oncogene (PDGF)

Types of proto-oncogene

• Growth factor receptore.g. tyrosine kinase receptors

Types of proto-oncogene

• G proteinse.g. ras

Types of proto-oncogene

• Nuclear transcription factorse.g. MYC

p53

• suppresses progression through the cell cycle in response to DNA damage

• initiates apoptosis if the damage to the cell is severe

• acts as a tumour suppressor• is a transcription factor and once activated, it

represses transcription of one set of genes (several of which are involved in stimulating cell growth) while stimulating expression of other genes involved in cell cycle control

Transformation is a multistep process

Transformation is a multistep process

Colorectal Cancer

• 11% of cancer-related deaths

• Tumor progression may take 10-35 years

• Adenomatous polyp develops into carcinoma

Chromosome changes in colorectal cancer

Cancer karyotype Stable karyotype

reading

URLs:

• http://www.infobiogen.fr/services/chromcancer/Kprones/RbKprID10031.html

• http://cgap.nci.nih.gov/

• http://www.intouchlive.com/home/frames.htm?http://www.intouchlive.com/cancergenetics/&3

• http://bioinformatics.weizmann.ac.il/hotmolecbase/entries/p53.htm

Books:

• Concepts of Genetics, Klug and Cummings, chapter 23

• Molecular Biology of the Cell