Genotype/Phenotype in Predisposition Syndromes Flashcards
Normally a _____ genotype gives a ____ phenotype
Normally a rare genotype gives a specific phenotype
What is the main cancer type predisiposition of Gorlin syndrome?
Basal Cell Carcinoma (a non-melanoma skin cancer)
A symptom of Gorlin syndrome can be Odontogenic keratocysts, what are these?
Cystic lesions of the mouth
A symptom of Gorlin syndrome can be Palmar/Plantar pits, what are these?
Small depressions of the skin of the hand (palmar) or foot (plantar)
A symptom of Gorlin syndrome can be Falx cerebri calcification, what is this?
Calcification of a certain brain region
A symptom of Gorlin syndrome can occasionally be what?
Meningiomas (can be a result of early life chemo), medulloblastoma, and developmental abnormalities
PTCH1 is part of what signalling pathway?
The SHH (sonic hedgehog)
What is PTCH1 (SHH pathway) responsible for?
Specification of neuronal cells and signalling for epithelial cells
50-90% of Gorlin Syndrome patients have what genetically?
LOF of PTCH1
Standard sequencing + MLPA + RNA identifies what portion of cases of Gorlin syndrome?
67%, leaving 33% we can’t test the family for
1 in 4 Gorlin syndrome patients that don’t have a PTCH1 LOF show what?
a SUFU Loss of Function
Where is SUFU in the SHH pathway?
Downstream of PTCH1
What is distinctive about Gorlin syndrome patients with SUFU mutations?
They appear like classical GS patients PLUS an increased risk of childhood medulloblastomas
How do PTCH1 Gorlin’s patient’s differ from Gorlin’s patients with no identified variant?
They tend to be diagnosed earlier, get jaw cysts, and get bifid ribs etc.
How do patients with missense variants in PTCH1 differ from those with nonsense, frameshift or SP variants in PTCH1?
Later diagnosis, fewer BCCs, fewer jaw cysts
What do SUFU variants correlate with?
Higher risk of medulloblastoma (inc. childhood), fewer jaw cysts, higher risk of meningioma and ovarian fibroma.
What do NF2 variants increase the risk of? 2 things.
Schwannomas and Meningiomas
What is the most common cause of both schwannomas and Meningiomas?
Biallelic inactivation of NF2
What are meningiomas?
The most common primary CNS tumour. (meningeal tissue of brain)
What’s the Female to Male ratio of meningiomas?
2F:1M
What’s the likely reason that the female to male ratio of meningiomas is 2:1?
Hormone issues
What can bilateral vestibular schwannomas of NF2 patients lead to?
Hearing loss
What portion of NF2 related schwannomatosis patients develop cranial meningiomas?
> 50%
What’s the female to male ratio of meningiomas in the spine?
10 to 1
Where is NF2 in the genome?
22q
NF2 variants tend to be what type? How about milder ones?
Truncating.
But splicing and missense in milder individuals.
Which exons (1-17) are mutually exclusive in NF2?
16 and 17
What’s the NF2 structure?
3x FERM subdomains, then alpha helical domain. And then a C-terminal domain.
What percentage of people with an NF2 variant have at least one cranial meningioma? And which type of variant lead to the most?
48% of NF2 variant carrier had at least one cranial meningioma. Those with one generally had truncating variants early on in the protein
What specific areas of the NF2 gene were variants most likely to be?
The junctions between domains
What is the accumulative meningioma risk in NF2 schwannomatosis patients by 70 years?
80%
What is SMARCB1 a core subunit of?
The SWI/SNF chromatin remodelling complex
The SWI/SNF Chromatin remodelling complex has implications in what percentage of cancers?
20%
What are 2 key parts of the SMARCB1 protein?
A DNA binding motif, and a nuclear localisation signal
Where in the genome is SMARCB1?
22q, just like NF2
What can mutations in SMARCB1 predispose someone to?
Schwannomatosis (just like NF2), and atypical teratoid/rhabdoid tumours, and coffin-siris syndrome
How is SMARCB1 Schwannomatosis different to NF2 Schwannomatosis?
SMARCB1 - Lack of cutaneous and vestibular schwannomas. Symptoms >30 years.
What’s a hallmark symptom of SMARCB1 Schwannomatosis?
Intractable pain and neurological dysfunction
Tell me about the SMARCB1 related atypical teratoid and rhabdoid tumours?
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.
Tell me about Coffin-Siris syndrome caused by SMARCB1 variants?
Developmental delay, hypoplastic fingers and toes. (Not a cancer syndrome).
What else can cause Coffin-Siris syndrome?
Mutations in other genes forming the SWI/SNF Complex
So why does SMARCB1 cause 3 different syndromes/ phenotypes?
Caused by different mutations of course.
What mutations are common in SMARCB1 to cause schwannomatosis?
Splice site, missense, 3’UTR and in-frame deletions. Also start and end of gene as a whole.
What mutations are common in SMARCB1 to cause Atypical teratoid/rhabdoid tumours?
Whole gene dupes or deletions. Nonsense mutations. Frameshifts.
Often in exons 2-7
What mutations are common in SMARCB1 to cause Coffin-Siris syndrome?
Missense or inframe deletions. Generally in last exons (ex8 and 9)
What’s the difference in cancer histopathology between regular schwannomas, SMARCB1 schwannomas and, and atypical teratoid/rhabdoid tumours?
Normal schwannoma - High SMARCB1 staining.
SMARCB1 schwannoma - Sporadic SMARCB1 stain.
AT/RT - No staining
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?
Breast cancer - BRCA1, BRCA2, TP53.
Lynch - MSH2, MLH1, MSH6, PMS2.
NF1.
FAP - APC.
Von Hippel Lindau - VHL.
Are predisposing syndromes always whole gene deletions?
No 2% WGD. 12% microdel/dupe.
What are features of Neurofibromatosis 1 (NF1) mutations?
Neurofibromas.
Optic pathway gliomas.
Cafe au lait.
Particular freckling.
Lisch nodules.
Skeletal malformations.
How many types of main NF1 deletions are there?
Types 1 -3 (in decreasing deletion size) (some repeat sequences lead to the deletion sizes I think).
Is just the NF1 gene in the NF1 loci that’s deleted in the 3 types of Neurofibromatosis type 1?
No a few genes seem to be there…. a few orfs too.
What makes NF1 have a more severe phenotype?
Between NF1 exons 26 and 27 there are 3 small genes. Delete these and you get a more severe phenotype.
NF2 phenotypes caused by WG Del can be mild but what can make it more severe?
A second hit, usually just an SNV, in the other copy of NF2.
