familial cancer

Question 1

what happens in a hereditary cancer?

Answer 1

there are multiple genetic changes

Question 2

what genes are involved in cancer?

Answer 2

oncogenes and tumour supressor genes

Question 3

what is the prevalence of cancer?

Answer 3

1 in 2 people will get cancer

Question 4

how can you work out if a cancer is hereditary?

Answer 4

look at a family history

Question 5

what are individual risks due to?

Answer 5

environmental and genetic factors resulting in inter-individual variation which can lead to cancer

Question 6

what genes are involved in genetic factors?

Answer 6

gatekeeper and caretaker genes

Question 7

what is the role of gatekeeper genes?

Answer 7

they are involved in cell cycle control and programmed cell death - the key one is TP53 - they ensure that cells do not go wrong or grow out of control through apoptosis

Question 8

what is the role of caretaker genes?

Answer 8

for DNA repair and carcinogen metabolism - there is activity when the damage has occurred through repair

Question 9

what are environmental factors?

Answer 9

macro and micro environment

Question 10

what is microenvironment?

Answer 10

it is oxyradicals, hormones and growth factors

Question 11

what is macroenvironment?

Answer 11

chemical, physical agents, viruses and radiation

Question 12

what is meant by the steps to cancer?

Answer 12

there are different stages t a cell being unregulated forming cancer. There is a series of genetic changes within the cell that leads to increasingly abnormal behaviour and histology

Question 13

what is an epithelial multi-stage carcinogenesis?

Answer 13

it is when normal epithelium has a mutation such as 5q leading to loss of FAP leading to hyper-prolific epithelium. This can lead to early adenoma, intermediate and late adenoma, which with another mutation can cause carcinoma which will then metastasise

Question 14

what is the definition of penetrance?

Answer 14

the percentage of those with a gene that will go on to develop the condition

Question 15

what modifies penetrance?

Answer 15

genetic an environmental factors

Question 16

give an example of penetrance?

Answer 16

does not necessarily mean that they will develop condition if have gene e.g. BRCA1 - 80% have a very high risk of developing breast and ovarian cancer, 20% do not develop

Question 17

how can you influence the risk?

Answer 17

adapting environmental factors e.g. not smoking

Question 18

what are important cancer gene functions?

Answer 18

gatekeepers - directly regulate tumour growth - monitor and control cell division and death and therefore prevent accumulation of mutations - key genes in monitoring cell growth and apoptosis
caretakers - improve genomic stability - repair of mutation and DNA damage
landscapers - control the surrounding stromal environment

Question 19

what is the relationship between penetrance and gene function

Answer 19

likelihood of developing cancer depends on the importance of gene function

Question 20

how do genetic mutations lead to colorectal cancer?

Answer 20

mutations lead to polyps which determine whether cancer develops - risk of cancer from polyp is 5% for adenomatous

Question 21

where is the mutation when the risk of developing colorectal cancer is >95%?

Answer 21

in gatekeeper genes

Question 22

what is the chance of developing colorectal cancer if mutation in caretaker gene?

Answer 22

around 70%

Question 23

what results from a mutation in landscaper genes?

Answer 23

hamartomatous polyps in 10-20% - lower as gene is not as important

Question 24

what is the role of TSGs?

Answer 24

they protect cells from becoming cancerous and the loss of function will result in an increased risk of cancer

Question 25

what are examples of TSGs?

Answer 25

Rb, BRCA1/2, TP53, APC

Question 26

what is the role of oncogenes?

Answer 26

regulate growth and differentiation - the gain of function or activating mutations will increase risk of mutations

Question 27

what are some examples of oncogenes?

Answer 27

growth and signal transduction factors and the RET gene

Question 28

what is Knudson’s two hit hypothesis?

Answer 28

most cancer genes obey this such as retinoblastoma. It works for inherited and sporadic and inherited at the cellular level and autosomal dominant. In sporadic two hits are required in a single gene as in someone who does not carry a mutation, both alleles of gene would have to become mutated in order for cancer to develop. In inherited - one additional hit in a single cell - for the offspring to develop a cancer, a tumour will begin to form when the second copy of the gene gains a mutation

Question 29

what increases cancer risk?

Answer 29

inherited pattern of inheritance

Question 30

what does autosomal dominant patterns result in?

Answer 30

most cancer syndromes show an autosomal dominant inheritance pattern - 50% chance of passing onto the offspring, penetrance as well can pass on

Question 31

what do autosomal recessive inheritance result in?

