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CancerGen > Genotype/Phenotype in Predisposition Syndromes > Flashcards

Genotype/Phenotype in Predisposition Syndromes Flashcards

1
Q

Normally a _____ genotype gives a ____ phenotype

A

Normally a rare genotype gives a specific phenotype

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2
Q

What is the main cancer type predisiposition of Gorlin syndrome?

A

Basal Cell Carcinoma (a non-melanoma skin cancer)

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3
Q

A symptom of Gorlin syndrome can be Odontogenic keratocysts, what are these?

A

Cystic lesions of the mouth

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4
Q

A symptom of Gorlin syndrome can be Palmar/Plantar pits, what are these?

A

Small depressions of the skin of the hand (palmar) or foot (plantar)

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5
Q

A symptom of Gorlin syndrome can be Falx cerebri calcification, what is this?

A

Calcification of a certain brain region

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6
Q

A symptom of Gorlin syndrome can occasionally be what?

A

Meningiomas (can be a result of early life chemo), medulloblastoma, and developmental abnormalities

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7
Q

PTCH1 is part of what signalling pathway?

A

The SHH (sonic hedgehog)

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8
Q

What is PTCH1 (SHH pathway) responsible for?

A

Specification of neuronal cells and signalling for epithelial cells

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9
Q

50-90% of Gorlin Syndrome patients have what genetically?

A

LOF of PTCH1

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10
Q

Standard sequencing + MLPA + RNA identifies what portion of cases of Gorlin syndrome?

A

67%, leaving 33% we can’t test the family for

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11
Q

1 in 4 Gorlin syndrome patients that don’t have a PTCH1 LOF show what?

A

a SUFU Loss of Function

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12
Q

Where is SUFU in the SHH pathway?

A

Downstream of PTCH1

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13
Q

What is distinctive about Gorlin syndrome patients with SUFU mutations?

A

They appear like classical GS patients PLUS an increased risk of childhood medulloblastomas

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14
Q

How do PTCH1 Gorlin’s patient’s differ from Gorlin’s patients with no identified variant?

A

They tend to be diagnosed earlier, get jaw cysts, and get bifid ribs etc.

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15
Q

How do patients with missense variants in PTCH1 differ from those with nonsense, frameshift or SP variants in PTCH1?

A

Later diagnosis, fewer BCCs, fewer jaw cysts

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16
Q

What do SUFU variants correlate with?

A

Higher risk of medulloblastoma (inc. childhood), fewer jaw cysts, higher risk of meningioma and ovarian fibroma.

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17
Q

What do NF2 variants increase the risk of? 2 things.

A

Schwannomas and Meningiomas

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18
Q

What is the most common cause of both schwannomas and Meningiomas?

A

Biallelic inactivation of NF2

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19
Q

What are meningiomas?

A

The most common primary CNS tumour. (meningeal tissue of brain)

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20
Q

What’s the Female to Male ratio of meningiomas?

A

2F:1M

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21
Q

What’s the likely reason that the female to male ratio of meningiomas is 2:1?

A

Hormone issues

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22
Q

What can bilateral vestibular schwannomas of NF2 patients lead to?

A

Hearing loss

23
Q

What portion of NF2 related schwannomatosis patients develop cranial meningiomas?

A

> 50%

24
Q

What’s the female to male ratio of meningiomas in the spine?

A

10 to 1

25
Q

Where is NF2 in the genome?

A

22q

26
Q

NF2 variants tend to be what type? How about milder ones?

A

Truncating.
But splicing and missense in milder individuals.

27
Q

Which exons (1-17) are mutually exclusive in NF2?

A

16 and 17

28
Q

What’s the NF2 structure?

A

3x FERM subdomains, then alpha helical domain. And then a C-terminal domain.

29
Q

What percentage of people with an NF2 variant have at least one cranial meningioma? And which type of variant lead to the most?

A

48% of NF2 variant carrier had at least one cranial meningioma. Those with one generally had truncating variants early on in the protein

30
Q

What specific areas of the NF2 gene were variants most likely to be?

