Cancer Genetcis: A Clinical Perspective Flashcards Preview

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Flashcards in Cancer Genetcis: A Clinical Perspective Deck (30)

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


Variable expression of a gene

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


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



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
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
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
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

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

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