Genetic pre-disposition to cancer

Question 1

Why do most cancers happen?

Answer 1

most happen by chance or due to environmental factors
small proportion happen because of an increased inherited predisposition to cancer

Question 2

What are the two types of gene mutations that cancer arises from?

Answer 2

somatic mutations -cell within body develops some genetic alteration and this predisposes to another and another- eventually cancers arise

germline mutations- person inherits an alteration that came to them through egg or sperm
heritable

Question 3

What are the 3 main different genetic processes associated with cancer?

Answer 3

oncogenes

tumour suppressor genes- cancer arises when BOTH brakes fail

DNA damage response genes- cancer arises when both copies of genes fail, speeding the accumulation of mutations in other critical genes

Question 4

Describe microsatellite instability?

Answer 4

MMR corrects errors that spontaneously occur during DNA replication like single base mismatches or short insertions and deletions
Cells with abnormally functioning MMR tend to accumulate errors.
Microsatellites (aka Simple Sequence Repeats SSR) are repeated sequences of DNA, can be made of repeating units of 1 – 6 base pairs
MSI (changes in microsatellite sequences) is the phenotypic evidence that MMR is not functioning normally – genetic hypermutability

Question 5

How do we identify someone with hereditary non polyposis colon cancer?

Answer 5

looking within tumour for footprint of microsatellite instability

Question 6

Describe benign tumour?

Answer 6

– lacks ability to metastasize. Rarely or never become cancerous. Can still cause negative health effects due to pressure on other organs.

Question 7

Describe dysplastic tumour?

Answer 7

benign’ but could progress to malignancy. Cells show abnormalities of appearance & cell maturation. Sometimes referred to as ‘pre-malignant’.
(NB distinguish from ‘hip dysplasia’ which is macroscopically abnormal but not pre-malignant!)

Question 8

Describe malignant tumour?

Answer 8

not ‘benign’. Able to metastasize.
(NB distinguish from ‘malignant hypertension’, ‘malignant hyperthermia’)

Question 9

Examples of oncogenes and what they cause?

Answer 9

MEN2- caused by alteration in RET oncogene
and familial medullary cancer likewise

Question 10

Examples of tumour supressor genes and what they cause?

Answer 10

BRCA1 and BRAC2 causing breast and ovarian cancer
APC causing FAP
P53 causing Li-fraumenu syndrome
RB1 causing retinoblastoma

Question 11

Give examples of DNA mis match repair genes?

Answer 11

MLH1, MSH2 , MSH6, PMS1 ,PMS2
causing HPNCC/ Lynch syndrome

Question 12

What conditions are de novo mutations common in?

Answer 12

Familial adenomatous polyposis ~30% of cases
Multiple endocrine neoplasia 2B ~50% of cases
Hereditary retinoblastoma ~50% of cases

Question 13

Give features of retinbolastoma?

Answer 13

1 in 20,000 children
Most common eye tumor in children
Occurs in heritable and nonheritable forms
Identifying at-risk infants substantially reduces morbidity and mortality

Question 14

How do we tell between heritable and non heritable retinoblastoma? (germline mutations in RB1 gene)

Answer 14

heritable tumour- bilateral, some family history, young diagnosis age, increases risk of osteosarcoma and other sarcomas

alteration in tumour not in germline- acquired
if you find alteration in both germline and tumour- inherited

Question 15

Risk factors for breast cancer?

Answer 15

ageing
family history
early menarche
late menopause
nulliparity (not having kids)
estrogen use
dietary factors
lack of exercise

Question 16

High risk and moderate risk genes contributing to familial breast cancer?

Answer 16

high risk:
BRCA1
BRCA2
TP53
PALB2
PTEN
STK11
CHEK2 homozygotes
ATM mutation c.7271T>G

Moderate risk:
CHEK2 heterozygous mutation
ATM (except c.7271T>G)
BRIP1
Possibly RAD51C & RAD51D

Question 17

High risk and moderate risk genes contributing to familial ovarian cancer?

Answer 17

high risk
BRCA1
BRCA2
TP53
RAD51C
RAD51D
Mis-match repair genes

moderate risk
PALB2
BARD1

Question 18

Difference between BRCA1 and BRCA2 cancers?

Answer 18

BRCA1
breast cancer, secondary breast cancer, ovarian

BRCA2
breast
ovarian
male breast
-increases risk of prostate, laryngeal and pancreatic

Question 19

risk factors for colorectal cancers?

Answer 19

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

Question 20

Describe the adenoma to carcinoma sequence?

Answer 20

normal epithelium acquires APC mutations and leads to hyper proliferation of the epithelium.
Then with additional k ras mutations you get dysplastic adenoma and then with p53 mutation- get carcinoma.

Question 20

Clinical features of HNPCC?

Answer 20

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 21

Clinical features of FAP?

Answer 21

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 22

Give features of attenuated FAP?

Answer 22

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 23

What do multiple modifier genes of lower genetic risk explain?

Answer 23

May explain families with history of cancer and no identified mutation

May explain differences in cancer penetrance in families with same mutation

Question 24

How do we manage cancer risk in adenomatous polyposis syndromes?

Answer 24

Surveillance
Surgery
Chemoprevention