http://www.cellbio.drake.edu/Cancer/CancerBioMail.html

http://www.mostgene.org/gd/gdvol17g.htm

Information source:

15% of all cancer patients have an inherited risk. 15% of all cancer patients have an inherited risk.

Figures source: http://www.drkoop.com

Genetic Cancer Syndromes

Genes that cause cancer are:

DNA Repair GenesOncogenesTumor Supressor GenesGenes that affect the immune system responseto cancer.Anti-apoptosis genes

Have several close family members been affected by cancer?

Has cancer occurred at an unusually young age in your family?

Has anyone in your family had more than one cancer (such as breast and colon, or both breasts)?

Are there unusual or rare types of cancer in your family?

Risk Factors for Inherited Cancers

Bloom Syndrome

...is inherited as an autosomal recessive disease which causes increased frequencies of breaks and interchanges of chromosomes.

The probable gene product of the BLM gene associated with Bloom syndrome has been identified as a DNA helicase, an enzyme involved in maintaining DNA integrity.

TP53

Neurofibromatosis 1 NF1

Tuberous sclerosis 2 TSC2

Hereditary Wilms' tumor WT1

Li-Fraumeni syndrome

breast cancer

colon cancer

melanoma,

papillary renal cell carcinoma,

retinoblastoma,

leukemia/lymphoma associated with immunodeficiency disorders and chromosome instability syndromes,

multiple endocrine neoplasias (MEN1, MEN2),

von Hippel-Lindau disease

BRCA1 and BRCA2 are genes which normally help to prevent breast cancer by making proteins which inhibit abnormal cellular growth.

While a woman with an average risk for breast cancer has a 10% chance of developing the disease sometime in her lifetime, a woman who has either the BRCA1 or BRCA2 has an estimated 50-87% chance of developing breast cancer by the age of 70.

In addition to a possible increased susceptibility to breast cancer, BRCA1and BRCA2 mutations are thought to contribute to earlier onset of the disease.

Breast cancers caused by BRCA1 or BRCA2 mutations usually occur before menopause, whereas most non-genetic breast cancers usually occur after menopause.

BRCA1; located on chromosome 17

BRCA2; located on chromosome 13

What are the options for women who test positive?

More aggressive screening More aggressive screening

ChemopreventionChemoprevention

Prophylactic SurgeryProphylactic Surgery

( removal of breasts or ovaries) Some studies have shown that removal of both ovaries can even significantly reduce the risk of breast cancer in this group of patients.

FAP is an autosomal dominant inherited disease due to mutations in the APC gene in chromosome 5.

Familial colon cancers:Familial colon cancers:

A second kind of inherited colon cancer is hereditary nonpolyposis colorectal cancer (HNPCC).

Familial colon cancers:Familial colon cancers:

Melanoma:Melanoma: tumor suppressor gene p16 or proto-oncogene CDK

Approximately one in ten individuals with melanoma has an inherited predisposition to this cancer.

Scientists have now isolated the gene that causes BCNS, suspected of being behind basal cell carcinoma. They found it by isolating a gene whose mutation causes runaway cell growth in fruit flies, then identifying the comparable gene in humans.

Basal Cell CarcinomaBasal Cell Carcinoma

Retinoblastoma:Retinoblastoma:The gene responsible for retinoblastoma is the tumor suppressor gene, RB.

100% of bilateral cases of retinoblastoma (average age of onset is eight months) are of genetic etiology as are 10-15% of sporadic unilateral cases (average age of onset is two years of age).

The Rb gene codes for a 105,000 MW protein that regulates the cell cycle.

Retinoblasts are precursors of cone cells of the retina.

Genetic testing is now available for breast,ovarian, colon, prostate and some skin cancers.

Most genetic tests are performed on a blood sample.

·(HNPCC) Screening and Mismatch Repair Gene(s) DNA Sequencing

·BRCA1 and BRCA2 Protein Trucation Testing

·BRCA1 and BRCA2 Direct Testing for known mutations

·Fanconi Anemia

·Bloom syndrome

·Bone marrow (blood and tissue) karyotyping

·Fluorescent in situ Hybridization (FISH) for marrow transplantation monitoring

·FISH for tumor translocations

·7-FISH and Comparative Genomic Hybridization (CGH) for unknown cancer karyotypic change

·PCR molecular testing for common tumor

markers

Available tests and the associated cancers:

BRCA1BRCA1, for cancers of Breast, Colon, Ovaries, Prostate

BRCA2BRCA2, for cancers of Breast, Colon, Ovaries, Prostate

p53p53, for cancers of Breast, Bone, Leukemia, Brain Tumor

APCAPC, for Colon cancer

RETRET, for Medulary Thyroid cacnner

VHLVHL, Von Hipple Lindau

NF1NF1, for Neurofibrosarcoma

RB1RB1, for Retinoblastoma

BLMBLM, for cancers of Colon, Esophaeal, Tongue, Leukemia and Wilms Tumor

http://www.cancergenetics.org/medcase2.htm

Cancer Genetics Case Studies

Cancer Genetics Case Studies

How important is DNA repair?

