Neoplasm 3

Question 1

What is carcinogenesis

Answer 1

Cause of cancer

Question 2

What are the main risk factors for cance

Answer 2

A combination of intrinsic host factors such as heredity, age and gender (especially hormonal), and extrinsic factors related to the environment and behaviour account for cancer risk. Much of the increased cancer incidence over the last century is due to prolonged life-span. About 30% of cancer deaths are due to the five leading behavioural and dietary risks: high body mass index, low fruit and vegetable intake, lack of physical activity, tobacco use, and alcohol use. Tobacco smoke alone is associated with approximately a quarter of all cancer deaths.

Question 3

Where does most of the evidence about cancer risk come from

Answer 3

Most of the evidence about cancer risk comes from epidemiological and animal studies.

Question 4

What are the 3 main categories for extrinsic carcinogens

Answer 4

Extrinsic factors account for approximately 85% of a population’s cancer risk. Extrinsic carcinogens fall into 3 main categories: chemicals, radiation and infections, to be described next.

Question 5

Describe the relationship between the carcinogen exposure and neoplasm onset

Answer 5

(1) there is a long delay (sometimes decades) between carcinogen exposure and malignant neoplasm onset;
(2) the risk of cancer depends on total carcinogen dosage;
(3) there is sometimes organ specificity for particular carcinogens, e.g. 2-napthylamine causes bladder carcinoma
The dependence on dosage is why industrial carcinogens, e.g. asbestos, coal tars, vinyl chloride, have an effect primarily on the relevant workers and tobacco smoke’s effect is largely limited to smokers.

Question 6

What are initiators and promotors

Answer 6

Some chemical carcinogens, called initiators, must be given first followed by a second class of carcinogens called promoters. The Ames test shows that initiators are mutagens, while promoters cause prolonged proliferation in target tissues. This culminates in a monoclonal expansion of mutant cells
Not yet fully malignant (needs to undergo progression)
Initiators create mutations, promoters drive them

Question 7

How can mutagenic carcinogens be classified

Answer 7

Mutagenic chemical carcinogens (i.e. initiators) can be classified as polycyclic aromatic hydrocarbons, aromatic amines, N- nitroso compounds, alkylating agents and diverse natural products, e.g. aflatoxin, asbestos.

Question 8

What are complete carcinogens

Answer 8

Some of these chemicals are pro-carcinogens and are only converted to carcinogens by the cytochrome P450 enzymes in the liver.

Question 9

What are pro-carcinogens

Answer 9

Some of these chemicals are pro-carcinogens and are only converted to carcinogens by the cytochrome P450 enzymes in the liver.
Eg. Need rat liver in Ames test so as not to underestimate carcinogenicity

Question 10

What is radiation

Answer 10

Radiation is any type of energy travelling through space and some forms are mutagenic.

Question 11

What is UV, X rays and gamma rays

Answer 11

Ultraviolet (UV) light does not penetrate deeper than skin. Ionising radiation strips electrons from atoms and includes X-rays and nuclear radiation arising from radioactive elements.

Question 12

How can radiation cause dna damage?

Answer 12

Nuclear radiation comprises alpha particles, beta particles and gamma rays. Radiation can damage DNA directly and also indirectly by generating free radicals.
Ionising radiation damages DNA bases and causes single and double strand DNA breaks.

Question 13

What are important sources of radiation

Answer 13

The most important type of radiation is UV because we are exposed daily from sunlight leading to increased skin cancer risk. For most people the main exposure to ionising radiation is natural background radiation from radon, which seeps from the earth’s crust.

Question 14

How can infections be carcinogenic

Answer 14

Some infections directly affect genes that control cell growth. Others affect growth indirectly by causing chronic tissue injury where the resulting regeneration acts either as a promoter for any pre-existing mutations or else causes new mutations from DNA replication errors.

