cancer genetics: a clinical perspective Flashcards
a mutation in a single cancer gene can:
- predispose to different tumours in the same individual i.e. variable expression
- be linked with increasing likelihood of tumours over time i.e. age-related penetrance
cancer predisposition genes
1) proto-oncogenes
- genes whose action positively promoted cell proliferation
2) tumour-suppressor genes (most common)
- genes who inhibit cell proliferation
3) mutator genes
- genes whose normal function is to maintain genome integrity e.g. mismatch-repair genes
proto-oncogenes syndromes
Multiple Endocrine Neoplasia (MEN) type 2: RET gene, germline point mutations medullary thyroid cancer (90%) parathyroid tumour (20-30%) phaeochromocytoma (50%)
Hereditary Papillary Renal Carcinoma:
MET gene, germline missense mutations
.
MET encodes growth factor receptor
syndromes: tumour suppressor genes
MET encodes growth factor receptor
young-onset cancers (esp. sarcoma and breast)
Breast & Ovarian cancer: BRCA1 & BRCA2
Cowden syndrome: PTEN
Breast, thyroid & some skin cancers
Familial Adenomatous Polyposis: APC
Colorectal & others
breast cancer: BRCA1 and 2
- Mutations in BRCA1 and BRCA2 are associated with inherited breast and ovarian cancer
- BRCA1 also linked to prostate cancer
- BRCA2 linked to prostate, pancreatic & male breast cancer
Familial Adenomatous Polyposis (FAP)
- Colorectal cancers (CRC) linked to APC gene mutations
- > 100 colorectal adenomatous polyps (or fewer with first-degree relative, FDR)
- 50% have polyps by age 16 yrs (7% have CRC at 21 yrs if untreated)
- Average age of CRC is 39 years if untreated
knudson’s two hit hypothesis
Gene mutations may be inherited or acquired during a person’s life
Cells can only form a tumour when it contains two mutant alleles
syndromes: mutator genes/mismatch-repair genes
Mutations in hMLH1 and hMSH2 Problem with DNA repair (mismatch repair)
–> Hereditary non-polyposis colorectal cancer (HNPCC) (also called Lynch Syndrome)
development of colorectal cancers
Inherited APC (or MLH) mutations increase chance of CRC
risk estimation
families:
is the family history likely to be genetic?
individuals:
Is my cancer risk increased?
What can I do to address this risk?
Is there a genetic test?
clinical risk guidelines
• Purpose: decide who should be screened - type of screening package - who requires onward referral • Purpose: decide who should be screened - type of screening package - who requires onward referral • Should be evidence-based and lead to equitable treatment
interpreting pedigrees
- The exact pedigree structure is important
- The number of affected and unaffected individuals is important
- The tumour types are important
- Even though a family history may look ‘genetic’, the probability of finding a mutation in one of the known genes may be low
key features of familial cancer predisposition
what to look for: • Early-onset tumours • Multiple tumours in close relatives • Multiple tumours within an individual • Clusters of different tumours in a recognisable pattern
uncommon cancer predisposition syndromes: von Hippel-Lindau (VHL) syndrome: VHL gene
• Unusual tumours at young ages • Autosomal dominant • Incidence 1:36,000 Tumors arising in multiple organs Haemangioblastomas (retinal or CNS), Renal Carcinoma, Phaeochromo-cytoma, Pancreatic tumours
pedigree assessments
carried out in family history clinic or clinical genetics service
• Take pedigree
• Confirm family history including diagnoses
- if affected individual(s) dead, obtain details from Cancer Registry, patient notes or death certificate
- if affected individual alive, obtain consent to see medical records via the patient you are reviewing
risk modification: options
- surveillance
- Prophylactic surgery and/or chemoprevention
- Diagnostic and predictive molecular genetic testing
surveillance
- Generally surveillance is offered when there is a greater than 10% risk of developing cancer
- Needs to be balanced against side-effects of screening e.g. colonoscopy, mammography
- Needs to be cost-effective e.g. MRI vs. mammography for breast screening
- Should be regularly reviewed
surveillance: breast/ovarian cancer
- Mammography from 40 to 50 and NBSP (National Breast Screening Programme)
- MRI scanning from 35 to 50 yrs
- Ovarian screening by transvaginal ultrasound scan and CA125 levels tested annually
