Cancer Genetics

Question 1

Describe Retinoblastoma

Answer 1

• Commonest childhood eye tumour
• 1 in 15,000 children
• 3rd most common childhood malignancy
• Average age of onset 18 months
• 60% present with leukocoria (white pupil
• Treat with radiotherapy/ laser/ cryotherapy or enucleation

Question 2

What is the 2 hit hypothesis?

Answer 2

-2 groups of children with retinoblastoma
-Early onset and bilateral, vs later and single tumour
-Early= germline copy of damage gene present in all cells, second hit occurs somatically
-Chance of germline mutation carrier to get second somatic mutation greater than none carrier to get two hits in same cell
=Both copies of the tumour suppressor gene must be inactivated or lost before neoplastic transformation can take place.
=If an individual has 2 good copies of the tumour suppressor gene then two separate somatic “hits” will be required in the same cell before neoplastic

Question 3

What is a tumour suppressor gene?

Answer 3

-Controls cell growth and differentiation
-Function as “cellular recessives”
-Dampening or oppressive effect on regulation of cell cycle/ promote apoptosis
-Recessive at phenotypic level for cancer to develop
-Mutations inherit in autosomal dominant fashion at genotypic level
=Genes involved in the control of abnormal cell proliferation.
=Encode proteins that negatively regulate cell growth
=Loss or inactivation of both copies of a tumour suppressor gene leads to the development of malignancy.

Question 4

Describe molecular testing in Retinoblastoma

Answer 4

-Predisposition to develop Retinoblastoma (“first
hit” germline mutation) inherited in autosomal
dominant fashion
-10% of RB is familial
-If no FHx and bilateral RB 90% chance of RB1
germline mutation
-If no FHx and unilateral multifocal RB 15-90%
chance of RB1 germline mutation
-If no FHx and unilateral unifocal RB 15% chance
of germline mutation
-Risk of non-ocular tumours – lifestyle advice

Question 5

Describe Neurofibromatosis type 1 (NF1)

Answer 5

-Affects 1 in 2,500
-Multisystem disorder
-Dominant inheritance
-Fully penetrant, all will develop condition
-Highly variable expressivity
=Great variability between affected individuals in the same family
=Learning disability, large tumour load/ discrete signs

Question 6

Describe the NF1 gene

Answer 6

• The NF1 gene on chromosome 17 encodes the protein Neurofibromin
• 59 exons (350kb genomic DNA)
• 50% cases NF1 new mutations (50% have family history)
• Neurofibromin suppresses Ras, a potent activator of cell growth and proliferation

Question 7

Describe the clinical features of NF1- neurofibromas

Answer 7

Neurofibromas

• Discrete cutaneous neurofibroma of dermis or epidermis
• Discrete subcutaneous neurofibromas that lie deeper in the skin
• Deep nodular neurofibromas
• Diffuse plexiform neurofibromas

Question 8

Describe the clinical features of NF1- other skin manifestations

Answer 8

Axillary freckling/ flexion crease freckling (axillary/ neck/ groin)

Question 9

Describe the clinical features of NF1- ophthalmological findings

Answer 9

-Lisch Nodules (90%)
=Growths that affect vision in iris
-Optic Glioma= growth around optic nerve
=15%
=Usually asymptomatic
=Can present with deteriorating vision
=Only treated if do affect vision

Question 10

Describe the clinical features of NF1- skeletal problems

Answer 10

-Scoliosis
=10%
=Usually mild
=Very small number with severe presentation
-Pseudarthrosis
=1%
=Usually of long bones
=Pathological fractures

Question 11

Describe the clinical features of NF1- CNS

Answer 11

-Learning disability
=Usually mild
=30-50%
-Large head circumference

Question 12

Describe the clinical features of NF1- Cancer predisposition

Answer 12

-Malignant tumour of the peripheral
nerve sheath
 Life time risk of 13%
 Usually from pre-existing plexiform
neurofibroma
-Astrocytoma 2%
-Phaeochromocytoma 0.7%
-Rhabdomyosarcoma 1.4%

Question 13

What is the Diagnostic criteria of NF1?

