types of cancer, mutations, and viral carcinogenesis

what is cancer

abnormal growth of cells in an uncontrolled way that can spread or metastasise into other tissues

what are the types of tumours

• benign

• malignant

what are benign tumours

abnormal growths that are no longer under normal regulation

what are malignant tumours

poorly differentiated cells, growing in a rapid, disorganised manner and can invade surrounding tissues and become metastatic, initiating the growth of similar tumours in distant organs

what are the different classifications of cancers based on cell origin

• carcinomas

• sarcomas

• lymphomas

• leukaemia

what is the most common type of cancer

• carcinomas

• 85%

what do carcinomas arise from

arise from the cells that cover external and internal body surfaces

what are the most frequent carcinomas

• lung

• breat

• colon

• including glandular epithelial tissue adenocarcinoma

what is the general principle of carcinomas

• cell with mutation

• hyperplasia

• dysplasia

• in situ cancer

• invasive cancer

what is the percentage that sarcomas make up for in cancer

12%

where do sarcomas originate from

• cells found in the supporting tissues of the body (mesenchymal layer-derived)

• e.g. bone, cartilage, fat, connective tissue, and muscle

sarcoma malignancy

highly malignant

what are the different types of sarcomas

• angiosarcoma

• osteosarcoma

• ewings sarcoma

• chondrosarcoma

• fibrosarcoma

• liposarcoma

• GI stromal tumour

how do lymphoma cancers arise

arise in lymph nodes and tissues of the body’s immune system (B, T, and NK cells) that can spread to intestine, spinal cord, bone, or brain

what type of cancer is leukaemia

cancers of the immature white blood cells that proliferate in the bone marrow and accumulate in the blood stream

what is the staging of cancer based on

1. site of primary tumour

2. size

3. how far it has invaded into local tissues and structures

4. whether it has spread to regional lymph nodes

5. whether it has metastasised to other regions of the body

what does a low number grade refer to

cancers with fewer cell abnormalities than those with higher numbers

what causes cancer

• carcinogenesis

• tumour progression

what is carcinogenesis

a multistep process resulting from the accumulation of mutations

how do normal cells evolve into tumour cells

through a process called tumour progression

what is tumour progression driven by

a series of random mutations and epigenetic alteration of DNA that affects the genes controlling proliferation and survival

when does cancer become more common

as we age

what are the 3 main ways that can result in DNA damage/mutation

1. mistakes in DNA replication- disincorporation of deoxynucleotides during replication

2. nucleotides within DNA molecules undergo chemical changes spontaneously- these changes often alter base sequences of DNA

3. effects of mutagenic agents- molecules generated endogenously by normal cell metabolism (ROS), mutagenic agents (UV) and chemical agents (vinyl chloride)

what causes an incorrect DNA lesion

• removal of altered bases affecting 3’-5’ exonuclease activity

• proofreading of incorrectly incorporated bases

what causes a missing base DNA lesion

• removal of altered bases by DNA glycosylases (Base excision repair)

• removal of purines by aid or spontaneously

what causes a 3’ deoxyribose fragment DNA lesion

by free radicals leading to strand breaks

what causes a DNA lesion in which there is a bulge due to a deletion or insertion of a nucleotide

intercalating agent that cause addition or loss of a nucleotide during recombination or replication

what causes single or double bond break DNA lesions

by ionising radiation or chemical agents

what causes linked pyrimidines DNA lesions

UV radiation

what causes cross-linked strand DNA lesions

covalent linkage of 2 strands alkylating agents

what are human familial cancer syndromes due to

inherited defects in repair e.g. BRCA1 and BRCA2

what can also cause cancer

viruses

what are one of the most important risk factors for developing cancer after smoking

viruses

DNA viruses that can cause cancer

• HHV

• HPV

• EBV

• HBV

what is an episome

circular DNA

what happens to the viral genome in DNA viruses that can cause cancer

• viral genome can persist in the infected cells as an episome

• promoting the expression of proteins that promote proliferation or that inhibit tumour suppressor genes

examples of RNA viruses that can cause cancer

• HCV

• HTLV1

how is RNA transformed into DNA

RNA is retro transcribed into DNA

how can an RNA virus cause cancer

• retro transcribed RNA incorporated into the host genome (provirus)

• replication occurs

what are the ways RNA viruses can cause carcinogenesis

1. providing a gene that alters growth- the RNA viruses can contain an extra gene additional to the sequences needed for viral replication

2. insertional mutagenesis- the virus integrates into the host genome close to a host gene that regulates growth and up regulates its expression

what are the 2 viral mechanisms of carcinogenesis called

• direct

• indirect

what happens in direct mechanisms of viral carcinogenesis

the virus is acting from within the cell that will form the tumour

where are direct-acting carcinogenic agents generally found

• in monoclonal form within the tumour cells

• these agents help to keep the tumour phenotype

what are the 2 direct mechanisms of viral carcinogenesis

• viral genomes can form episomes —> viral oncogene expression

• or integrate into the host genomic DNA —> viral cellular oncogene expression

• after infecting the target cells tumour viruses are persistently maintained as genetic elements

what happens in indirect mechanisms of viral carcinogenesis

the virus is acting from outside the cell that will form the tumour

what are the 2 ways the indirect mechanism of viral carcinogenesis works

• triggering chronic inflammation and oxidative stress that persistently damage local tissues e.g. HBV- major risk to develop hepatocellular carcinoma

• producing immunosuppression that reduces or eliminates anti-tumour immune surveillance mechanisms e.g. HIV- frequent development of lymphomas associated with EBV or KSV infection

what do all tumour viruses probably present

direct and indirect mechanisms

how many mutations are required for cancer

• many

• 3-20 required to develop cancer

what type of process is cancer

a multi-step process

what is hypertrophy

cells are normal but are much bigger

what is atrophy

cells are normal but much smaller

what is hyperplasia

increase in the number of cells but all cells exhibit normal regulatory control mechanisms

what can hyperplasia progress to

dysplasia

what is metaplasia

• where one cell type changes into another

• cells become another less differentiated cell

what is dysplasia

• increase in growth of immature cells

• abnormal and variable appearance

• cell-to-cell interactions broken down

what can progress into neoplasia

• metaplasia

• dysplasia

what is neoplasia

• after dysplasia and metaplasia

• neoplastic growth is rapid and results in a tumour, metastasis, and acquisition of more mutations

what are the phases of carcinogenesis

• initiation

• promotion- long process and reversible

• progression- rapid increase in tumour size

• metastasis- invasive and metastatic mutations

what is tumorigenesis

a step-wise transformation

what is genomic instability

an increased tendency of gene alteration during cell division