Module 3 Part 2 - Neoplasia Epidemiology and Molecular Basis for Carcinogenesis

Question 1

Carcinogenesis

Answer 1

Multistep process
- accumulation of permanent genetic alterations - mutations resulting in abnormal control of growth over time
- tumour progression (invasiveness, growth, escape from immune system)
Cells need to divide to maintain the organism
- cell division is highly regulated to avoid runaway growth
- to achieve net cell gain, cells must divide at an increased rate and avoid death by apoptosis

Question 2

Molecular Basis of Carcinogenesis

Answer 2

Carcinogenesis is a process that results in transformation of normal cells to neoplastic cells through permanent genetic alterations
Carcinogen = cancer causing
Site of action = DNA
> 1 agent required

Question 3

Molecular Basis of Carcinogenesis - Genes that Encode Regulating Proteins

Answer 3

Promoters of cell growth are called proto-oncogenes and those that restrict are called anti-oncogenes
Apoptosis and senescence assist in controlling the health of cells - recognise DNA damage and eliminate the cell
Proto-oncogenes normally control cell proliferation and when activated by changes in adjacent genes or themselves, lead to a mutation forming oncogenes that stimulate cell proliferation

Question 4

Other Causes of Carcinoma

Answer 4

Chemicals
Irradiation: X-Ray, UV, Ionising
Hormones - may be required to promote tumour growth
Physical target - asbestos
Diet
Virus/bacterial preneoplastic dysplasias
Autoimmune diseases

Question 5

Host Factors in Carcinoma

Answer 5

Race - increased risk of melanoma
Diet - hi ‘toxic’ fat, EtOH
Constitutional factors - sex, inherited risk
Premalignant lesions and conditions - Helicobacter pylori
Transplacental exposure
Congential

Question 6

Initiation, Promotion and Progression of Carcinoma

Answer 6

Initiation - where a carcinogen induces the genetic alteration(s) that give(s) the transformed cell its neoplastic potential
Promotion - the stimulation of clonal proliferation of the initiated transformed cell
Progression - the process culminating in malignant behaviour characterised by invasion and its consequences

Question 7

Abnormalities in Genes Regulating Cell Proliferation that support Neoplasia

Answer 7

Four main mechanisms

1. Activation of oncogenes to stimulate growth
2. Loss of genes controlling proliferation e.g. tumour suppressor genes
3. Loss of normal control mechanisms for eliminating genetically damaged cells
4. Loss of gene products that repair damaged DNA leading to DNA instability and mutation in oncogenes and tumour suppressor genes

Question 8

Oncogenes

Answer 8

Proto-oncogenes are genes that code for proteins involved in the control of cell growth (act as on and off switches for cell proliferation)
Oncogenes were originally isolated from tumour forming RNA retroviruses (v-oncs)
Viral oncogenes (v-oncs) are genes within a virus that code for a protein
Cellular oncogenes (c-oncs) are genes that code for protein in the development of neoplasia

Question 9

Genetic Reasoning for Neoplastic Transformation

Answer 9

Proto-oncogene mutations form oncogenes that stimulate cell proliferation by 3 mechanisms:

1. Point mutation - caused by a single nucleotide change resulting in changed amino acids
2. Translocation of a gene or part of one to a different chromosome - leads to altered expression of gene products
3. Gene amplification - leads to raised protein levels

Question 10

HER2/neu Gene

Answer 10

HER2 is a cell membrane surface-bound receptor tyrosine kinase and is normally involved in the signal transduction pathways leading to cell growth and differentiation
It is encoded within the genome by HER2/neu, a known proto-oncogene
Approx 30% of breast cancers have amplification of the HER2/neu gene or over expression of its protein product

Question 11

What stops Carcinogenesis?

Answer 11

Tumour suppressor genes or anti-oncogenes
Rb1, APC, p53 regulate cell proliferation and trigger apoptosis
When these triggers for cell regulation are inactivated, mutant cells may survive and proliferate as immortal cells
- p53 missing in most carcinomas