Question 15

Give examples of viruses linked to neoplasm

Answer 15

Human Papilloma virus (HPV), which is strongly linked to cervical carcinoma, is a direct carcinogen because it expresses the E6 and E7 proteins that inhibit p53 and pRB protein function respectively, both of which are important in cell proliferation. In contrast, Hepatitis B and C viruses are indirect carcinogens that cause chronic liver cell injury and regeneration. Human Immunodeficiency virus (HIV) works differently - acts indirectly by lowering immunity and allowing other potentially carcinogenic infections to occur.

Question 16

Giev an explame of a bacteria inked to neoplasm

Answer 16

Bacteria and parasites can also indirectly lead to neoplasms. Helicobacter pylori causes chronic gastric inflammation and parasitic flukes cause inflammation in bile ducts and bladder mucosa, increasing the risk for gastric, cholangio- and bladder carcinomas
respectively

Question 17

Explain the 2 hit hypothesis (common exam q)

Answer 17

INHERITED PREDISPOSITION TO NEOPLASIA CAN OCCUR THROUGH GERMLINE MUTATIONS: In the 1800s a type of malignant retinal tumour called retinoblastoma was reported in multiple members of the same family. A dominant pattern of inheritance was seen. As well as running in families, this tumour occurred sporadically. In the 1970s Knudson postulated a two hit hypothesis to explain the differences between tumours occurring in families and those occurring in the general population. For familial cancers, the first hit was delivered through the germline and affected all cells in the body. The second hit was a somatic mutation. In the case of retinoblastoma this was in one of the 10 million+ retinal cells already carrying the first hit. In contrast, sporadic retinoblastoma has no germline mutation and so requires both hits to be somatic mutations and to occur in the same cell. In 1986 the actual gene, RB, was identified. Several other malignant neoplasms are now recognised that have both familial and sporadic counterparts and that follow the same two hit genetic basis as retinoblastoma.
Straight line - a single even constannt - 1 hit
2 hit hypothesis explains curve
Second hit likely - bilateral
Sporadic - bc chance - then by chance a second one occurs - very unlikely - unlikely to happen in 2 cells in same person - rarely bilateral
Timing of.2 hits differs for germline and sporadic

Question 18

What are tumour suppressor genes and Porto oncogenes

Answer 18

INITIATION AND PROMOTION LEAD TO NEOPLASMS WHEN THEY AFFECT PROTO- ONCOGENES AND TUMOUR SUPPRESSOR GENES: Genes that inhibit neoplastic growth are known as tumour suppressor genes and are the same genes that Knudson described. Because they act like brakes on tumour growth, both alleles must be inactivated, which explains why they need two hits, i.e. one for each allele. In contrast, genes that enhance neoplastic growth are known oncogenes and are abnormally activated versions of normal genes called proto-oncogenes. Only one allele of each proto-oncogene needs to be activated to favour neoplastic growth.

Question 19

Give an exampleHow do different mutations co operate

Answer 19

PROTO-ONCOGENES AND TUMOUR SUPPRESSOR GENES PLAY OPPOSING ROLES IN CELL SIGNALLING PATHWAYS: The first human oncogene to be discovered was RAS and this is mutated in approximately a third of all malignant neoplasms. The RAS proto-oncogene encodes a small G protein that relays signals into the cell that eventually pushes the cell past the cell cycle restriction point. Mutant RAS encodes a protein that is always active, ultimately producing a constant signal to pass through the cell cycle’s restriction point

Question 20

-

Answer 20

In contrast, the RB gene restrains cell proliferation by inhibiting passage through the restriction point. Inactivation of both RB alleles 
therefore allows unrestrained passage through the restriction point. This illustrates how one component of growth control, the restriction point, can be deregulated either by an activated oncogene or inactivated TS gene. Proto-oncogenes can encode growth factors (e.g. PDGF), growth factor receptors (e.g. HER2), plasma membrane signal transducers (e.g. RAS), intracellular kinases (e.g. BRAF), transcription factors (e.g. MYC), cell cycle regulators (e.g. CYCLIN D1) or apoptosis regulators (e.g. BCL2). TS genes encode proteins in the same pathways but with anti-growth effects (e.g. TP53). One other class of genes will be described next to complete your understanding of cancer genes.

