A multi-disciplinary understanding of cancer: from tumour biology to clinical care Part 2

Question 1

What is “grade” of cancer and “stage”

Answer 1

GRADE:
How aggressive and unlike the originating cell type the cancer looks under
the microscope, in terms of proliferation and anaplasia

STAGE: How far has a cancer developed and spread in terms of: T, N and M

Question 2

What two types of genes are commonly mutated in
cancer and how do the oncogenic mechanisms for
mutation in these two types of genes differ?
Examples too

Answer 2

Changes to tumor suppressor genes (inactivated proteins aka not enough brake) and proto-oncogenes (overreactive proteins, aka too much throttle)

tumor suppressor genes: APC (familial adenomatosus polyposis)
and Lynch syndrome: MLH1 and MLH2)

Inactivating mutations of a tumour suppressor gene:
Inherited predisposition involves inheriting one defective germline copy (the first hit) and subsequent somatic mutation of the remaining normal copy in the tumour (the 2nd hit)

Sporadic cancers, with no inherited predisposition, involve sequential somatic
inactivation of both alleles – i.e. both the 1st and 2nd hits are somatic

Activating somatic mutations of a proto-oncogene (often of only one copy)

Question 3

What genetic testing is used for cancer to see if a patient is predisposed to cancer

Answer 3

Next generation sequencing

Question 4

What does it mean if next generation fails to show any DNA variants in a gene known to cause that cancer?

Answer 4

Likely a sporadtic cancer than inhertied cancer

Question 5

Treatment for colon cancer

Answer 5

FOLFIRI (5-Fluorouracil) and Cetuximab

Question 6

What is the precaution when assessing the Pharmacogenomics of 5-Fluorouracil (5-FU) for colon cancer patients?

Answer 6

Specific DPYD gene
sequences that cause toxicity to 5-FU.

Question 7

Why use Cetuximab for colon cancer?

Answer 7

EGF goes to EGFR causing KRAS activation = enhanced proliferation and survival of cells

In cancer stop EGF binding to EGF slows down cell growth

BUT if you have mutatn KRAS (doesnt need activation from EGF:EGRF) then drug Cetuximab does NOTHING TO slow down cancer.

Question 8

Immunotherapy: How do cancer cells evolve to evade immune attack

Answer 8

Activate Immune Checkpoints
Reduce HLA expression
Reduce immunogenicity (antigen editing)
Mutations that confer resistance to immune attack by immune cells
Release inhibitors (e.g. cytokine TGF-beta)
Activate inhibitory T cells (T Reg)
Reducing amino acid availability (tryptophan)

Question 9

Drugs that prevent Cancer cells stopping T cell activation

Answer 9

CTLA1:CD80 (cancer cell) ipilimumab

PD1:PD-L1 (cancer cell) nivolumab

Question 10

Classification of colorectal cancer: 2 groups

Answer 10

• Tumours with mismatch repair deficiency and/or microsatellite instability
  = (ICIs effective, immune cell immunotherapy)
• 95% of metastatic colorectal cancers are microsatellite stable and have
  chromosomal instability (ICIs ineffective unless high mutational burden)