Inherited cancers Flashcards
What is cancer characterised by
Genetic mutation - most is acquited
SOME is inherited
What % of cancer has an inherited component
5%
Type of genetic mutations in cancer
DNA mutations - single genes
Chromosome number changes
Chromosomal translocation
AMplifications/overexpression of genes
Cancer predisposition geens
Tumour supressor genes
Oncogenes
Tumour supressor genes how cause cancer
Protective role in repairing cells during growth
If inherited mutation in one allele, ‘second hit; in working copy -> cancer
What are oncogenes
Promote growth, often activate during early/embryonic life
When are oncogenes a problem
Acquire ‘gain of function’ ef activating mutatations -> proto-oncogenes -> cnacer risk increase
What gene mutation causes multiple endocrine neoplasia type 2
Acitvating mutations in MEN 2
What is knudosns hypothesis
Tumour supressor genes - second hit to working copy of tumour supressor gene
Retinoblastoma inherited mechanism
Inherited mutation in tumour supressor RB1 gene
Acquire seoncd hit easily
Who is at risk of 100% penetrance retinoblasmtomas
Bilateral
Family history
Examples of inherited cancer caused by mutation in tumour supressor gene
Retinolblastoma - RB1
Li-fraumeni syndrome - TP53
FAP - APC
Breast/ovarian cancer - BRAC1, BRAC2
What does li farumeni syndrome cause
Brain tumours
Sarcomas
Leukaemias
How is germline testing done
Blood test - purple top
Gene by gene - specific gene in mind
Panel approach - test panel of eg 15 relevant genes
Phenotype agnostic approach - all known cancer genes
What gene can cause diffuse gastric cancer inherited
CDH1
PARP inhibitor examples
Olaparib, niraparib, rucaparib
MOA of PARPis
Inhibit PARP protein (poly-ADP ribose polymerase) which helps damaged cells repair themselves
Tests for genetics in inherited cancers sus
Tumour genetic testing
Germline genetic test in family
MSI/IHC testing
Histopathology on other lesions
What test do on colorectal/endometrial tumours for lyng=ch syndrome
Micro satellite I
Immunohistochemistry testing
Von hippel lindau syndrome beinign features
Benign pancreatic and renal cysts
What syndrome predisposition for cancer -> benign skin tumours can ->
pTEN - trichilemmomas
- cowdens syndrome
Tests of familial predisposition to cancer
Germline single gene or gene panel
MSI/IHC
Options if found to ahve gene increasing risk of cacner
Extra screneing
Lifestyle advice
Chemoprophylaxis eg tamoxifen, aspirin
Risk reducing surgery options eg bilateral or complete mastectomy, gyanea surgery
Research studies
Patient support groups
What specifically avoid if risk of cancer from TP53 mutations
Radiation exposure eg CT scans
Which gene mutation risk specifically improves with aspirin
Colorectal cancer - Lynch syndrome
Goals of large scaling screening for cancer
Reduce risks, reduce complications of disease
Identify those more likely helped w further tests or treatment
Results, further investigation and treat
Preventative medicien through early diagnosis of at risk and affected individuals
Benefits of cancer screening
Early detection and better treatment
Identifies at risk individuals - preventative measures put in place
Identify carriers of heritable conditions allow for family planning
Control disease population level
Cost effective
Harms of large sclae cancer screening
False positives or negatives
Tests may be invasive
Insurance implications
Pscyholgocial implications
Epidemiology of breast cancer
Most common cancer in UK
1 in 8 women in lifettime
55,000 diagnoses per year
Most are sporadic
<10% are inherited genetic causes
NHS breast screening programme when offered
50-71st birthday every 3 years
>71 still eligible but need to self refer
Bowel cancer epidemiology
3rd most common cancer UK
1 in 14 men, 1 in 19 women during lifteime
1 in 4 have FH
5-6% inherited eg FAP, lynch syndrome
What is retinoblastoma
Inherited cancer of the eye
Most common ocular malignancy in children
Who gets retinoblastoma
Most commonly infants - average age fisangosis is 18 months
What causes retinoblastoma
Autosomal dominant inheritance of Retinoblastoma tumour supressor gene loss of function on chromosome 13
10% cases are hereditary, others are spontanous
Clinical features of retinoblastoma
Absence of red-reflex replaced by white pupil - leukocoria
Strabismus
Visual problems
Managmenet of retinoblastoma
Enucleation only treatment
Depends on how advanced tumour is - can do external beam radiation therapy, chemotherapy, photocoagulation
What is li fraumeni syndrome and what is it caused by
Mutatuon in tumour supressor gene 53
Cant stop malignancies
1 in 4 inherited
Features of li fraumeni syndrome
Several multiple cancers in children and young adults ef soft tissue and bone sarcomas, breast cancer, brain tumours, adrenocortical carcinoma and acute leukaemia
Others - GI, lung, kidnye, thyroid, skin, gonads
Chance of developing cancers with li-fraumeni syndrome
nearly 100% if female of breast cancer in lifetime
90% of any cancer over lifetime
50% cahnce by age of 30
Crtieria for li fraumeni syndorme
Sarcoma < 45
First degree relatives any cancer <45
Second relatives as above
Managemnet of li fraumeni sundrome
every 3 months - complete physical exam and bloodcount, abdo US, pelvic US, urinalysis
Annually - MRI brain and Whole body MRI
Endoscopy, colonoscopy and breast screening
What gene causes FAP
APC gene mutation 80% cases
Dominant
Management of FAP
Flexible sigmoidoscoy from 15 years
If no polyps - 5 yearly from 20
If polyps -> resectional surgery
What is peutz-jeghers syndrome
Multiple benigin intestinal hamartomas
Episodic obstruction and intussusception, increased risk of GI cancers and gonadal cancers
Management of peutx jeghers syndorme
Annual examination
Pan intestinal endoscopy every 2-3 years
What causes peutx jeghers syndrome
STK11 - LKB11 mutation on chromosme 19
What is cowden disease
Mutation of PTEN fene on 10q22 chromosome, dominant
Feautres of cowdens syndrome
Macrocephaly
Multiple intestinal hamartomas
Multiple trichilemmomas
89% risk of cancer at any site
16% risk colorectal
Breast cancer 80%
Thyroid, uterine cancer
Lynch syndrome features
Colorectal cancer, enometrial, gastric
Scanty colonic pouos
Colonic tumours tend to be R side and mucinous
Extra colonic cancers
