Utility Of Molecular Diagnostics In Cancer Management

Question 1

Tests of tumour pathology may involve evaluation of what?

Answer 1

• secreted products (variety of proteins)
• presence of tumour cells (can be shed - e.g. in sputum, urine, blood)
• tumour nucleic acids
• tumour tissue

Question 2

Tumours aberrantly produce proteins which can be secreted and used for diagnosis, prognosis, monitoring and screening. Give some examples

Answer 2

• CRCs = CEA
• Ovarian cancers = CA125
• Hepatocellular cancers = AFP
• Pancreatic cancers = CA19-9
• Prostrate cancers = PSA

Question 3

What are the 6 P’s of cancer genetics?

Answer 3

• Predisposition (gene variants informing on risk of cancer development)
• Profile (gene variants present in tumour)
• Prognosis (gene variants informing on outcome)
• Prediction (gene variants informing on response to therapy)
• Pharmacogenetic (gene variants informing on how the body handles a therapy)
• Pharmacotherapeutic (targetable genes)

Question 4

How are the 6 P’s of cancer genetics split based on germline and tumour DNA?

Answer 4

• Germline DNA involves predisposition and pharmacogenetics

- Tumour DNA covers profile and in turn prognosis, prediction and pharmacotherapeutics

Question 5

It is important that tumour is present in the tissue sample or else you have risk of a false negative result. This is also affected by the limit of detection of the method - provide details

Answer 5

• Sanger seq requires minimum of 20% tumour cells
• Pyrosequencing will pick up mutations in around 5% of tumour cells
• Real time ARMS PCR can pick up 1% of mutant cells

Question 6

What are the main reasons behind finding a mutation?

Answer 6

• Implications for the patient: risk of other cancers (BRCA1/2 for breast and ovarian), influence treatment options (e.g. PARP inhibitors)
• Risk to relatives: predictive testing, prophylactic surgery/screening

Question 7

Which individuals/families will benefit from mutation testing?

Answer 7

• large enough fhx of one type of cancer/those that fit together (e.g. BRCA1 + breast/ovarian)
• earlier age of onset (more likely to have one inherited mutation for the two hit hypothesis)
• Phenotypic features point towards inherited mutation (e.g. multiple GI polyps in FAP)
• tumour characteristics that indicate predisposition (e.g. MSI, BRCA1 triple neg tumours)

Question 8

Cancer research U.K. has launched a stratified medicine initiative. What are some of the biomarkers involved?

Answer 8

• CRC: KRAS, BRAF, TP53, PI3KCA
• Breast: TP53, PI3KCA, PTEN, CYP2D6
• Ovary: BRAF, PI3KCA, PTEN
• Prostrate: PTEN, TLR4
• Lung: EGFR