Answer 13

Two or more of:
->/ 6 café au lait spots
=>/ 1.5cm in post pubertal individuals
=>/ 0.5cm in prepubertal individuals
->/ neurofibromas or >/ 1 plexiform neurofibroma
-Freckling in axilla, neck or groin
-Optic glioma
->/2 Lisch nodules
-Distinctive bony lesion:
=Dysplasia of sphenoid or dysplasia of lone bone cortex
-First degree relative with NF1

Question 14

What are genetic counselling issues?

Answer 14

 Variability in phenotype
makes reproductive
decision making difficult
=Can't predict how it will affect family members
 Value of screening -
differences between
different healthcare
systems
 Mutation analysis of
limited value

Question 15

What is Von Hippel Lindau Disease?

Answer 15

-Affects 1 in 35,000 individuals
-Autosomal dominant
-Penetrance high
-Associated with a wide variety of tumours,
 retinal angiomas (60%)
 haemangioblastomas
 (cerebellar 60%, spinal 25% and brainstem 18%)
 renal cell carcinoma (28%)
 phaeochromocytoma (15%).
=Cysts in kidneys

Question 16

Describe the vHL gene

Answer 16

vHL protein
suppresses tumour
growth and
downregulates
angiogenic factors.
 ~ 90% individuals
with clear
diagnosis of vHL
will have mutation
identified

Question 17

Describe the screening regimen for vHL (yearly)

Answer 17

-Ages 5-18
=Eye/retinal examination
=24 hour urine collection for catecholamines
-Ages 18-65
=Eye/retinal examination
=Physical examination
=24 hour urine collection for catecholamines
=MRI of abdomen
-MRI of brain and spine (2-3 yearly)

There is an agreed screening protocol which begins with yearly opthalmological assessment from the age of 5 followed by urinary metanephrin estimation from age 10 and MRI scanning from age 18.

Question 18

What is Familial Adenomatous Polyposis?

Answer 18

 1 in 10,000
 polyps develop during second decade
 colonic malignancies third decade
-Underlying APC mutations
 Associated features
=CHRPE (ophthalmologist, affects fundus)(congenital hypertrophy of the retinal pigment epithelium) 
=Gastroduodenal polyposis.
= Desmoid tumours (connective tissue growths)
= Osteomas (bony growth of skull or jaw)

Question 19

Describe APC mutations

Answer 19

• Majority truncating mutations

- attenuated FAP

Question 20

Overview of mutations in cancer

Answer 20

Cancer is predominantly a disease of the elderly caused by the acquisition of mutations in somatic DNA. In a small subset it can be caused by an inherited predisposition, a germline mutation in an oncogene, mismatch repair gene or tumour suppressor gene. The majority of inherited cancer syndromes are caused by mutations in tumour suppressor genes.

Question 21

Screening for FAP

Answer 21

Because of the possibility of developing a bowel cancer in the second decade of life, sigmoidoscopy is generally recommended yearly from the age of 15. When polyps begin to appear, prophylactic colectomy should be discussed. Because of the risk of small bowel tumours, we recommend upper GI endoscopy in adult life although there is little evidence that early detection of small bowel tumours influences disease outcome. Extra-colonic manifestations of APC are dealt with as and when they arise.

Question 22

When can a pregnancy legally be terminated?

Answer 22

• Continuation of the pregnancy would involve risk, greater than if the pregnancy was terminated, of injury to the physical or mental health of the pregnant woman or any existing children of her family.
• There is a substantial risk that if the child were born it would suffer from such physical or mental abnormalities as to be seriously handicapped.
• If continuation of the pregnancy would result in grave permanent injury to the physical or mental health of the pregnant woman