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Familial cancer syndromes Flashcards

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1
Q

What is an epigenetic alteration?

A

An enduring change in gene expression that does not involve the DNA sequence
i.e. methylation of the promoter region of genes with inactivation of the genes (increasingly recognised at the somatic alterations in cancer)

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2
Q

Is the RET gene causing MEN 2 an oncogene with dominant gain of function or a tumour suppressor gene with recessive loss of function?

A

an oncogene

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3
Q

Is BRCA an oncogene with gain of function or a tumour suppressor gene with recessive loss of function?

A

TSG

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4
Q

Is MMR genes an oncogene with gain of function or a tumour suppressor gene with recessive loss of function?

A

TSG

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5
Q

What types of cancer does BRCA1 increase risk

A 
Breast cancer (40-80% lifetime risk)
Ovarian cancer (20-40% lifetime risk)
Prostate cancer (1.5- 2 x increase risk)
Primary peritoneal cancer 2% after salpingoophorectomy
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6
Q

BRCA2 causes increase risk of which cancers

A

Breast cancer (40-60% lifetime risk)
Ovarian cancer (10-20%)
Breast cancer in males (6% lifetime risk)
Pancreatic cancer (3.5%)
Prostate cancer (4 x increase relative risk)
Melanoma risk also increased

Note if biallelic mutation causes Fanconi anaemia!

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7
Q

Which chromosome contains BRCA1

A

Chromosome 17

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8
Q

Which chromosome contains BRCA2

A

Chromosome 13q

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9
Q

How is BRCA associated prostate cancer different?

A

Tends to be more aggressive with T3/4 disease and node positive more often and mets at diagnosis more likely.
Less likely to be managed with active surveillance as not low risk

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10
Q

How does BRCA gene actually work to increase risk?

A

Normally involved in DS DNA repair. Function as tumour suppressor genes. Inactivation leaves DNA damage unrepaired–>cancer.
See sporadic OC but not often sporadic BC

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11
Q

What are the typical features of a BRCA1 tumour?

A 
High grade
more likely hormone receptor negative
pushing borders
;ess DCIS
medullary/atypical medullary histo
Stain + for basal keratins = basal epithelial subtype

BRCA2 tumours do not have specific phenotypic features

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12
Q

What histological type of ovarian Ca is more common with the BRCA mutations?

A 
Serous papillary (85% vs 40% in sporadic)
Mucinous adenoCa and borderline tumours are NOT associated.
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13
Q

Clinically, what are the differences between BRCA associated OC and sporadic?

A

More likely to respond to platinum agents, and re respond when relapse
Increased progression free survival and overall survival

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14
Q

What are the recommendations regarding testing for the BRCA genes in invasive epithelial Ca?

A

All non-mucinous cancers under the age of 70

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15
Q

Who qualifies for publicly funded BRCA testing?

A

three or more cases of breast or ovarian ca in first or second degree relative

or

two or more cases of breast or ovarian cancer in first or second degree relative with at least one high risk feature (male BC, under age 40, bilateral BC, ovarian cancer.)

There are also computer programs to calculate risk, and then often use 10% as cutoff

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16
Q

What surveillance strategies are used in known BRCA carriers?

A

Breast self examination and clinical examination 6 monthly from age 25-10 (no evidence)
Breast imaging- yearly MG and MRI from 25-30 years (higher sensitivity than MG under age 50 but no proven survival benefit and high false positives)
Ca125 and TVUS not done
Bilateral mastectomy best protection (but residual about 5%). Best to do before age 50- risk declines as age increases so less benefit if operate later on.
Risk reducing oophorectomy age 40
Limit alcohol
Breast feed for at least one yr if possible
Can offer pre-implantation genetic diagnosis with IVF
tamoxifen pre-men or raloxifene post men daily for 5 years reducesrisk moderate breast cancer by 40%

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17
Q

What effect does bilateral salpingoophorectomy have in BRCA?

A

4% risk in BRCA1 carrier before age 40 so can consider BSO selectively at age 35
Reduces risk OC by 80% and all cause mortality at age 70
Residual risk primary peritoneal cancer 2-5%
Decreases risk of BC if performed before menopause
Need to watch bone health

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18
Q

What is PALB2?

A 
new gene that looks like BRCA2
35% risk to age 70 of breast cancer
a loss of function mutation
not sure re: male, pancreatic, ovarian ca
will be added to panels
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19
Q

Chemoprevention in high risk women with BRCA?

A

Called “risk reducing medication”
Tamoxifen in pre and post menopausal women and raloxifene in post menopausal women reduce risk hormone positive cancer by 30-40% but no proven survival benefit
Tamoxifen reduces risk of second cancer in BRCA mutation carriers even if hormone negative
Younger women have greater risk benefit ratio

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20
Q

Can you give HRT after bilateral SPO in BRCA carriers?

