A report on Carcinogenesis and Genome instability

Cancers and tumors are caused by a series of mutations. Each mutation alters the behavior of the cell somewhat.
The central role of DNA damage and epigenetic defects in DNA repair genes in carcinogenesis
Longitudinally opened freshly resected colon segment showing a cancer and four polyps. Plus a schematic diagram indicating a likely field defect (a region of tissue that precedes and predisposes to the development of cancer) in this colon segment. The diagram indicates sub-clones and sub-sub-clones that were precursors to the tumors.
Tissue can be organized in a continuous spectrum from normal to cancer.
Many tumor suppressor genes effect signal transduction pathways that regulate apoptosis, also known as "programmed cell death".
Multiple mutations in cancer cells

During the process of tumorogenesis, it is known that diploid cells acquire mutations in genes responsible for maintaining genome integrity (caretaker genes), as well as in genes that are directly controlling cellular proliferation (gatekeeper genes).

- Genome instability

However, it was pointed out by Rubin that "the vast majority of studies in cancer research has been done on well-defined tumors in vivo, or on discrete neoplastic foci in vitro. Yet there is evidence that more than 80% of the somatic mutations found in mutator phenotype human colorectal tumors occur before the onset of terminal clonal expansion…" More than half of somatic mutations identified in tumors occurred in a pre-neoplastic phase (in a field defect), during growth of apparently normal cells.

- Carcinogenesis
Cancers and tumors are caused by a series of mutations. Each mutation alters the behavior of the cell somewhat.

6 related topics with Alpha

Overall
DNA damage resulting in multiple broken chromosomes

DNA repair

3 links

Collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome.

Collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome.

DNA damage resulting in multiple broken chromosomes
Structure of the base-excision repair enzyme uracil-DNA glycosylase excising a hydrolytically-produced uracil residue from DNA. The uracil residue is shown in yellow.
Double-strand break repair pathway models
DNA ligase, shown above repairing chromosomal damage, is an enzyme that joins broken nucleotides together by catalyzing the formation of an internucleotide ester bond between the phosphate backbone and the deoxyribose nucleotides.
DNA repair rate is an important determinant of cell pathology
Most life span influencing genes affect the rate of DNA damage
A chart of common DNA damaging agents, examples of lesions they cause in DNA, and pathways used to repair these lesions. Also shown are many of the genes in these pathways, an indication of which genes are epigenetically regulated to have reduced (or increased) expression in various cancers. It also shows genes in the error-prone microhomology-mediated end joining pathway with increased expression in various cancers.

Such alterations are thought to occur early in progression to cancer and to be a likely cause of the genetic instability characteristic of cancers.

Epigenetic repression of DNA repair genes in accurate DNA repair pathways appear to be central to carcinogenesis.

Colectomy specimen containing a malignant neoplasm, namely an invasive example of colorectal cancer (the crater-like, reddish, irregularly shaped tumor)

Neoplasm

3 links

Type of abnormal and excessive growth of tissue.

Type of abnormal and excessive growth of tissue.

Colectomy specimen containing a malignant neoplasm, namely an invasive example of colorectal cancer (the crater-like, reddish, irregularly shaped tumor)
Neoplastic tumor of the cheek skin, here a benign neoplasm of the sweat glands called hidradenoma, which is not solid but is fluid-filled
Diagram illustrating benign neoplasms, namely fibroids of the uterus
The central role of DNA damage and epigenetic defects in DNA repair genes in malignant neoplasms
Longitudinally opened freshly resected colon segment showing a cancer and four polyps, plus a schematic diagram indicating a likely field defect (a region of tissue that precedes and predisposes to the development of cancer) in this colon segment. The diagram indicates sub-clones and sub-sub-clones that were precursors to the tumors.

Once a cancer is formed, it usually has genome instability.

Various other terms have been used to describe this phenomenon, including "field effect", "field cancerization", and "field carcinogenesis".

Tumour heterogeneity

2 links

Tumour heterogeneity describes the observation that different tumour cells can show distinct morphological and phenotypic profiles, including cellular morphology, gene expression, metabolism, motility, proliferation, and metastatic potential.

Tumour heterogeneity describes the observation that different tumour cells can show distinct morphological and phenotypic profiles, including cellular morphology, gene expression, metabolism, motility, proliferation, and metastatic potential.

