Cancer Genetcis: A Clinical Perspective Flashcards
Variable expression of a gene
A mutation in a single cancer gene can predispose to different tumours in the same individual
Risk of genetic predisposition to cancer in common tumours
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
Age related penetrance
It takes time for an individual to accumulate the other hits necessary to cause a tumour
Genes that can be inherited:
Proto oncogenes-> action can positively promote cell proliferation
Tumour suppressor-> inhibit cell proliferation
Mutator genes-> maintain the integrity of the genome
Syndromes caused by mutations in proto oncogenes
RET-> multiple endocrine neoplasia type 2
-> medullary thyroid cancer 90%
-> parathyroid tumours 20-30%
MET-> hereditary papillary renal carcinoma
Syndromes caused by mutations in tumour suppressor genes
TP53-> Li-Fraumeni syndrome -> young onset cancers -> particularly sarcoma and breast BRAC1/2-> breast and ovarian cancer APC-> familial adenoma tours Polyposis coli
BRAC1
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
Familial adenomatous Polyposis coli
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
Knudsons two hit hypothesis
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
Syndromes causes by mutations in mismatch repair genes
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
Clinical risk guidelines
High-> surveillance indicated-> secondary care-> gene testing
Moderate-> surveillance indicated-> secondary care
Low-> surveillance not indicated
General pop risk
Familial cancer predisposition
Early onset tumours
Multiple tumours in close relatives
Multiple tumours within an individual
Cluster of different tumours in a recognisable pattern
Pedigree risk assessment
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
Breast cancer clinical risk categorisation
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
Bowel cancer clinical risk categorisation
Low-> 1 in 10
Moderate-> 1 in 6 to 1 in 10
High-> 1 in 6
Count relatives, check ages
Uncommon cancer predisposition syndromes
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
Structure of family history services
GP and clinical-> family history risk assessment
- > low-> discharge
- > moderate-> screening clinic
- > high-> clinical genetics
Assessment in family history clinic
Take pedigree
Confirm family history
Confirm diagnosis in affected relatives
Risk modification strategies
Surveillance
Prophylactic surgery and/or chemo prevention
Diagnostic and predictive molecular genetic testing
Surveillance breast cancer
Mammography 40 to 50 and NBSP
MRI scanning from 35-50
Ovarian screening via translational ultra sound and CA125 annually
Management in FAB
Annual flexible sigmoidoscopy from 11-15
Once polyps identified, discuss prophylactic colectomy
Annual rectal stump surveillance
Upper GI endoscopy from 25
HNPCC management
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
Prophylactic surgery in BRAC1 and BRAC2
Prophylactic mastectomy
Prophylactic salpingo-oompherectomy
Reduces risk of Fallopian tube malignancies
Chemo prevention in BRAC1 and 2
Oral contraception
-> may increase BR CA risk in >35
-> reduce ovarian cancer risk
Tamoxifen -> studies found no benefit
Treatment in HNPCC
NSAIDS and progesterone IUD being investigated
Prophylactic surgery
Diagnostic mutation analysis and predictive genetic testing
Need living relative or stored DNA
Referral of patients at 50% risk with known family mutation
Confirm mutation in affected relative
-> predictive testing
Breast and ovarian cancer moderate risk
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
Breast and ovarian cancer high risk
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
Colorectal moderate risk
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
High risk colorectal cancer
2 relatives-> 2 fdr colorectal under 50
3 relatives-> 3 fdr or sdr with colorectal on same side of family
