Week 18 - Breast Cancer

Question 1

Describe how DNA replicates within the cell cycle

Answer 1

Interphase - G1, S, G2 - Growth, DNA replication and prep all happening
Mitosis - Prophase, Metaphase, Anaphase, Telophase
Cytokinesis- cytoplasm splitting

Question 2

Describe the type of errors that can occur during cell cycle

Answer 2

Nucleotides damaged or matched up incorrectly
Point mutations
DNA amplification
Chromosomal rearrangement
Epigenetic modifications - methylation, etc.

Question 3

Describe how errors that occur during cell cycle may be repaired, what consequences they have

Answer 3

Point mutations
DNA amplification
Chromosomal rearrangement
Epigenetic modifications - methylation, etc.

Mutations can allow cell to bypass checkpoints - by two main mechanisms - activating oncogenes (RAS, MYC) and deactivating tumour suppressor genes (BRCA, p53, APC)

FIXING ERRORS:
Proofreading - DNA polymerases can “check their work” with each base that they add.
Mismatch repair - after proofreading, a protein coplex comes through cutting away errors that were missed
Direct reversal of damage - some issues can be reversed
Base excision repair - specialised glycosylases remove specific pieces of damage
Non-homologeous end joining - gluing damaged bits together after breakge
Homologous end joining - Broken chromosome pairs with its homologue so piece is replaced

Question 4

Outline cell cycle control mechanisms

Answer 4

Cell cycle ‘checkpoints’ - do not let process progress if any issues - controls progression from G1/S, G2/Mitosis, Metaphase/A

Mitogens - cytokines that stimulate cell proliferation

Question 5

What is the relevance of cell cycle control mechanisms and their relevance to tumour development

Answer 5

Checkpoints, repair mechanisms

Mutations can allow cell to bypass checkpoints - by two main mechanisms - activating oncogenes (RAS, MYC) and deactivating tumour suppressor genes (BRCA, p53, APC)

RAS mutation means a lot of phosphorylation of proteins in the cell, which starts making a lot of CDK and cyclins

Mutations to tumour suppressor genes means that cells will no longer be able to make proteins that perform regulatory functions (like pausing growth/division, facilitating repairs and initiating apoptosis)

Question 6

Outline the role and timing of two key tumour suppressor proteins

Answer 6

p53 - S phase - coded by TP53 which is ‘guardian of the genome’
pRb - G1/S phase - regulates transcription

Question 7

What are the 4 stages of carcinogenesis?

Answer 7

Initiation, Promotion, Progression, Malignant conversion

Question 8

What are the different types of carcinogens?

Answer 8

Chemical, physical and viral

Question 9

What is the difference between proto-oncogenes and oncogenes?

Answer 9

Proto-oncogenes - normal cellular genes which regulate cell growth
Oncogenes - a proto-oncogene that has been activated by mutation or over-expression

Question 10

Types of alterations that transform proto-oncogenes into oncogenes (3)

Answer 10

Point mutation
Gene amplification
Chromosomal translocation

Question 11

What does HER2 need to be active?

Answer 11

Dimerisation (with itself or another)

Lind with ligand (human epidermal growth factor)

Question 12

What are the treatment options for HER2+ cancers? (2)

Answer 12

Trastuzumab (Herceptin) and pertuzumab

Question 13

Describe process of BCR-ABL1 mutation and treatment

Answer 13

In 95% of cases of myeloid leukaemia
Chromosomal translocation creates Philadelphia chromosome
BCR section now stimulates ABL section
Can be treated successfully with Imatinib

Question 14

How does BRCA 1/2 work as a DNA repair gene?

Answer 14

Repair double strand breaks
(if it is mutated, there is nothing that fixes double strand breaks - as PARP only fixes single strand breaks which start to add up)

Question 15

What is a PARP inhibitor?