A

The junctions between domains

31
Q

What is the accumulative meningioma risk in NF2 schwannomatosis patients by 70 years?

A

80%

32
Q

What is SMARCB1 a core subunit of?

A

The SWI/SNF chromatin remodelling complex

33
Q

The SWI/SNF Chromatin remodelling complex has implications in what percentage of cancers?

A

20%

34
Q

What are 2 key parts of the SMARCB1 protein?

A

A DNA binding motif, and a nuclear localisation signal

35
Q

Where in the genome is SMARCB1?

A

22q, just like NF2

36
Q

What can mutations in SMARCB1 predispose someone to?

A

Schwannomatosis (just like NF2), and atypical teratoid/rhabdoid tumours, and coffin-siris syndrome

37
Q

How is SMARCB1 Schwannomatosis different to NF2 Schwannomatosis?

A

SMARCB1 - Lack of cutaneous and vestibular schwannomas. Symptoms >30 years.

38
Q

What’s a hallmark symptom of SMARCB1 Schwannomatosis?

A

Intractable pain and neurological dysfunction

39
Q

Tell me about the SMARCB1 related atypical teratoid and rhabdoid tumours?

A

These are very rare, fast growing tumours in the first 6 months of life. They make up 3% of paediatric cancers and have a very poor survival.

40
Q

Tell me about Coffin-Siris syndrome caused by SMARCB1 variants?

A

Developmental delay, hypoplastic fingers and toes. (Not a cancer syndrome).

41
Q

What else can cause Coffin-Siris syndrome?

A

Mutations in other genes forming the SWI/SNF Complex

42
Q

So why does SMARCB1 cause 3 different syndromes/ phenotypes?

A

Caused by different mutations of course.

43
Q

What mutations are common in SMARCB1 to cause schwannomatosis?

A

Splice site, missense, 3’UTR and in-frame deletions. Also start and end of gene as a whole.

44
Q

What mutations are common in SMARCB1 to cause Atypical teratoid/rhabdoid tumours?

A

Whole gene dupes or deletions. Nonsense mutations. Frameshifts.
Often in exons 2-7

45
Q

What mutations are common in SMARCB1 to cause Coffin-Siris syndrome?

A

Missense or inframe deletions. Generally in last exons (ex8 and 9)

46
Q

What’s the difference in cancer histopathology between regular schwannomas, SMARCB1 schwannomas and, and atypical teratoid/rhabdoid tumours?

A

Normal schwannoma - High SMARCB1 staining.
SMARCB1 schwannoma - Sporadic SMARCB1 stain.
AT/RT - No staining

47
Q

Other than NF2 shwannomatosis and PTCH1 causing Gorlin syndrome, what are some other genes that when deleted as a whole gene cause a predisposing syndrome?

A

Breast cancer - BRCA1, BRCA2, TP53.

Lynch - MSH2, MLH1, MSH6, PMS2.

NF1.

FAP - APC.

Von Hippel Lindau - VHL.

48
Q

Are predisposing syndromes always whole gene deletions?

A

No 2% WGD. 12% microdel/dupe.

49
Q

What are features of Neurofibromatosis 1 (NF1) mutations?

A

Neurofibromas.
Optic pathway gliomas.
Cafe au lait.
Particular freckling.
Lisch nodules.
Skeletal malformations.

50
Q

How many types of main NF1 deletions are there?

A

Types 1 -3 (in decreasing deletion size) (some repeat sequences lead to the deletion sizes I think).

51
Q

Is just the NF1 gene in the NF1 loci that’s deleted in the 3 types of Neurofibromatosis type 1?

A

No a few genes seem to be there…. a few orfs too.

52
Q

What makes NF1 have a more severe phenotype?

A

Between NF1 exons 26 and 27 there are 3 small genes. Delete these and you get a more severe phenotype.

53
Q

NF2 phenotypes caused by WG Del can be mild but what can make it more severe?

A

A second hit, usually just an SNV, in the other copy of NF2.

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