Familial Cancer

Question 1

Tumour Suppressor Genes (TSGs)

1. What are the 3 normal functions of tumour suppressor genes and give 2 examples of TSGs for each function [9]
2. How many mutated gene copies is needed for the tumorigenic effect of the gene to occur? [1]
3. What is the general tumorigenic effect of the gene? [1]
4. When TSG mutation is inherited, how does this show up on a pedigree? [2]

Answer 1

1. normal functions of TSGs:
   
   • inhibits progression through the cell cycle + cell proliferation
     
     • e.g. TP53, NF1
   • promotes apoptosis
     
     • e.g. TP53, BAX
   • act as stability genes to minimise genetic alterations
     
     • e.g. BRCA1/2, MUTYH
2. need 2 inactivated gene copies
3. loss of protein function
4. usually shows an autosomal dominant pattern of cancer predisposition but with incomplete penetrance

Question 2

Proto-oncogenes

1. normal functions of proto-oncogenes? [2]
2. mutations in proto-oncogenes are not usually inherited. what is the exception to this rule? [1]
3. how many mutated gene copies is needed for the tumorigenic effect of the gene to occur? [1]
4. what is the general tumorigenic effect of the gene? [1]

Answer 2

1. normal functions:
   
   • stimulation of the cell cycle
   • promotes cell division and growth
2. mutations in proto-oncogenes are not usually inherited, except in RET gene (which causes the condition MENS2)
3. only need 1 mutated gene copy for tumourigenic effect
4. gain of function in protein

Question 3

What capabilities must be acquired for a cell to develop into a cancer cell? [4]

Answer 3

1. immortality = ability to bypass replicative senescence
2. proliferative signalling
3. avoidance of apoptosis
4. insensitivity to anti-growth signalling

Question 4

What are the 2 general types of cancer? [2]

Answer 4

1. familial cancer
2. sporadic cancer

Question 5

Describe the features of sporadic cancer [4]

Answer 5

1. non-inherited
2. common
3. late onset
4. single primary tumour

Question 6

Describe the features of familial cancer [4]

Answer 6

1. likely caused by a combination of genetic and environmental risk factors
2. uncommon
3. early onset
4. often multiple primaries (e.g. having both ovarian and breast cancer)

Question 7

Most of the more common cancer predisposition syndromes are inherited in an autosomal dominant fashion. What is the exception to this? [1]

Answer 7

MUTYH responsible for colon cancer is autosomal recessive

Question 8

What is the general cause of most cancers? [2]

Answer 8

1. most are due to the inheritance of an altered TSG
2. involves subsequent inactivation of the wild type allele

Question 9

Breast Cancer

1. normal function of BRCA1 and BRCA2 proteins? [1]
2. which gene is responsible for male breast cancer? [1]
3. how do you test for BRCA1 and BRCA2 mutations? [1]
4. possible preventative measures for breast cancer? [4]

Answer 9

1. DNA repair by homologous recombination of double stranded breaks
2. BRCA2
3. DNA testing by MPLA for detection of deletions
4. possible preventative measures:
   
   • examinations
   • screening by mammography or MRI
   • BRCA1/2 mutations carriers may be offered:
     
     • prophylactic bilateral mastectomies
     • prophylactic oophorectomies

Question 10

Ovarian Cancer:

1. caused by which 3 mutations? [3]
2. possible treatments? [2]

Answer 10

1. mutations in BRCA1, BRCA2, HNPCC gene: MLH1 or MSH2
2. possible treatments:
   
   • prophylactic surgery
   • PARP (poly-ADP ribose polymerase) inhibition → olaparib

Question 11

What are the 3 types of colon cancer? [3]

Answer 11

1. hereditary non-polyposis colon cancer (HNPCC)
2. familial adenomatous polyposis (FAP)
3. MUTYH (MYH) polyposis

Question 12

Hereditary Non-Polyposis Colon Cancer (HNPCC)

1. clinical presentation? [1]
2. associated cancers? [3]
3. genetic basis? [2]
4. how is HNPCC screened for? [2]

Answer 12

1. usually only a few polyps in colon (less than 10)
2. associated cancers:
   
   • endometrial
   • stomach
   • ovarian
3. genetic basis:
   
   • autosomal dominant
   • due to inheritance of mutation in MMR system genes
4. screening:
   
   • from age 25, colonoscopies every 2 years
   • from age 50, upper GI endoscopy every 2 years

Question 13

Familial Adenomatous Polyposis (FAP)

1. definition? [1]
2. mode of inheritance? [1]
3. caused by what type of mutation? [1]
4. common complication? [1]
5. screening? [1]

Answer 13

1. development of more than 100 adenomatous colon polyps
2. autosomal dominant
3. caused by mutation of APC gene on chromosome 5
4. congenital hypertrophy of retinal pigment epithelium
5. annual bowel screening from age 11

Question 14

MUTYH (MYH) Polyposis

1. definition? [1]
2. mode of inheritance? [1]
3. normal function of BER gene? [1]
4. screening? [1]

Answer 14

1. development of 15-200 polyps (the mild “attenuated” form of FAP)
2. autosomal recessive
3. produces DNA glycosylase for base excision repair
4. colonscopy every 2 years

Question 15

Li Fraumeni Syndrome

1. definition? [1]
2. caused by what type of mutation? [1]
3. normal function of causative gene? [1]

Answer 15

1. rare autosomal dominant cancer predisposition syndrome that puts you at increased risk of several cancers incl. breast cancer, brain tumours, leukaemia, sacroma and adrenocortical carcinoma
2. caused by mutations in master control gene TP53
3. normal function of p53
   
   • regulation of cell cycle to prevent cells from dividing uncontrollably