Question 21

What are 3 types of dna repair

Answer 21

Nucleotide excision repair, mismatch repair, dsb repair

Question 22

What is XP?

Answer 22

XERODERMA PIGMENTOSUM (XP) IS DUE TO MUTATIONS IN DNA REPAIR GENES: Some inherited cancer syndromes have germline mutations that cause malignant neoplasms indirectly by affecting DNA repair. XP, which is autosomal recessive, is due to mutations in one of 7 genes that affect DNA nucleotide excision repair (NER). These patients are very sensitive to UV damage and develop skin cancer at a young age.

Question 23

What is HNPCC

Answer 23

Hereditary non-polyposis colon cancer (HNPCC) syndrome, which is autosomal dominant, is associated with colon carcinoma and the germline mutation affects one of several DNA mismatch repair genes

Question 24

Name. A cancer related to dsb repair

Answer 24

Familial breast carcinoma is associated with either BRCA1 or BRCA2 genes that are important for repairing double strand DNA breaks. These various mutations can also be found in sporadic malignant neoplasms.

Question 25

What is genetic instability

Answer 25

Chromosome segregation during mitosis can also be abnormal in malignant cells. Together, these alterations account for the accelerated mutation rate found in malignant neoplasms that is known as genetic instability. Genes that maintain genetic stability belong to a class of tumour suppressor genes called caretaker genes.

Question 26

Describee the nature of the mutations needed to make a malignant neoplasm and give an example

Answer 26

MULTIPLE MUTATIONS ARE REQUIRED TO MAKE A MALIGNANT NEOPLASM: Most malignant tumours require alterations affecting a combination of multiple TS genes and proto-oncogenes. This is illustrated by colon carcinoma, which usually starts as a colonic adenoma, from which arises a carcinoma. This is known as the adenoma- carcinoma sequence.

Question 27

What is progression?

Answer 27

Analysis of early adenomas, later adenomas, primary carcinomas and metastatic carcinomas showed that mutations accumulate during this sequence and the time frame is typically decades. This illustrates a general principle of step-wise accumulation of mutations in malignant neoplasms.
This steady accumulation of multiple mutations is called cancer progression. Therefore cancer evolves by initiation and promotion as described above and finally by progression.

Question 28

How many mutations are needed for a fully evolves malignant cell

Answer 28

Process keeps going until suffient mutations to make a malignant neoplasm. The exact number of mutations needed for a fully evolved malignant neoplasm is unknown but is thought to be approximately ten or less.

Question 29

What are 6 hallmark cellular behaviour that cancer mutations affect

Answer 29

It is now believed that a fully evolved malignant neoplasm exhibits six hallmarks of cancer plus one enabling feature:
(1) self-sufficiency in growth signals;
(2) resistance to growth stop signals;
(3) no limit on the number of times a cell can divide (cell immortalisation);
(4) sustained ability to induce new blood vessels (angiogenesis);
(5) resistance to apoptosis;
(6) the ability to invade and produce metastases.
Hallmarks 1 to 5 are primarily about increased growth and are therefore likely to be relevant to both benign and malignant neoplasms. Hallmark 6 is exclusively relevant to malignant neoplasms. Genetic instability is regarded as an enabling characteristic. Newer hallmarks have been suggested but I will not discuss these.

Question 30

I’ve examples of how hallmarks are achieved in different types of cancer

Answer 30

-

Question 31

Give an overview of a model of cancer pathogenesis

Answer 31

First, somatic cells are exposed to environmental carcinogens (chemicals, radiation, infections) that are either initiators (that cause mutation) or promoters (that cause sustained proliferation) culminating in a monoclonal population of mutant cells . In about 5% of cancers inherited mutations in the germline can be present. By chance, some of these clones harbour mutations affecting a proto-oncogene or a tumour suppressor gene, whose protein transcripts play crucial roles in cell signalling pathways affecting “hallmark” changes. During progression the cells acquire further activated oncogenes or inactivated tumour suppressor genes, including ones that cause genetic instability. This eventually results, after many years or even decades, in a population of cells that have acquired a set of mutations that produce all of the “hallmarks of cancer”.