Introduction

Question 1

What is a benign variant

Answer 1

variant that is unlikely to be linked to disease

Question 2

What is a pathogenic variant?

Answer 2

disease causing variant

Question 3

Explain how genetic diseases are common

Answer 3

8% of live births will have some sort of recognisable genetic disorder before adulthood

In the UK, 1 in 2 will develop cancer in their lifetime

3% of new cancers in the UK are classified as a Leukaemia

Two thirds of us will suffer from a complex disease with a genetic component in its etiology

Question 4

What are constitutional diseases?

Answer 4

the assumption here is that every cell in the body has the same “genotype”.

Constitutional diseases are diseases that you are born with and may be clustered to make diagnostic pipelines more efficient.

Question 5

Examples of constitutional diseases

Answer 5

Complex disorders - Epilepsy, depression
Neurogenic disorders - Huntintons disease, ALS
Sickle cell anemia
Inborn errors of metabolism and haemosis - Zellwager syndrome
Connective tissue disorders - Osterogenesis Imperfecta
Developmental disorders - Autism
Reproductive genetics - Common aneuploidy
Respiratory disorders - Cystic fibrosis
Mitochondrial disorders - mitochondrial myopathy

Question 6

What are oncology genetics?

Answer 6

“acquired genetic diseases”,

Question 7

Why are cancers considered separate to constitutional diseases?

Answer 7

. The reason why these cancers are considered separately to constitutional disease is because for these cancers to develop to a stage where they are detectable – other abnormalities will have occurred and accumulated in the malignant cells.

Question 8

Whats important to consider about the genotype of a cancer cell?

Answer 8

that the genotype of a cancer cell or cancerous tissue will certainly be different to the genotype of the rest of the patient.

Question 9

Example of oncology diseases

Answer 9

Hereditary cancers
Breast and ovarian (BRCA1/2)

Solid tumours
Breast, Bladder, Colorectal, Pancreatic, Lung etc

Haematological Malignancies
Lymphoma, Multiple Myeloma, Leukaemia, MDS

Pharmacogenetics
Herceptin: Breast cancer

Question 10

What are the four main pillars of clinical diagnostics (pathology)

Why are there four?

Answer 10

Microbiology, Blood Sciences, Cellular Sciences and Genetics

because many diseases require the expertise of clinicians across a wide range of scientific specialisms

Question 11

Cytogenetics
Examples
What are they used to investigate and underpin?
Why are they still used for cancer diagnosis?

Answer 11

These are cytogenetics that include G-Banding and FISH, which are used to investigate gross-microscopically visible chromosomal aberrations. Cytogenetics used to underpin most prenatal, fertility and developmental delay referrals.
Since cytogenetics is able to report on important genetic abnormalities at the level of a single cell, whilst maintaining tissue architecture and cell and nuclear morphology, the cytogenetic techniques are still vital for cancer diagnoses.

Question 12

Examples of molecular genetic techniques

Answer 12

PCR (Taqman, MLPA)
Technologies based on sequencing (sanger, pyro, illumina)
Microarrays

Question 13

PCR and sequencing techniques

Answer 13

are used to detect submicroscopic abnormalities such as copy number variants, changes to the sequence of the coding regions of genes as well as changes to the level of gene expression.

Question 14

How is cancer thought to arise?

Answer 14

) via the accumulation of genetic abnormalities that inactivate or suppress the expression of tumour suppressors or enhance the function of oncogenes.

Question 15

Tunour suppressor genes

Answer 15

Tumour suppressors are genes that have “anti cancer” roles in cells. Such genes are responsible for halting the cell cycle when DNA damage has been detected, repair of damaged DNA or the initiation of apoptosis when genomic insults have not been repaired.

Question 16

Oncogenes

Answer 16

Oncogenes on the other hand are genes that control pro-growth and proliferation signals to cells.

Question 17

WHat is not sufficient to cause cancer?
However, what can this lead to and result in?

Answer 17

. The inactivation of a single tumour suppressor or overexpression of a single oncogene are not sufficient cause disease in the vast majority of cases. But as these accumulate they permit more mutations, which increase the likelihood of acquiring even more.– this is called a “mutator phenotype” and can result in the malignant transformation of normal tissues.

Question 18

What is a key concept about this module?

Answer 18

our understanding of cancer is incomplete – and as such not all genetic abnormalities that are observed – are informative at this time.

The biomarkers that we do end up characterising and using to diagnose disease may include the initial priming mutations in tumour suppressors or oncogenes, or they could have been generated downstream of these initial events.

In any case – because of how cancer presents (often weeks, months or even years after the initial priming mutations) it is rare and perhaps impossible for us to know whether a mutation was there at the beginning.