Case 15: chemo Flashcards

Question

Questions to consider with geneticists when deciding about cancer treatment

Answer 1

- Does this family have a higher (and how much higher) risk of certain cancers? - Is extra screening warranted?; are risk reducing options indicated? - How to advise other family members.

Answer 2

- Protective role in repairing cells during growth. Normally protect patient from cancer and genetic changes. - Mutation in tumour suppressor gene means we only have one normal working copy of the gene (the other is non functional) - Germline mutations need a ‘second hit’ in the working copy (Knudson’s hypothesis): will mean neither copy of the gene work - More complex than this

Answer 3

- Promote growth - Often activate during early/embryonic life - If they acquire ‘gain-of-function’ (i.e. ‘activating’) mutations they are termed ‘proto-oncogenes’ and increase the chance of cancer- cause uncontrolled cell growth - E.g. activating mutations in MEN2 as a cause of Multiple Endocrine Neoplasia type 2

Answer 4

- an individual is genetically predisposed **to cancer, but cancer is not inevitable - acquired mutations are still needed - penetrance may not be 100%

Answer 5

- Bilateral Retinoblastoma or those with a family history are highly likely to have an inherited germline mutation in one copy of their RB1 gene - Have one faulty RB1 gene only get retinoblastoma if there is a mutation in the second one - Without inheritance would have to acquire a mutation in both genes

Answer 6

- Retinoblastoma - RB1 - genes function is cell division, DNA replication and cell death - Li-Fraumeni syndrome (brain, tumours, sarcoma, leukemia) - TP53 - gene function in cell division, DNA repair and cell death - Familial adenomatous polyposis - APC - gene functions in cell division, DNA damage, cell migration, cell adhesion, cell death - Breast and/or ovarian cancer - BRCA1, BRCA2 - gene functions in repair of double stranded DNA breaks, cell division, cell death

Answer 7

- Need germline- generally blood DNA - Gene by gene – traditional approach e.g. test BRCA1/2 in breast/ovarian family; test CDH1 in diffuse gastric cancer family - Panel approach (often used now) e.g. in family with colorectal cancer/polyps test a panel of 15 relevant genes. Used in Melanoma/renal - ‘phenotype agnostic approach’ – large panel to test all known cancer predisposition genes or whole genome test - Enter cancer genome and germline genome in patient with cancer: in order to know which mutations are inherited and which are acquired. in order to give targeted treatment and discuss familial inheritance

Answer 8

- tumour genetic testing - germline genetic tests in other family members - MSI or IHC testing for colorectal or endometrial cancer (esp in suspected Lynch syndrome) - histopathology on other lesions (e.g. benign skin tumours can be a clue to some rare inherited cancer predisposition syndromes) - investigations to explore phenotype

Answer 9

- any test which analyses DNA whether a single nucleotide or an entire genome. Either: - Diagnostic- a test which seeks to confirm a clinical diagnosis - Predictive: a test offered to the relative of someone in whom diagnostic testing has confirmed a genetic disorder

Answer 10

- Each nucleated cell contains two copies of the genome - Contains billions of nucleotides

Answer 11

- Use Giemsa due and analyse under a microscope - Karyotype analysis detects whole chromosome changes like trisomy, monosomy and translocation. Becoming outdated is being replaced by array CGH - FISH (fluorescent in situ hybridisation): detects microdeletions or microduplications. Used to detect Chromosome translocations and in cancer diagnostic i.e. to detect gene fusion

Answer 12

- Is replacing karyotyping= as can detect detect duplications and absences in smaller chromosome regions - Allows high resolution chromosome analysis: done with DNA in solution rather than whole chromosome preparation - Can detect trisomy, CNVs, microdeletions and smaller ins/dels but it will not detect single nucleotide changes and cannot, at present, detect balanced translocations.

Answer 13

- Not useful: cannot detect single nucleotide changes. Cannot detect balanced translocations (karyotyping can) - Clinical use of array CGH: pre-implantation diagnosis, for prenatal diagnosis after anomalies are detected by US

Answer 14

- DNA from patient and control are broken down into little pieces and are both labelled with different dyes - They then hybridise to a detector array - If the patient is missing some DNA it will go the control colour. If there is equal patient and sample DNA a fusion colour will form. If the patient has duplication of DNA it will give the patient colour signal. - If DNA is missing: red colour (control) - If DNA duplicated: green (patients)

Answer 15

- Originally used Sanger technique - Now use NGS (next generation sequencing): which can read fragments of DNA in solution very quickly and reliably. Sanger sequencing then confirms these mutations - Normally analyse a ‘panel of genes’ - Can do ‘agnostic’ analysis where you see if there is anything of interesting - Standard genetic test: whole exome and whole genome sequencing, followed by focussed analysis of sequence data

Answer 16

- Can read the whole exome (1% of the genome) - The ‘Clinical exome’ (18,000 genes associated with the disease) - The whole genome

Answer 17

1. Sensitivity: This is the ability of the test to find the mutation 2. Specificity: variation in a single gene can sometimes cause different diseases 3. Technical: how good is a particular laboratory technique at identifying a genomic abnormality? 4. Gene coverage: can we test all relevant parts of the genes associated with a particular phenotype? 5. Phenocopy: the existence of non-genetic conditions that mimic a genetic disorder.

Answer 18

1. Normal 2. Abnormal (a mutation, or ‘pathogenic variant’) 3. Uncertain (a ‘variant of uncertain significance’, or VUS)

Answer 19

- testing CAG repeat in HTT for Huntington's - high diagnostic specificity because negative genomic test can exclude the diagnosis

Answer 20

- Testing for mutations in genes associated with familial hypertrophic cardiomyopathy - lower diagnostic specificity because: - gene panel tests do not cover every possible gene associated with HCM - HCM is not the only cause of LV hypertrophy - mutation in a particular gene does not always cause HCM (may cause dilated cardiomyopathy or may have no consequence) - variable expressivity/ penetrance

Answer 21

- Pros: such testing may clarify a genetic diagnosis, the cause of the patients cancer and other diseases risks for the patient and their family family - Cons: a lot to take in at a difficult time, worry about other cancer risks, worry about family

Answer 22

- Widespread germline genetic testing- will receive info on: other important single gene medical conditions (i.e. BRCA1), recessive disease carrier status and Pharmacogenomic information - Not generally offered on the NHS but might be in the future

Answer 23

- Anything that is not typically expected in a person - May be: benign, likely benign, uncertain clinical significance, likely pathogenic, pathogenic

Answer 24

- DNA mutations in single genes - amplifications/ over expressions of certain genes - chromosome number changes - chromosomal translocations - Cancer predisposition genes are often Tumour suppressor genes

Answer 25

- A type of targeted cancer drug which treats ovarian cancer - Includes Olaparib, Niraparib and Rucaparib

Answer 26

- Tumour genetic testing in patient - Germline genetic tests in other family members - MSI (Microsatellite instability)/IHC (Immunohisto chemical) testing – particularly on colorectal / endometrial tumours – particularly if suspect Lynch - Histopathology on other lesions e.g. benign skin tumours can be a clue into some rare inherited cancer predisposition syndromes (e.g. trichilemmomas in PTEN)

Case 15: chemo Flashcards

(50 cards)