Genetic Predisposition to Cancer

Question 1

What are somatic mutations?

Answer 1

Occur in nongermline tissues

Question 2

What are germline mutations?

Answer 2

Mutations in germ cells - responsible for producing eggs and sperm. Heritable, cause cancer family syndromes

Question 3

What is the function pf proto-oncogenes?

Answer 3

Codes for proteins that regulate cell growth and differentiation

Question 4

What is an oncogene?

Answer 4

Mutated proto-oncogene

Question 5

what is the effect of oncogenes?

Answer 5

Accelerate cell division

Question 6

How many mutations of the chromosomes are needed before control of the cell cycle is lost in oncogenes?

Answer 6

1 mutation needs to occur

Question 7

What is the function of tumour suppressor genes?

Answer 7

Slow down cell division
Repair DNA mistakes
Tell cells when to die (a process known as apoptosis or programmed cell death)

Question 8

What is the function of DNA damage response genes?

Answer 8

The repair mechanics for DNA

Cancer arises when both genes fail, speeding the accumulation of mutations in other critical genes

Question 9

What is the function of Mismatch repair genes?

Answer 9

MMR corrects errors that spontaneously occur during DNA replication like single base mismatches or short insertions and deletions

Question 10

What does Micro satellite instability an indicator of?

Answer 10

Phenotypic evidence that MMR is not functioning normally.

Cells with abnormally functioning MMR tend to accumulate errors, simple sequence repeats are created

Question 11

Give an example of a cancer syndrome associated with Oncogenes

Answer 11

MEN2 (Multiple endocrine neoplasia)
Familial medullary thyroid cancer

Can be caused by viruses

Question 12

Give an example of a cancer syndrome associated with Tumour suppressor gene

Answer 12

Breast/ovarian cancer FAP Li-Fraumeni syndrome Retinoblastoma

Question 13

Give an example of a cancer syndrome associated with DNA repair (mis-match repair)

Answer 13

HNPCC / Lynch Syndrome

(Hereditary non-polyposis colon cancer)

Question 14

What are other causes of cancer?

Answer 14

Autosomal recessive syndromes
E.g. MYH polyposis

Multiple modifier genes of lower genetic risk

Question 15

What is a De Novo mutation?

Answer 15

New (de novo) mutation occurs in germ cell of parent
No family history of hereditary cancer syndrome

A new mutation in a germ cell?

Question 16

Describe cancer susceptibility genes

Answer 16

They are dominant with incomplete penetrance

Question 17

Is heritable retinoblastoma usually bilateral or unilateral?

Answer 17

Usually bilateral

Question 18

Does heritable retinoblastoma usually contain a family history?

Answer 18

Yes in 20 percent of cases

Question 19

What are the risk factors of breast cancer?

Answer 19

Ageing, family history, Early menarche - first period, late menopause, Nulliparity -not having children
Estrogen use, dietary factors, lack of exercise.

Question 20

What are the common genes responsible for breast cancer?

Answer 20

BRCA1
BRCA2
TP53
PTEN
Undiscovered genes

Question 21

What is the function of BRCA1?

Answer 21

Checkpoint mediatorDNA damage signalling and repairChromatin remodelling (inactive X chromosome)Transcription (not essential for this)

(PROTEIN THAT ACTS AS A TUMOUR SUPPRESSOR)

Question 22

What is the function of BRCA2?

Answer 22

DNA repair by HR (homologous recombination)

Question 23

What are the BRCA1 associated cancers?

Answer 23

Breast cancers, second primary breast cancer

Ovarian cancer

Question 24

What are the BRCA2 associated cancers?

Answer 24

Breast cancer, ovarian cancer, male breast cancer

Increased risk of prostate, laryngeal, and pancreatic cancers (magnitude unknown)

Question 25

What are risk factors for colorectal cancers?

Answer 25

Ageing
Personal history of CRC or adenomas
High-fat, low-fibre diet
Inflammatory bowel disease
Family history of CRC

Question 26

What is the sequence of events for Adenoma to carcinoma?

Answer 26

Epithelium becomes hyperactive, adenoma forms, carcinoma forms

Question 27

How many adenomas are present in non-polyposis (Hereditary Colorectal Cancer (CRC) syndromes)

Answer 27

few to no adenomas

HNPCC (hereditary non-polyposis colon cancer / Lynch Syndrome) - CRC &/or endometrial cancer (EC

Question 28

How many adenomas are present in polyposis (Hereditary Colorectal Cancer (CRC) syndromes)

Answer 28

(multiple adenomas)

FAP – severe colonic polyposis +/- CRC
AFAP - less severe colonic polyposis +/- CRC
MAP – varying degrees of colonic polyposis +/- CRC

FAP – familial adenomatous polyposis
AFAP – attenuated FAP
MAP – MYH associated polyposis

Question 29

What are the clinical features of HNPCC

Answer 29

Early but variable age at CRC diagnosis (~45 years)
Tumor site throughout colon rather than descending colon
Extracolonic cancers: endometrium, ovary, stomach, urinary tract, small bowel, bile ducts, sebaceous skin tumors

Question 30

What are clinical features of FAP?

Answer 30

Estimated penetrance for adenomas >90%
Risk of extracolonic tumors (upper GI, desmoid, osteoma, thyroid, brain, other)
CHRPE may be present
Untreated polyposis leads to 100% risk of cancer

Question 31

Describe the effect of attenuated FAP

Answer 31

Later onset (CRC ~age 50)
Few colonic adenomas
Not associated with CHRPE
Upper GI lesions 
Associated with mutations at 5' and 3' ends of APC gene

Question 32

What condition is similar to attenuated FAP?

Answer 32

Recessive MYH polyposis

Common mutations in mut- MYH gene

Question 33

What can Multiple modifier genes explain?

Answer 33

May explain families with history of cancer and no identified mutation

May explain differences in cancer penetrance in families with same mutation

Question 34

How can you manage caner risk in Adenomatous Polyposis syndromes?

Answer 34

Surveillance
Surgery
Chemoprevention

Question 35

What portion of cancers are due to inherited mutations?

Answer 35

Only a small portion