Cancer Genetcis: A Clinical Perspective

Question 0

Variable expression of a gene

Answer 0

A mutation in a single cancer gene can predispose to different tumours in the same individual

Question 1

Risk of genetic predisposition to cancer in common tumours

Answer 1

5-10% if breast cancer cases due to highly penetrant germ line mutations in cancer predispositions genes
-> up to half of these will have a mutation in BRCA1 and BRCA2
1% of colorectal cancer cases due to mutation in APC
5% of colorectal cancers due to mutations in one of the HNPCC genes

Question 2

Age related penetrance

Answer 2

It takes time for an individual to accumulate the other hits necessary to cause a tumour

Question 3

Genes that can be inherited:

Answer 3

Proto oncogenes-> action can positively promote cell proliferation
Tumour suppressor-> inhibit cell proliferation
Mutator genes-> maintain the integrity of the genome

Question 4

Syndromes caused by mutations in proto oncogenes

Answer 4

RET-> multiple endocrine neoplasia type 2
-> medullary thyroid cancer 90%
-> parathyroid tumours 20-30%
MET-> hereditary papillary renal carcinoma

Question 5

Syndromes caused by mutations in tumour suppressor genes

Answer 5

TP53-> Li-Fraumeni syndrome
-> young onset cancers
-> particularly sarcoma and breast
BRAC1/2-> breast and ovarian cancer
APC-> familial adenoma tours Polyposis coli

Question 6

BRAC1

Answer 6

Mutation on chromosome 17
Cumulative risk of breast and ovarian cancer
Risk increases with age
Also contra lateral tumour risk-> prostate cancer
Same with BRAC2 but lower cumulative risk
Other cancers-> prostate, pancreatic, male breast

Question 7

Familial adenomatous Polyposis coli

Answer 7

APC gene
Greater than 100 colorectal adenomatous polyps
Or
Fewer than 100 polyps and an FRR with FAP
50% of patients age 16 have polyps
If untreated get colorectal cancer by 39
Other cancers-> thyroid, liver, duodenum, pancreas

Question 8

Knudsons two hit hypothesis

Answer 8

Gene mutations may be acquired during a persons life
-> a cell can only initiate a tumour when it contains 2 mutant alleles-> sporadic tumour
Or
1st mutant allele is inherited (present in all cells)aH 2nd mutation srises in a somatic cell in the organ which the tumour develops-> tumour only develops when the second mutation occurs> hereditary tumour

Question 9

Syndromes causes by mutations in mismatch repair genes

Answer 9

hMLH1 and hMSH2-> colorectal, endometrial, ovarian, ureteric or enable pelvis and brain-> hereditary non-Polyposis colorectal cancer
Can’t fix mutations
-> deletion mutation-> APC-> increased cell growth
-> K-Ras-> adenoma
-> LOH-> PCC
-> TP53-> carcinoma
-> NM23-> metastasis

Question 10

Clinical risk guidelines

Answer 10

High-> surveillance indicated-> secondary care-> gene testing
Moderate-> surveillance indicated-> secondary care
Low-> surveillance not indicated
General pop risk

Question 11

Familial cancer predisposition

Answer 11

Early onset tumours
Multiple tumours in close relatives
Multiple tumours within an individual
Cluster of different tumours in a recognisable pattern

Question 12

Pedigree risk assessment

Answer 12

4 relative with breast or ovarian cancer-> high risk including males
One relative with both counts as two people
Cervical cancer unconnected
1 relative over 40-> low risk
Test for other cancers
Sarcoma+breast-> Li-fraumeni
Ovarian+endometrial-> HNPCC
4 relatives with bowel cancer-> high risk HNPCC or FAD

Question 13

Breast cancer clinical risk categorisation

Answer 13

Low risk-> less 2x pop risk
Moderate-> 2-3x pop risk
High-> 3x pop risk
Assigned by number of relatives with B/Ca and the age they got it

Question 14

Bowel cancer clinical risk categorisation

Answer 14

Low-> 1 in 10
Moderate-> 1 in 6 to 1 in 10
High-> 1 in 6
Count relatives, check ages

Question 15

Uncommon cancer predisposition syndromes

Answer 15

Unusual tumours at young ages
Von hipple-lindau syndroms
Haemongioblastomas
Renal cell Ca, multiple renal cysts, phaecochromocytoma
Multiple pancreatic cyts, pancreatic tumours
Autosomal dominant
Birth incidence 1 in 36,000

Question 16

Structure of family history services

Answer 16

GP and clinical-> family history risk assessment

• > low-> discharge
• > moderate-> screening clinic
• > high-> clinical genetics

Question 17

Assessment in family history clinic

Answer 17

Take pedigree
Confirm family history
Confirm diagnosis in affected relatives

Question 18

Risk modification strategies

Answer 18

Surveillance
Prophylactic surgery and/or chemo prevention
Diagnostic and predictive molecular genetic testing

Question 19

Surveillance breast cancer

Answer 19

Mammography 40 to 50 and NBSP
MRI scanning from 35-50
Ovarian screening via translational ultra sound and CA125 annually

Question 20

Management in FAB

Answer 20

Annual flexible sigmoidoscopy from 11-15
Once polyps identified, discuss prophylactic colectomy
Annual rectal stump surveillance
Upper GI endoscopy from 25

Question 21

HNPCC management

Answer 21

1-2 yearly colonoscopy from 25-65
Endometrial and ovarian surveillance
2 yearly upper GI endoscopy from 50-75
Annual urine cytology if FH transitional cell carcinoma from 30-60

Question 22

Prophylactic surgery in BRAC1 and BRAC2

Answer 22

Prophylactic mastectomy
Prophylactic salpingo-oompherectomy
Reduces risk of Fallopian tube malignancies

Question 23

Chemo prevention in BRAC1 and 2

Answer 23

Oral contraception
-> may increase BR CA risk in >35
-> reduce ovarian cancer risk
Tamoxifen -> studies found no benefit

Question 24

Treatment in HNPCC

Answer 24

NSAIDS and progesterone IUD being investigated

Prophylactic surgery

Question 25

Diagnostic mutation analysis and predictive genetic testing

Answer 25

Need living relative or stored DNA
Referral of patients at 50% risk with known family mutation
Confirm mutation in affected relative
-> predictive testing

Question 26

Breast and ovarian cancer moderate risk

Answer 26

3 relatives -> 3 fdr or sdr with breast cancer at an average age of over 60
-> 1 fdr or sdr with ovarian cancer and 2 fdr or sdr with breast average age over 60
2 relatives-> one fdr and one fdr or sdr average age over 50 breast
-> one ovarian and one breast over 50
-> one fdr or sdr with bilateral breast and one breast over 60
1 relative-> with breast under 40 or male breast or bilateral over 50

Question 27

Breast and ovarian cancer high risk

Answer 27

4 or more-> breast or ovarian any age
3 relatives-> 3 with breast under 60
-> 1 with ovarian and 2 with breast under 60
-> I male breast and 2 with breast under 60
2 relatives-> one fdr and one fdr or sdr with breast under 50 or ovarian at any age
-> one ovarian and one breast under 50
-> one bilateral and one breast under 60
-> one male and one breast under 60

Question 28

Colorectal moderate risk

Answer 28

1 relative-> 1 fdr with colorectal under 45
2 relatives-> 2 fdr with colorectal 50-70
-> 1 fdr and 1 sdr with colorectal under 70

Question 29

High risk colorectal cancer

Answer 29

2 relatives-> 2 fdr colorectal under 50

3 relatives-> 3 fdr or sdr with colorectal on same side of family