Familial cancer

Question 1

Consultation of genetic conselling

Answer 1

1. draw out family tree then verify diagnosis
2. estimate likelihood of predisposing gene mutation
3. discuss screening, risk facors and preventative meausures
4. Test for mutations (e.g BRCA-1)

Patient History
Family: >1 individual in same family affected by similar cancer
Individual: multitude 1o tumours, early age of onset

Question 2

Capability of cell to develop/ cancer

Answer 2

proliferating signalling
avoidance of apoptosis (loss p53)
by passing replicate senescence (inactivation of p53/ Rb signalling)
Insensitivty to anti-growth signalling (TGF-B signalling)
escape from immune surveillance (T-reg)

Question 3

Control of cell cycle

Answer 3

Tumour supressor genes - 90

• inhibit progression through cell cycle (eg Rb, p53)
• promote apoptosis (p53) or act as stability genes (loss of funtion)

Stability genes- type of tumour supressor gene, minimise genetic alterations, when inactivated mutation in other genes more common

Proto-oncogenes

• stimulate progression
• activate- oncogenes with gain of function to result in cancerous proliferation

Question 4

Familial cancer

Answer 4

Uncommon (5-10%)
early onset
multiple primary tumours

Single mutation in life

Question 5

Sporadic

Answer 5

common (90-95%)
late onset
single primary tumour

Two mutations in life
- mostly inherited in AD fashion

Question 6

Knudsons two hit hypothesis

Answer 6

require two mutations for disease to develop (tumour supressor gene)

Question 7

Le Fraumeni Syndrome

Answer 7

Autosomal dominant
Mutation - TP53

Characteristic - earl onset, development of multiple cnacer

Question 8

Tumour suppressor genes

Answer 8

BRAKES
Normal function
1. inhibit progression through the cell cycle and cell proliferation - RB, TP53, NF1, APC
2. promote apoptosis TP53, BAX or
3. Stability genes - MLH1, MSH2, BRCA1, BRCA2

Mutation results in loss of function of protein
Need 2 inactivet gene copies for tumourgenic effect of gene (second hit after inheritance of one inactivated copy)
where inherited, pedigree shows an autosomal dominant pattern of cancer predisposition with incomplete penetrance

Question 9

Proto-oncogenes

Answer 9

Proto-oncogenes

Normal function

1. stimulates the cell cycle or
2. promtoe cell division.growth

Mutations

• not usually inherited Except RET gene - causes MEN2
• activated by mutation results in “oncogenes” - gain of function
• need 1 mutated gene copy for tumouregenic effect of gene

Question 10

Breast cancer Genes

Answer 10

BRCA 1- chromosome 17
BRCA 2- chromosome 13

BRCA1 - 1/2 found in 84% of familiies that have had 4 people with breast cancer before 60 years old

Ovarian cancer increases the chances of BRCA1 Male breast cancer increases the chances of BRCA2

BRCA 1: 65% of breast cancer by 70 maybe 80 if modifier genes
40% of ovarian cancer

BRCA 2: 45% risk of breast cancer 11% risk of ovarian cancer 5-6% risk of male breast cancer

Question 11

Other genetic mutations that can cause breast cancer

Answer 11

TP53 (Li fraumeni syndrome) PALB2

PTEN (thyroid and endometrial cancer)