Genetics - Lecture 18: Cancer Genetics

Cancer

A group of diseases characterized by cell proliferation

• 1/5 people in the US will die from cancer

• Not a single disease (heterogeneous group of disorders characterized by the presence of cells that do respond to then normal controls on divisions)

• most common: breast, prostate, lung, colon and rectum, and skin

Cancer cell

• divide rapidly and continuously creating tumours that crowd out normal cells, eventually robbing healthy tissues of nutrients

• cells of an advanced tumour can separate and travel to distant sites in the body, where they may take up residence and develop into new lungs

• Have a abnormal proliferation

Cancer in Canada

• Leading cause of death in Canada - represent of 30% of all deaths

• ~ 254,800 new cancer cases and 87,400 cancer deaths in 2025.

• ~ 698 people would be diagnosed with cancer, and 239 people would die from cancer each day in 2025

• 131,800 males and 122,900 females would be diagnosed with cancer

• Prostate cancer would account for about 1/5 (23%) of all new cancer cases in males

• Breast cancer would account for about 1/4 (26%) of all new cancer cases in females

• Lung and bronchus (lung) cancer would be the second most common cancer in both males (after prostate) and females (after breast)

• A greater number of females (17,500) than males (15,400) would be diagnosed with lung cancer

Tumor formation

normal cells grow, divide, mature, and die in response to a complex set of internal and external signals, tumors (neoplasm) are an abnormal mass of tissue that forms when cells grow and divide more than they should or do not die when they should

• normal cell receives both stimulatory and inhibitory signals and its growth and division are regulated

• in cancer cells, one or more of these signals has been disrupted, which causes the cell to proliferate at and abnormally high rate

• fundamentally a disease of the cell cycle

Cancer as a genetic disease

• raised because of fundamental defects in the regulation of cell division

• most, if not all, cancers arise from defects in DNA

  • fundamentally a genetic disease, though some can be inherited

  • most tumors arise from somatic mutations that accumulate over a persons life span, either through spontaneous mutation or in response to environmental mutagens

  • in most cancers, more than two mutations are involved in the transformation of normal cells into cancer cells

* only certain genes will cause cancer

* not every mutation in DNA will cause cancer

The Clonal Evolution of Tumors

• Tumor cells accumulate somatic mutations that allow them to become increasingly more aggressive in their proliferative properties

• Mutated genes can be inherited (inheritable cancer)

• Chromosomal abormalities and carcinogens can cause cancer as well

Types of tumors

1. Malignant

2. Benign

Malignant

Tumor consisting of cells that invade other tissues (cancerous)

Benign

• not cancer

• may grow larger but do not spread other parts of the body

• nonmalignant

Metastasis

the movement of cells that separate from malignant tumors to other sites, where they establish secondary tumors

Role of environmental factors in cancer

• most cancer are not inherits, many are influenced by environmental factors

• migrant populations typically take on cancer incidence of host country

• Other contributing factors include:

  • tobacco use

  • diet

  • obesity

  • alcohol

  • UV radiation

mutations in several types of genes that contribute to cancer

• Cancer is caused by alterations of DNA

• over 350 human genes have been linked to cancer (probably more)

• the signals that regulate cell divisor fall into two basic types:

1. molecules that stimulate cell division

2. molecules that inhibit it

Ex:

• oncogenes

• tumor-supressor genes

Oncogenes

Dominant-acting gene that stimulated cell division (promote proliferation), leading to the formation of tumors of contributing to cancer

• arises from a mutated copy if a normal cellular gene (proton-oncogene)

Proto-Octogene

Normal cellular gene responsible for basic cellular function

• when mutated may become on octogene and contribute to the development of cancer

Tumor-suppressor genes

gene that normally inhibits cell division

• recessive mutations n such genes often contribute other cancer

  • both copies must be mutated to produce excessive cell proliferation

• hereditary

• often predisposed to cancer because the inactivation or loss of the one remaining normal allele is all that is required to completely eliminate the tumor-suppressor gene product

• much higher risk of cancer

Control of the Cell Cycle

• activity dividing cells pass through the G1, S, and G2 phases of interphase and then move directly into the M phase, in which cell division takes place

• Non-dividing cells pass from G1 to G0 stage, in which they are functional but not actively growing or dividing

• Progession from one stage of cycle t another is influenced by internal and external signals and is regulated at key points in the cycle, called checkpoints