A

yes and you should to age 50 to reduce cardiovascular risk but NEVER give if prior breast Ca

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21
Q

Can you give OCP in BRCA carriers?

A

Yes- this reduces risk of ovarian cancer too

weigh increase risk of BC against benefits of contraception

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22
Q

What is Li Fraumeni syndrome?

A

p53 mutation- leading to a “breast sarcoma syndrome”
chromosome 17
autosomal dominant inheritance
Penetrance cancer 90% by age 60
rare
can be de-novo
pre-menopausal breast cancer often HER2 positive
sarcomas
GBM
adrenocortical and other pediatric cancers
should have breast MRIs and prophylactic mastectomies
CRC

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23
Q

Australian colorectal ca risks?

A

Male 1 in 18

Female 1 in 23

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24
Q

FAP- what does the inside of the bowel look like?

A

hundreds or thousands of adenomatous polyps in the large bowel
90% have CRC by age 45
Suspect if more than 10–>APC gene testing

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25
Other than adenomatous polyps, what issues is FAP associated with?
duodenal and gastric polyps Increased risk stomach cancer increased risk thyroid cancer hepatoblastoma in kids
26
FAP has what mode of inheritance?
Autosomal dominant but 30% cases due to new mutations There is the MutYH syndrome which is autosomal recessive with no desmoid disease and 100s instead of 1000s of polyps
27
FAP caused by the mutation in what gene?
the APC gene
28
Related to FAP, what is Gardner syndrome?
FAP + extra-intestinal features of osteomas, desmoid tumours, epidermoid cysts
29
What is Turcot syndrome?
Familial colon ca + brain ca - medulloblastoma in FAP - GBM in Lynch syndrome
30
How does FAP genetic testing work?
Mutation has to be identified in a person who has FAP- when the family specific mutation is known, other family members can be tested
31
How do you manage FAP?
Commence surveillance at puberty (13-16 years) Yearly colonoscopy + upper GI surveillance Proctocolectomy once polyposis develops, usually age 18 Endoscopic screening for duodenal adenomas and rectal ca predictive genetic testing when available, with counselling. Test all first degree
32
What is attenuated AFP?
Distinct from classical disease Mutations at five prime and three prime ends of the gene May have few to less than 100 polyps, especially right sided later onset of cancer by about 15 years average consider if 10-20 plus adenomatous polyps
33
What's the deal with desmoids in FAP?
``` aggressive growths of fibrous tissue in 10-30% patients with FAP common cause of death in patients usually intra-abdominal can recur post op can need TPN cause pain, mass, SBO, fistula, hydronephrosis, GI bleed observe or use NSAID or anti-oestrogens can be indolent or rapidly progressive surgery last resort ```
34
What is MYH polyposis?
Autosomal recessive condition that looks like attenuated FAP Homozygous mutation in MYH gene 60% risk CRC age 60 colectomy at time of polyposis or observe and polypectomy duodenal polyposis in 20% and increased duodenal ca NO desmoids Consider if more than 10 polyps
35
How do sessile serrated adenomas compare with hyperplastic polyps (both types of serrated polyps)
SSA higher risk crc
36
HNPCC or Lynch syndrome what type inheritance
autosomal dominant
37
Genetic cause of HNPCC
mutations in mismatch repair genes-->genetic instability (usually act between S and G2) More often associated with microsatellite instability (meaning the microsatellite segments which are meant to have fixed lengths change length due to insertions and deletions)
38
CRC under age 50 in victoria get what additional testing now?
Immunohistochemistry to look at MMR genes expression changes - this seeks to detect lynch syndrome.
39
What are the clinical characteristics of HNPCC?
``` More likely to have proximal tumours equal risk genders earlier cancer- 40-50 more likley to be mucinous more likely to be poorly differentiated more likely to have lymphoid reaction (chron's like on histo- confers better prognosis) ```
40
What cancers are associated with HNPCC?
``` CRC 30-80% endometrial 30-50% stomach less than 105 ovarian less than 10% Urothelial small bowel biliary skin, brain, bladder prostate 2 x increased risk ```
41
Management of HNPCC?
