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Y3 - genetics > genetic predisposition to cancer > Flashcards

genetic predisposition to cancer Flashcards

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1
Q

what is the result of disease-associated mutations

A

non-functional or missing proteins - truncating mutation, causes disease through haploinsufficiency
proteins with reduced function

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2
Q

how much breast and ovarian cancer is hereditary

A

breast - 5-10% hereditary (single gene influence), 15-20% family clusters (polygenetic inheritance or accumulation of genetic susceptibility factors accumulating in a family)
ovarian - 5-10%

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3
Q

what are the causes of hereditary susceptibility to colorectal cancer

A

sporadic - 65-85%
familial - 10-30% - polygenic inheritance
Lynch syndrome (HNPCC - hereditary non polyposis colorectal cancer) - 5%
FAP (familial adenomatous polyposis) - 1%
rare CRC syndromes - <0.1%

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4
Q

how do HNPCC and FAP lead to colorectal cancer

A

HNPCC - single gene (alterations in mismatch repair genes)

FAP - single mutation in APC, carpet of polyps in colon, very high risk of cancer

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5
Q

what are tumours

A

clonal expansions of cells and accumulation of genetic faults
cell contains mutation within its DNA
genetic alteration is replicated
with each replication additional mutations can occur

high rate of growth

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6
Q

what are germline mutations

A

inherited from single alteration in egg or sperm
heritable
cause cancer family syndromes
generally dominant

mutation in egg/sperm of parent –> all cells affected in offspring regardless of area affected by cancer

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7
Q

what are somatic mutations

A

occur in non-germline tissues
non-heritable

cause the vast majority of cancers

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8
Q

what genes control the first part of cell growth

what genes control the synthesis phase

A

oncogenes
tumour suppressor genes
DNA repair genes

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9
Q

alterations in which part of the cell cycle generally predispose to familial and sporadic cancer

A

familial - tumour suppressor and DNA repair

sporadic - oncogenes (one mutation is enough to cause cancer)

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10
Q

give an example of an oncogene mutation which leads to cancer

A

oncogene ABL
fuses sporadically w/ BCR (similar genetic sequence)
BCR-ABL fusion protein
on switch in BCR switches on activity of ABL
drives formation of leukaemia

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11
Q

what is this called

A

leukocoria

sign of retinoblastoma

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12
Q

how can tumour suppressor gene mutations lead to cancer

A 
normal genes (prevent cancer)
1st mutation - susceptible carrier - generally germline single base pair variant 
2nd mutation/loss - leads to cancer
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13
Q

describe multi-step carcinogenesis e.g. colon cancer

A

prinicple used in familial colon cancers in terms of prevention

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14
Q

what is the main mechanism for familial cancer

A

faulty DNA mismatch repair

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15
Q

what causes Lynch syndrome/HNPCC
what cancers does it result in
opportunities for intervention

A

mutation in mismatch repair genes - germline predisposition to mismatch repair
XS of colorectal, endometrial, urinary tract, ovarian and gastric cancers
adenoma –> carcinoma sequence for polyp formation
opportunities for prevention

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16
Q

clinical features of HNPCC

A

early but variable age at CRC diagnosis - ~45y/o

tumour site in proximal colon predominantly

17
Q

cancer risks in Lynch syndrome

A 
WOMEN: 
CNS  4%
stomach 19%
endometrial 60%
ovarian 11%
MEN: 
biliary tract 18%
urinary tract 10% - esp kidneys and upper renal pelvis 
colon 78%
sebaceous glands 9%
18
Q

BRCA1 and BRCA2 associated cancer lifetime risks

A

WOMEN:
breast - 60-80%, often early age at onset
2nd 1y breast cancer - 40-60%
ovarian 20-50% (1>2)

MEN:
increased risk of prostate cancer and breast cancer (BRCA2)

19
Q

describe autosomal dominant inheritance

A

each child has 50% chance of inheriting the mutation
no skipped generations
equally transmitted by men and women

20
Q

describe mendelian risk

A

dominant high penetrance syndrome

21
Q

when to suspect hereditary cancer syndrome

A

cancer in ≥2 close relatives (on same side of family)
early age at diagnosis
multiple 1y tumours
bilateral/multiple rare cancers
characteristic pattern of tumours (e.g. breast and ovary)
evidence of autosomal dominant transmission

22
Q

who is at highest risk for hereditary cancer

A

account for only a small proportion of all cancer

cancer FHx is key to:

  • accurate risk assessment
  • effective genetic counselling
  • appropriate medical follow up
23
Q

guidelines for risk estimation for individuals based on FHx

A
  • all scottish genetic centres
  • similar to UK national guidelines
  • recommended use by all doctors
  • classify as gene carrier, high, medium or low risk
  • low risk is low genetic risk - similar to population average risk
24
Q

cancer genetics process

A
  • obtain detailed FHx
  • confirm diagnosis of cancer
  • risk estimation
  • counselling
25
Q

what does a clinical genetics consultation involve

A 
FHx
risk estimation
explanation of basis of risk 
interventions
genetic testing - consider in high risk
26
Q

what interventions can be offered in clinical genetics consultation

A

increased awareness of symptoms/signs e.g. checking breasts
lifestyle - diet, smoking, exercise
prevention - oestrogen (don’t use postmenopausally for a long time), aspirin use (CRC, lynch syndrome), tamoxifen in women at risk of familial cancer
screening
prophylactic surgery

27
Q

breast cancer surveillance options

A

breast awareness
early clinical surveillance 5yr < 1st Ca in family
- annual/clinical breast exams
- mammography (moderate/high risk family: 2yrly from 35-40, yrly 40-50),
- high risk: yrly check ups 50-64
- MR screening those at highest risk - largely gene carriers

28
Q

genetic testing in familial breast and ovarian cancer

  • what cancers
  • why is it useful
A

moving to mainstream/1st line at diagnosis where risk >10% (Manchester score >15)
- all non-mucinous ovarian, triple -ve breast <60, w/ FHx, BRCA <40

increasingly relevant for treatment

  • BRCA1/2 w/ mets - PARP inhibitor rather than normal care
  • e.g. platinum, , surgery direction (preventative mastectomy etc)

test proband if relative presents to clinic

29
Q

UK gene testing for familial breast and ovarian cancer

- what genes are tested for

A

BRCA1/2 essential
panels of all relevant highly penetrant genes become the norm - increase detection rate by ~1%

BREAST: BRCA1/2, PALB2, PTEN, p53, CHEK2
OVARIAN: BRCA1/2, Lynch genes (MLH1, MSH2, MSH6, PMS2), RAD51C, RAD51D

30
Q

BRCA1/2 gene carriers: prophylactic mastectomy

A
  • removes most but not all breast tissue
  • significantly reduces breast cancer risk in women w/ FHx
  • total (simple) mastectomy removes more breast tissue than subcutaneous mastectomy
  • BRCA2 mutation +ve women breast cancer incidence reduced to 5% (less than population risk)
31
Q

problem w/ MRI screening for breast cancer

A

may pick up cancers earlier but doesn’t remove the risk altogether

32
Q

prophylactic oopherectomy

A
  • eliminates risk of 1y ovarian cancer BUT peritoneal carcinomatosis may still occur
  • laparoscopic oophorectomy reduces post-surgical morbidity
  • induces surgical menopause but HRT till 50y/o (doesn’t change breast cancer risk)
  • risk of subsequent breast cancer halved in mutation +ve women
33
Q

surveillance for colorectal cancer

A

COLONOSCOPY:

  • gene carrier: 2yr.ly from 25
  • high moderate risk: 5yrly from 50-70
  • low moderate: once only @55

PROPHYLACTIC ASPIRIN

  • gene carriers
  • omeprazole cover if issues w/ ulcers
34
Q

surveillance for endometrial cancer

A

symptom awareness
prophylactic hysterectomy in some women

discuss options

35
Q

screening cancers for Lynch syndrome

A

IHC for mismatch repair gene proteins (MLH1, MSH2, MSH6, PMS2) or micro-satellite instability (MSI) testing - inexpensive way of telling if cancer is Lynch syndrome associated

if IHC/MSI - high gene screen to determine if a gene is implicated (2 somatic hits can mislead otherwise)

  • IHC/MSI recommended CRC management
  • useful for treatment too
36
Q

benefits of genetic testing

A
  • identifies highest risk
  • identifies non-carries in families with a known mutation
  • allows early detection and prevention strategies
  • may relieve anxiety
37
Q

risks and limitations of genetic testing

A
  • doesn’t detect all mutations (less relevant with modern testing methods)
  • continued risk of sporadic cancer
  • efficacy of interventions variable
  • may result in psychosocial or economic harm
38
Q

what causes Li-Fraumeni syndrome

A

germline TP53 mutation

rare

39
Q

defining features of Li-Fraumeni syndrome

A

rare cancers in very young people

Y3 - genetics (3 decks)

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