Answer 15

PARP usually fixes single strand breaks
PARP inhibitors can be used in patients with BRCA mutation - the cells will not be able to repair single or double strand breaks and will collapse and initiate apoptosis

Question 16

What is Rb and how does it work?

Answer 16

Retinoblastoma protein
Works in G1/S to regulate transcription
Binds to E2F which facilitates phosphorylation

Question 17

What is a mitogen?

Answer 17

Cytokine (small protein) that stimulates cell proliferation - some of them are proto-oncogenes

Question 18

Describe the cell cycle in cancer

Answer 18

PICTURE FROM FOLDER

Question 19

What is phosphorylation?

Answer 19

Reversible protein phosphorylation, principally on serine, threonine or tyrosine residues, is one of the most important and well-studied post-translational modifications. Phosphorylation plays critical roles in the regulation of many cellular processes including cell cycle, growth, apoptosis and signal transduction pathways.

Phosphorylation is the most common mechanism of regulating protein function and transmitting signals throughout the cell.

Question 20

Examples of non-neoplastic alterations in cell growth (5)

Answer 20

Hyperplasia - More of them
Hypoplasia - Less of them
Hypertropy - Bigger
Atrophy - Smaller
Metaplasia - Replacement with another cell type

All can be physiological or pathological

Question 21

Types of cells (3)

Answer 21

Permanent
Stable
Labile

Question 22

Define hyperplasia

Answer 22

Increase in tissue or organ size due to an increase in cell number

Question 23

Define hypoplasia

Answer 23

A decrease in organ or tissue size due to loss of cells

Question 24

Define hypertrophy

Answer 24

Enlargement because of increase in cell size

Question 25

Define atrophy

Answer 25

Shrinkage of a tissue or organ due to loss of cells and decrease in cell size

Question 26

Define metaplasia

Answer 26

Reversible replacement of one mature cell type with another

Question 27

Define dysplasia

Answer 27

Pre-malignant state, characterised by disordered maturation of cells within a tissue

Looks like malignancy, still within epithelium (has not broken through basement membrane)

Question 28

Benign vs malignant

Answer 28

Can’t vs can metastisise

Question 29

Carcinoma, sarcoma (define)

Answer 29

Carcinoma - suffix applied to malignant epithelial tumours

Sarcoma - suffix applied to malignant connective tissue tumours

Question 30

How do tumours develop? What kinds of things can cause this process?

Answer 30

Accumulation of mutations which over-ride the normal mechanisms which control cell proliferation.
Caused by things such as smoking, radiation, viruses, cancer-causing chemicals (carcinogens), obesity, hormones, chronic inflammation and a lack of exercise

Question 31

Benign vs malignant microscopic features

Answer 31

PICTURE IN FOLDER

Question 32

Outline types and locations of epithelium

Answer 32

Squamous - skin, GI tract
Cuboidal / columnar - glandular, hollow organs
Columnar - ureters, internal tubes

Question 33

What is an adenocarcinoma?

Answer 33

Cancer of the glandular epithelium

Question 34

Examples of non-epithelial tumours

Answer 34

Connective tissue tumours

PICTURE IN FOLDER

Question 35

How do tumours spread?

Answer 35

• directly into adjacent tissues (eg basal cell Ca of skin)
• via lymphatics (eg Ca breast, colon)
• blood vessels (eg renal cell Ca, small cell Ca lung, prostatic Ca, all sarcomas)
• along nerves (eg Ca pancreas, prostate)
• across coelomic cavities (eg Ca stomach, ovary)

Question 36

Example grading of tumours

Answer 36

well differentiated tumours (grade 1) resemble the tissue of origin and tend to behave less aggressively than poorly differentiated tumours (grade 3)

Question 37

Describe TNM system

Answer 37

T= tumour, generally tumour size, eg Ca breast, T1 <2cm, T4 >5cm or tethered to skin
N= nodes. Regional lymph node involvement is N1, distant nodes N2
M=metastases: M0 none, M1 present, MX not known