Colonoscopy every 1-2 year from age 25 or 5 years younger than first affected no proven benefit to screen for ovarian or endometrial cancer but option of TAH/BSO age 40 screen for urinary and stomach cancers if these run in the family consider taking out organ if cancer found aspirin dose CAPP2 study-->lancet 2011 1000 patients 600mg aspirin daily reduced risk of CRC Once CRC occurs, better prognosis for same stage If MSI high, some say avoid 5FU adjuvant (less likely chemo) No evidence for gastric or urothelial screening
42
When to suspect HNPCC? Based on the modified Amsterdam criteria...
Three patients with CRC or HNPCC related cancers (colon, endometrial, ovarian, TCC, small bowel) in at least TWO generations, ONE a first degree relative of the other two, ONE younger than 50 at diagnosis, and FAP excluded in the affected individuals Not just polyposis but actual cancer Bethesda criteria define who should have IHC for LS
43
Familial gastric cancer due to mutation in what gene?
germ line mutation in e-cadherin gene (CHH-1) | Autosomal dominant
44
What should you test when you diagnose a paraganglioma?
Immunohistochemistry for changes in expression of MMR genes
45
What proportion of pheos have an underlying genetic syndrome
quarter to third-von hippel lindau, MEN 2, SDH mutations, NF1
46
what tests in pheo (genetic)
Von hippel lindau | ICH for SDH
47
Gene mutation in VHL
germline mutation of VHL gene on chrom 3p | aut dom
48
Diagnosis of VHL?
2 or more of cerebellar or spinal haemangioblastomas retinal angiomas clear cell renal ca pheochromocytoma
49
What cancers are seen in NF1?
``` Up to 10% get cancers optic nerve gliomas astrocytoma malignant peripheral nerve sheath tumours childhood leukaemia pheochromocytoma GIST, other sarcomas ```
50
What risk is conferred by p16 mutations?
melanoma less than one percent cases CDKN2 mutations on chromosome 9 30% melanoma by age 50 increased risk pancreatic cancer
51
Most familial cancer syndromes are due to what genetic issue?
Loss of tumour supressor genes.
52
What's in MEN syndromes?
MEN 1 Pituitary adenoma, parathyroid hyperplasia, pancreatic tumours MEN 2A Parathyroid hyperplasia, medullary thyroid cancer, pheochromocytoma MEN 2B Medullary thyroid cancer, pheochromocytoma, mucosal neuromas, marfanoid body habitus. 2 A and B are from RET All AD Think MEN 1A if multiple parathyroid adenomas in the one person too.
53
What are the high risk genes associated with breast/ovarian Ca?
BRCA 1, 2- hereditary breast and ovarian cancer syndrome TP53- Li Fraumeni PTEN- Cowden syndrome
54
Young woman HER2 positive, what should you check?
p53 Li Fraumeni - usually a missense mutation
55
Peutz-Jegher syndrome
Hamartomatous polyposis sAmall intestin-->intusussception in kids Increased CRC and breast Lip and buccal pigmentation AD Gene is STK 11
56
What are the common 4 genes that encode for DNA mismatch repair in HNPCC?
MLH1 MSH2 MSH6 PMS 1 and 2 MSH 2 mosts common These proteins are short and so cannot cooperate as usual to fix DNA errors.
57
If it is a Lynch cancer, staining of mismatch protein will be what?
Absent. Should be seen in normal tissue.
58
What is the difference between head and neck / upper thorax paragangliomas and lower mediastinum, abdominal, pelvic paragangliomas?
Upper often parasympathetic and non functioning but 5% produce catecholamines (metabolites metanephrine, normetanephrine, 5'methyoxytyramine) Lower often sympathetic and functional Pheo is a paragangl in the adrenal medulla
59
Neurofibromatosis type 1 - clinical features - ?inheritance pattern - ?gene - ?clinical
AD but highly variable phenotype HIGHLY PENETRANT NF1 gene Neurofibromiin regulates cell signal transduction Too many mutations thought so a clinical diagnosis ``` 2 or more of: over 6 cafe au lait patches over 2 neurofibroma or one plexiform neurofibroma axillary freckling Lisch nodules on iris Optic glioma- vision normal usually Tibial pseudoarthrosis- pathological # never heals FH (but half are denovo) ``` CANCER RISK- optic nerve glioma, astrocytoma, peripheral nerve sheath, breast, pheo, GIST, juvenille myelomonocytic leukaemia
60
Neurofibromatosis type 2 is a TOTALLY DIFFERENT DISEASE - gene - inheritance - features
AD but often mosaic. Fully penetrant Merlin gene is a tumour supressor gene - NF 2 Bilateral accoustic schwannomas Other IC and spinal tumours eg meningiomas Polyneuropathy Cataracts, posterior subcapsular lens opacity Cutaneous tumours and plaques Need annual MRI from age 10 Don't get CAL, lisch nodules, axillary freckling
61
Von hippel lindau what inheritance and what effects?
AD Haemangioblastomas CNS and retina, renal clear cell ca, pheo
62
Complications of NF1?
``` Seizures 5% Learning difficulties CNS tumours esp optic nerve gliomas Malignant peripheral nerve sheath tumours Spinal neurofibromas ```

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