surveillance in FAP
- Annual flexible sigmoidoscopy from 11-15 yrs
- Once polyps identified, discuss prophylactic colectomy
- Annual rectal stump surveillance
- Upper GI endoscopy from 25 yrs, initially 3 yearly but depends on number of polyps
surveillance in HNPCC
- 1-2 yearly colonoscopy from 25-65 yrs
- Endometrial and ovarian surveillance as suggested by local gynecologist (e.g. some experts suggest screening from age 30yrs)
- 2 yearly upper GI endoscopy from 50 to 75 yrs
- Annual urine cytology from 30-60yrs, if Family History shows transitional cell carcinoma
prophylactic surgery: BRCA 1/2
prophylactic mastectomy
prophylactic salpingo-oopherectomy
• Residual risk of peritoneal cancer of < 1%
• Reduces/removes risk of fallopian tube malignancies
• May reduce risk of breast cancer
Chemoprevention: BRAC1/2
oral contraceptive pill:
• May increase the risk of breast cancer in women over the age of 35
• Appears to reduce the risk of ovarian cancer
tamoxifen:
• Tamoxifen appears to reduce the risk of contralateral breast cancer in carriers of BRCA1 & 2 mutations (see notes)
treatment in HNPCC
• Role of NSAIDs on colonic adenomas being investigated (aspirin recommended for Lynch)
• Role of progesterone IUD on endometrial cancer being investigated
• Role of OCP on endometrial and ovarian cancer unproven
• Prophylactic surgery
- colectomy
- TAH & BSO
diagnostic and predictive molecular genetic testing
identification of families appropriate for genetic testing:
• Usually only patients in the high risk category are eligible for molecular genetic testing
• However, not all patients within the high risk category are suitable for testing
• Various tools used to identify the patient group eligible for molecular genetic testing (Manchester score, Boadicea in Breast) (Amsterdam in Bowel)
• Genetic testing carried out by the Clinical Genetics Service/ Cancer services
manchester score
- Used for testing BRCA1 and BRCA2
- Test at score >15 (affected individual)
- Equates to 10% BRCA1/2 +ve rate
- score can be modified by histology (triple negative Breast Cancer are likely to be genetic)
boadicea
Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm:
• Computer algorithm (University of Cambridge)
- estimate risks of an individual developing breast cancer
- estimate the probability that they are carrying a BRCA1 or 2 mutation
• Test at >10% risk of being carrier
lynch syndrome: Amsterdam criteria
all of:
• 3+ relatives with verified Lynch syndrome-associated cancers (CRC, endometrial, small bowel, transitional cell carcinoma of the ureter or renal pelvis)
- one must be first-degree relative of the other two and in whom FAP has been excluded
• Lynch syndrome-associated cancers involving at least two generations
• One or more cancers were diagnosed before 50
lynch syndrome: histology
- MSI: Microsatellite instability indicates MMR gene dysfunction. Observed in both somatic and germline cancers (BRAF+ cells likely somatic)
- IHC: Immunohistochemistry stains proteins within histology sections. Lack of stain indicates absence of protein. Present in somatic and germline cancers (MLH1 promoter methylation tests for somatic)
- Use Bethesda criteria for suitability
lynch syndrome: bethesda
Colorectal (CRC) or uterine cancer diagnosed < 50
Presence of synchronous, metachronous colorectal, or other HNPCC-associated tumours, regardless of age
CRC with MSI-H histology diagnosed in a patient < 60
CRC in 1+ first-degree relatives with an HNPCC-related tumour, with one of the cancers being diagnosed < 50
CRC diagnosed in 2+ first- or second-degree relatives with HNPCC-related tumours, regardless of age
diagnostic mutation analysis
- Need living affected relative or a DNA sample (e.g. blood) stored from deceased
- Detailed discussion with genetic counsellor / consultant
- Fully informed written consent before blood can be taken for mutation analysis
other testing
• If no living relative available can do tumour testing
- obtain tumour sample from deceased relative
- can test DNA e.g. BRCA, Lynch
- mutations could be germline or somatic
- use to test relatives; if absent, reduces risk
• If no sample available can do indirect testing
- test unaffected 1st degree relative
- use risk-based criteria (e.g. Manchester >17-20)
- if no mutation continue surveillance based on risk