The cancer stem cell model asserts that within a population of tumour cells, there is only a small subset of cells that are tumourigenic (able to form tumours).

The acquisition of mutations is random as a result of increased genomic instability with each successive generation.

A coronal CT scan showing a malignant mesothelioma Legend: → tumor ←, ✱ central pleural effusion, 1 & 3 lungs, 2 spine, 4 ribs, 5 aorta, 6 spleen, 7 & 8 kidneys, 9 liver

Cancer

1 links

Group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body.

Group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body.

A coronal CT scan showing a malignant mesothelioma Legend: → tumor ←, ✱ central pleural effusion, 1 & 3 lungs, 2 spine, 4 ribs, 5 aorta, 6 spleen, 7 & 8 kidneys, 9 liver
Symptoms of cancer metastasis depend on the location of the tumor.
The GHS Hazard pictogram for carcinogenic substances
Share of cancer deaths attributed to tobacco in 2016.
The incidence of lung cancer is highly correlated with smoking.
Cancers are caused by a series of mutations. Each mutation alters the behavior of the cell somewhat.
The central role of DNA damage and epigenetic defects in DNA repair genes in carcinogenesis
Chest X-ray showing lung cancer in the left lung
Three measures of global cancer mortality from 1990 to 2017
Engraving with two views of a Dutch woman who had a tumor removed from her neck in 1689
University of Florida Cancer Hospital
CancerTreeMammal
An invasive ductal carcinoma of the breast (pale area at the center) surrounded by spikes of whitish scar tissue and yellow fatty tissue
An invasive colorectal carcinoma (top center) in a colectomy specimen
A squamous-cell carcinoma (the whitish tumor) near the bronchi in a lung specimen
A large invasive ductal carcinoma in a mastectomy specimen

Such alterations are thought to occur early in progression to cancer and to be a likely cause of the genetic instability characteristic of cancers.

Several studies have indicated that the enzyme sirtuin 6 is selectively inactivated during oncogenesis in a variety of tumor types by inducing glycolysis.

Epigenetics patterns in a normal and cancer cells

Cancer epigenetics

1 links

Study of epigenetic modifications to the DNA of cancer cells that do not involve a change in the nucleotide sequence, but instead involve a change in the way the genetic code is expressed.

Study of epigenetic modifications to the DNA of cancer cells that do not involve a change in the nucleotide sequence, but instead involve a change in the way the genetic code is expressed.

Epigenetics patterns in a normal and cancer cells
Epigenetic alterations in tumour progression
A DNA molecule fragment that is methylated at two cytosines
A chart of common DNA damaging agents, examples of lesions they cause in DNA, and pathways used to repair these lesions. Also shown are many of the genes in these pathways, an indication of which genes are epigenetically regulated to have reduced (or increased) expression in various cancers. It also shows genes in the error prone microhomology-mediated end joining pathway with increased expression in various cancers.
decitabine

Other histone marks associated with tumorigenesis include increased deacetylation (decreased acetylation) of histones H3 and H4, decreased trimethylation of histone H3 Lysine 4 (H3K4me3), and increased monomethylation of histone H3 Lysine 9 (H3K9me) and trimethylation of histone H3 Lysine 27 (H3K27me3).

Cancers have high levels of genome instability, associated with a high frequency of mutations.

Chromosomes in Down syndrome, one of the most common human conditions due to aneuploidy. There are three chromosomes 21 (in the last row).

Aneuploidy

0 links

Presence of an abnormal number of chromosomes in a cell, for example a human cell having 45 or 47 chromosomes instead of the usual 46.

Presence of an abnormal number of chromosomes in a cell, for example a human cell having 45 or 47 chromosomes instead of the usual 46.

Chromosomes in Down syndrome, one of the most common human conditions due to aneuploidy. There are three chromosomes 21 (in the last row).
Karyogram from a normal male human
Example of Trisomy 21 detected via quantitative PCR short tandem repeat assay

However, mitotic aneuploidy may be more common than previously recognized in somatic tissues, and aneuploidy is a characteristic of many types of tumorigenesis (see below).

Loss of tumor suppressor p53 gene often results in genomic instability, which could lead to the aneuploidy genotype.