Answer 31

a few cancer syndromes will result in such as MUTYH associated polyps. Each parent is a carrier of one copy usually unaffected, so there is 25% chance that children will inherit both copies. Appears to skip generations and may account for sporadic cases

Question 32

what types of mutation are important in gametogenesis and why?

Answer 32

splice site mutations, large scale duplication and deletion and translocations - these account for the genetic code of the individual

Question 33

how can we identify familial cancer genes?

Answer 33

disease causing translocations may give locations - family studies (linkage analysis), candidate gene analysis and new technologies - whole exome sequencing

Question 34

what is important when taking a family history for cancer?

Answer 34

include both maternal and paternal sides and at least 3 generations. The type of cancer and age of diagnosis is needed and confirm, if possible by medical records, cancer registries and death certificates

Question 35

what are the characteristics of sporadic cancers?

Answer 35

older age onset, one cancer in individual and other relatives not affected, rarely genetic - cervix such as from HPV

Question 36

what are the characteristics of familial cancer?

Answer 36

younger age onset, other family members affected and same type or genetically related cancers

Question 37

what are the main purposes of genetic testing?

Answer 37

diagnosis and explanation of family history, counselling of advantages and disadvantages of testing, risk of further cancers for affected cases and that cancer for unaffected, screening, prevention and treatment and research

Question 38

what are the disadvantages of testing?

Answer 38

anxiety, unhappiness, genetic discrimination, results may not lead to any change in management, NHS costs

Question 39

what is the difference between diagnostic and predictive genetic testing?

Answer 39

initial diagnostic testing is mutational analysis and is done on DNA from affected individual - referred and then there is predictive test for family to determine if they are at risk or not

Question 40

what is retinoblastoma?

Answer 40

it is a very rare childhood occular cancer (1 in 15000-30000 live births) that occurs in around 30-50 children in the UK each year. It is a classic example of Knudson’s two hit hypothesis that is in the Rb1 gene, it is bilateral and 15% of cases are sporadic

Question 41

what is familial adenomatous polyposis?

Answer 41

hundreds of bowel polyps from late teens onwards that accounts for around 1% of bowel cancers and has a high risk of up to 100% if left untreated. Other features are CHRPE, desmoid tumours and ostemoas and it is in the APC tumour supressor gene. It is of autosomal dominant inheritance and it dealt with through colonoscopies, total colectomies in late teens or early 20s

Question 42

what is the risk of hereditary non-polyposis colorectal cancer?

Answer 42

in lynch syndrome polyps are common but not polyposis. it accounts for around 2-3% of bowel cancer and there is a 60-80% risk of adenomas or cancer from around mid 20s onwards - other cancers are also a risk such as endometrial or ovarian.

Question 43

where is the mutation in hereditary non-polyposis colorectal cancer?

Answer 43

in mismatch repair genes MLH1 (50%) and MLH2(40%). It is autosomal dominant inheritance with two affected generations and three affected relatives, one of which is a first degree, under 50 years old and with exclusion of FAP

Question 44

what is the management of hereditary non-polyposis colorectal cancer?

Answer 44

colonscopy every 18-24 months after age of 25, removal every 1-2 years and women may chose a hysterectomy. Prophylactic colectomy is not usually recommended.

Question 45

what are the BRCA1 and 2 genes used for a what are the risks if there are mutations in them?

Answer 45

they are involved in DNA repair - mutations account for around 10% of breast cancer cases in those under 40. The risk of breast cancer is around 80% and ovarian with BRCA1 is 40% and BRCA2 10-20%. There is some increased risk of other cacners such as male breast, prostate and melanoma and men can have but lower penetrance so less severe

Question 46

what is the mode of inheritance for BRCA?

Answer 46

autosomal dominant

Question 47

how is BRCA managed?

Answer 47

annual MRI from 30-50 years and annual mammography from 40 onwards. If wanted there are risk reducing masectomies and reconstruction and risk reducing BSO (removal of ovaries and fallopian tubes) as well as lifestyle changes, pharmacological prevention studies

Question 48

in what syndrome is the value of genetic testing unclear?

Answer 48

LiFraumeni

Question 49

what is LiFraumeni syndrome?

Answer 49

it is an autosomal dominant condition with a mutation in p53 - rare. There is a 50% risk of cancer by 40y/o and 100% in lifetime. The prognosis is poor and there is no screening except MRI for breast. Radiotherapy must be avoided as it can induce cancer, and breast, brain, sarcoma and adrenocortical leukaemia are common