Nearly all DNA damage is harmful. Therefore, it is essential to reduce this damage to a tolerable level. DNA is the only biomolecule that is specifically repaired. All others are replaced.

>100 genes participate in various aspects of DNA repair, even in organisms with very small genomes.

Cancer is caused by mutations. DNA repair mechanisms promote genomic stability and prevent cancer. Many, perhaps most, cancers are at least partially attributable to defects in DNArepair.

http://mcbio.med.buffalo.edu/RPN530/Lecture_Intro_Damage.html

DNA molecules, like all other biomolecules, can be damaged in numerous ways.

Spontaneous damage due to replication replication errorserrors, deaminationdeamination, , depurinationdepurination and oxidationoxidation is compounded in the real world by the additional effects of radiationradiation and environmental chemicalsenvironmental chemicals.

The number of ways that DNA molecules can be damaged is very large. Since repair systems must be capable of recognizing and dealing with each type of damage, it is not surprising that there is a large number of different types of repair systems.

Summary of types of DNA damage

http://mcbio.med.buffalo.edu/RPN530/Lecture_Intro_Damage.html

Cytosine deamination

http://mcbio.med.buffalo.edu/RPN530/Lecture_Intro_Damage.html

http://mcbio.med.buffalo.edu/RPN530/Lecture_Intro_Damage.html

Question:Question: what is meant by "complementation group", for example in reference to the complementation groups ofCockayne's syndrome and Xeroderma pigmentosum?

Answer:Answer: a complementation group can be thought of as a collection of mutations, all of which are in the same gene. The various complementation groups affecting nucleotide excision repair were distinguished from each other by observing that DNA from cells in one complementation group could cure the mutant phenotype of cells from a different complementation group when transfected into those cells, but could not cure the mutant phenotype of cells from the same complementation group.

Types of Repair

Although all cells possess a large number of different types of repair system, each relatively specific for a certain type of DNA damage, those repair systems can be grouped into 3 broad categories:

Direct reversal of damage.

Excision of damaged region, followed by precise replacement.

Damage tolerance: attempts to minimize the effects of damage that cannot be repaired.

Five types of proteins encoded

by proto-oncogenes

participate in control of cell

growth:

Class I: Growth Factors Class II: Receptors for Growth Factors and Hormones

Class III: Intracellular Signal Transducers

Class IV: Nuclear Transcription Factors

Class V: Cell-Cycle Control Proteins

Examples of Cellular Oncogenes

erb-B codes for a receptor for epidermal growth factor; involved in glioblastoma, a brain cancer, and breast cancer

erb-B2 also called HER-2 or neu; involved in breast, ovarian, and salivary gland cancers

Ki-ras codes for a protein that relays a stimulatory signal; involved in lung, ovarian, colon, and pancreatic cancers

N-ras involved in leukemias

c-Myc, N-myc, L-myc all genes for transcription factors that activate growth promoting genes; involved in leukemias, breast, stomach, and lung cancers (c-Myc, L-myc); neuroblastoma (N-myc)

Bcl-1 codes for cyclin D1, a component of the cell cycle clock; involved in breast, head and neck cancers

Examples of Tumor Supressor Genes

DPC-4 involved in pancreatic cancer; participates in a cytoplasmic pathway that inhibits cell division

NF-1 involved in neurofibromas of the nervous system and myeloid leukemia; codes for a protein that inhibits Ras, a cytoplasmic inhibitory protein

NF-2 involved in cancers of the nervous system; codes for a nuclear protein

RB involved in retinoblastoma as well as bone, bladder, small cell lung, and breast cancers; codes of the pRB protein, a nuclear protein that is a major brake in the cell cycle

p53 involved in a wide range of tumors; inactive or lost in more than 50% of cancerous cells; codes for the cytoplasmic p53 protein that regulates cell division and can induce cells to kill themselves (apoptosis); inheritance of p53 mutations through the germ line is also associated with the Li-Fraumeni cancer syndrome

WT1 involved in Wilms tumor of the kidneys

BRCA1 involved in breast and ovarian cancer

BRCA2 involved in breast cancer