• key events are controlled by by Cyclin-Dependent Kinases. These are important proteins which only function when bound to cyclin

Cyclin-dependant kinase (CDK)

A key protein in the control of the cell cycle; functional only in combination with cyclin

Kinase

Enzymes (proteins) that phosphorylate other proteins

• phosphorylation may activate or inactive there other protein

Cyclin

A key protein in the control of the cell cycle

• combines with cyclin-dependent kinase (CDK)

• levels oscillate during the cell cycle

Checkpoints

• control professional through the cell cycle

• regulated by interactions between cyclins and cyclin-dependent kinases

Ex: G1-to-S Transition:

• Retinoblastoma (RB) Protein: Classic tumor-suppressor that acts to check cell cycle progression (by binding transcription factor E2F) and is deleted or mutated in several human cancers

Genes that control the cell cycle are…

frequently mutated in cancer cells

Apoptosis and autophagy…

also influence cancer development and genes that affect these processes are frequently mutated in cancer cells

Telomere

Stable end of a eukaryotic chromosome

Telomerase

Ribonucleoprotein enzyme that replicates the ens (telomeres) of eukaryotic chromosomes

• normally live in stem and germ cells, not normally expressed in somatic cells

• Without telomerase activity somatic cells can only divide so many tomes during to chromosome shortening

  • leads to destruction of the chromosomes and cell death, so somatic cells are capable of only a limited number of cell division

• in tumor cells, telomerase is unregulated, allowing cells to replicate indefinitely

• the inappropriate activation of telomerase can contribute to the progression of cancer

Angiogenesis

A gene that promotes vascularization and the spread of tumors

• new blood vessel growth is requires for tumour growth/survival

• stimulated by growth factors

  • tumor cells overexpresses these growth factors

  • Ex: Vascular endothelial growth factor (VEGF) is a key protein involved in angiogenesis, and it is often overexpressed in cancer cells

• inhibitors og angiogenesis have been used in part to limit tumor growth

Epigenetic changes

alterations of chromatin structure that affect gene expression

• alternation of DNA methylation, chromatin or histone structures is seen in many cancer cells

  • Hypermethylation - an overall higher level of DNA methylation

  • Hypomethylation - an overall lower level of DNA methylation .

Excessive methylation may…

inhibit transcription of tumor-suppressor genes, thereby stimulating the development of cancer

• It is assumed that hypomethylation leads to transcription of oncogenes, which then stimulate cancer. Some evidence also suggests that hypomethylation causes chromosome instability, a hallmark of many tumors

Sequential Mutation

• part of the progression of cancer

• the ordered acquisition of multiple genetic mutations within a cell, where each new cells mutation will cause increase proliferation, then malignancy, then metastasis

  • step-by-step over time

  • earlier mutations enabling later ones

Ex: colorectal cancer

Colorectal cancer

• Colorectal cancer arises in the cells lining the colon and rectum

• Colorectal cancer is thought to originate as benign tumors called adenomatous polyps

• mutations in multiple genes contribute to the progression of colorectal cancer

* Most cancers arise from mutations in several genes, often a combination of oncogenes and tumor-suppressor genes

Changes in chromosome number and structure in relation to cancer

• most tumors contain cells with chromosome mutations

  • chromosome instability is a general feature of cancer cells

• Deletions, inversions, and translocations are associated with certain types of cancers

• aneuploidy

* cancer cells often have chromosomes abnormalities (missing, extra, or rearrangements)

Ex: colon cancer cell have numerous chromosome abnormalities

Chromosome deletions

can eliminate or inactive genes that control the cell cycle

Chromosomes inversions and translocations

can cause breaks in genes that:

• suppress tumors

• fuse genes to produce cancer-causing proteins

• move genes to new locations where they are under the influence of different regulatory sequences

Ex: A reciprocal translocation between chromosomes 9 and 22 causes chronic myelogenous leukemia

Aneuploidy

missing or extra chromosomes

Viruses

• responsbile for many cancers in animals and a few human cancers

Ex: about 95% of all women with cervical cancer are infected with human papillomavirus (HPV).

Retroviruses

Virus that injects its RNA genome into a host cell

• many viruses that cause caner in animals are retroviruses

• cause cancer by:

  • mutating or rearranging host genes

  • converting proton-oncogenes into oncogenes

  • altering the expression of host genes

  • inserting promotors near proto-oncotogenes

• often contain strong promotors to ensure that their own genetic material is transcribed by the host cell