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breast cancer > cancer genetics: a clinical perspective > Flashcards

cancer genetics: a clinical perspective Flashcards

1
Q

a mutation in a single cancer gene can:

A
  • 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
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2
Q

cancer predisposition genes

A

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

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3
Q

proto-oncogenes syndromes

A 
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

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4
Q

syndromes: tumour suppressor genes

A

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

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5
Q

breast cancer: BRCA1 and 2

A
  • 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
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6
Q

Familial Adenomatous Polyposis (FAP)

A
  • 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
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7
Q

knudson’s two hit hypothesis

A

Gene mutations may be inherited or acquired during a person’s life
Cells can only form a tumour when it contains two mutant alleles

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8
Q

syndromes: mutator genes/mismatch-repair genes

A

Mutations in hMLH1 and hMSH2 Problem with DNA repair (mismatch repair)
–> Hereditary non-polyposis colorectal cancer (HNPCC) (also called Lynch Syndrome)

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9
Q

development of colorectal cancers

A

Inherited APC (or MLH) mutations increase chance of CRC

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10
Q

risk estimation

A

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?

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11
Q

clinical risk guidelines

A 
•	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
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12
Q

interpreting pedigrees

A
  • 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
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13
Q

key features of familial cancer predisposition

A 
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
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14
Q

uncommon cancer predisposition syndromes: von Hippel-Lindau (VHL) syndrome: VHL gene

A 
•	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
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15
Q

pedigree assessments

A

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

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16
Q

risk modification: options

A
  • surveillance
  • Prophylactic surgery and/or chemoprevention
  • Diagnostic and predictive molecular genetic testing
17
Q

surveillance

A
  • 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
18
Q

surveillance: breast/ovarian cancer

A
  • 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
19
Q

surveillance in FAP

A
  • 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
20
Q

surveillance in HNPCC

A
  • 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
21
Q

prophylactic surgery: BRCA 1/2

A

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

22
Q

Chemoprevention: BRAC1/2

A

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)

23
Q

treatment in HNPCC

A

• 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

24
Q

diagnostic and predictive molecular genetic testing

A

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

25
Q

manchester score

A
  • 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)
26
Q

boadicea

A

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

27
Q

lynch syndrome: Amsterdam criteria

A

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

28
Q

lynch syndrome: histology

A
  • 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
29
Q

lynch syndrome: bethesda

A

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

30
Q

diagnostic mutation analysis

A
  • 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
31
Q

other testing

A

• 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

breast cancer (10 decks)

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