Familial cancer syndromes Flashcards
What percentage of CRC is familial and what are the associated genetic syndromes?
15% is familial
3-5% is due to Lynch syndrome
1% due to FAP (APC), Juvenille polyposis syndrome (SMAD4 BMPR1A), Peutz-jeghers (STK11) and PTEN harmatoma syndrome
BMPR1A and PTEN may be deleted in 10q23 contiguous del syndrome with syndromic features dev delay and polyps
What genes are mutated in Lynch syndrome
MLH1, MSH2 (~70%)
PMS2- 1&
MSH6- 6-10%
EPCAM <1%
Lynch syndrome results in an increased risk of which cancers?
CRC, endometrial, small intestine, hepato-billiary, pancreatic, gastric, renal pelvis, bladder, prostrate, ovary, breast
what is the mean age of onset of Lynch?
45 yrs. it is older for MSH6 and PMS2 as these are the non-obligate partners onf the MutSa and MutLa heterodimers so are associated with later onset and reduced penetrance
what is the mutations spectrum
- LOF mutations
- MLH1 and MSH2 are most commonly mutated and have highest penetrance
- 3% are due to deletions of the 3’ edn of the EPCAM gene, this results in loss of the stop codon and poly-A signal resulting in polymerase readthrough into downstream MSH2 and promoter hypermethylation. the EPCAM deletion can also include the MSH2 promoter or coding sequence. The result for all is LOF of MSH2
- 10Mb iinversion of chromosome 2 can disrupt MSH2 and is reported in cases of unexplained lynch syndrome
what is the clinical criteria for testing for lynch syndrome?
2 different criteria:
Amsterdam- developed to identify LS patients for research studies
Bethesda- designed to identify CRC patients who should be tested for LS. Lower specificity but higher sensitivity than Amsterdam criteria
describe IHC testing in LS
95% sensitivity
standard to test FFPE tumour tissues for the expression of LS genes by IHC
- If the obligate partner is lost e.g. MLH1 or MSH2 you will also see concurrent loss of the partner. But if the non-obligate partner is lost (MSH6 or OMS2 there is not concurrent loss of the obligate partner)
- If a patient shows loss of staining by IHC there is no need to also test for MSI as this is assumed
- IHC has lower sensitvity than MSI as it may miss LOF mutations that do not result in NMD e.g. missense mutations
- therefore if a patient is -ve for IHC should also perform MSI testing
- techinically difficult to distinguish +ve staining from artefact
if a patient shows loss of staining for MLH1/PMS2 they should have MLH1 methylation studies before proceeding to germline mutation testing
describe MSI testing in LS
MMR proteins repair mismatches and a defect in the pathway results in an increased mutation rate.
micro satellites are highly mutable making them a good target to screen for MMR deficiency
- generally screen tumour vs germline (blood samples) or regions of tumour and non-tumour on an FFPE slide.
-2/5 markers should show instability to confirm MSI
- if only 1 marker shows instability it is not enough to confirm MSI but may indicate the need for further studies
- can also be used for ovarian and endometrial cancer, but has been designed for CRC so is most snsitive for this
-if MSI is not detected an MMR defect is ruled out.
what are the most common mutations in sporadic CRC?
MLH1 promoter methylation is present in 15% and results in an absence of MLH1 by IHC. it can be detected by MS-MLPA which can methylation sites in the promoter region (can also detect MSH2 methylation due to an EPCAM deletion).
- rarely seen as a germline chage and is acquuired somatically.
V600E BRAF mutation is associated with MLH1 and indicates sporadic CRC- can be used to screen for sporadic CRC and avoid unnecessary germline mutation testing
What techniques are used for germline mutation testing in LS?
- sequencing and MLPA (although more likely to now all be performed as part of an NGS panel
- PMS2 is complicated by the presence of a highly homologous pseudogene so need to use long range PCR with primers anchored in region of divergence between the native and pseuogene to select for the native gene. nester PCR with preimers for the exons of interest for sanger seq.
what is the testing strategy?
1) test tumour for IHC or MSI- cant diagnose LS but can confirm a defect in MMR and IHC may indicate the likely affected gene
2) MLH1 promoter methylation and BRAF V600E testing to rule out spradic cases
3) test for germline MMR proteins
Describe the role of the MMR genes?
MSH2-MSH6 (MutSa) recognises single base mismatches and monoculoetide repts. MutSb recognises larger looped out errors e.g. dint rpts
MutSa inititiate repair by binding to the mismatch. Other molecules are recruited- PCNA, RCF, MutLa(MLH1-PMS2). this assembly activates the exonuclease activity of PPMS2 which makes ss breaks near the mismatch and opens EXO1 nucelase entry site. this mismatch is then excised, gap filled by a pol and nick ligated
What is associated with homozygous/compound het LS mutation?
associated with constituional mimsatch repair cancer syndrome- rare childhood cancer syndrome resulting in hematological, brain/CNS, CRC, intestinal polyps
what are the treatment and surveillance options for CRC?
full coloectomy and ilorectal anastomosis recommended
- prohylactic colectomy is not recommended as colonoscopy is effective
- removal of ovary and uterus may be considered after completion of childbearing
surveillance: colonoscopy and removal of precancerous lesions every 1-2 years from 25 years
aspirin is recommended for chemoprevention in at risk individuals
Predictive testing
Available to all at risk adults. CRC not associated with childhood cancer so testing before then is not required.
requires referral from a GC
-ve result reduces risk to that of the general population
+ve result increases risk of developing cancer- level of risk is dependent on gene, age, mutation, lifestyle, sex,
What is FAP
Familial Adenomatous polyposis
most common polyps syndrome due to AD APC mutations
- characterized by the development of 100s of colonic polyps in the seconsd decade and 95% have polyps by 35
- almost 100% penetrance if left untreated- treatment is by colctomy at an early age (when 20-30 poyps are present)
- screening starts at 10-12 years and detects most CRC before onset
PST in FAP
PST is offered from 10yrs so that colonoscopy can be offered due to early age of onset
- VHL and NF1 are other cancer syndromes with early onset where early PST is appropriate
APC gene
Loss of APC is an early event in colorectal adenoma.
The APC gene function in the wnt pathway by regulating phosphorylation is B-catenin and marking it for degradation, in the absence of APC B-catenin is not degraded resulting in uncontrolled cell proliferation.
APC mutation spectrum
- there is an alternatively spliced transcript of exon 9 lacking codons 312-412. This isoform is present in normal tissues and if the mutated codon is in this region it can be removed by normal splicing in the intestinal mucosa resulting in a milder phenotype.
- large final exona and nonsense muts in thus region do no always undergo NMD resulting in the presence of a partially functional protein.
- 5’ mutation. There is an internal ribosomal entry site early in the transcript. therefore truncating mutation in the 1st exon can escape NMDF by initiating translation at a downstream sites- results in attenuated FAP
- Missense mutations do no confirm a diagnosis. No statistically significant increased cancer risk and PST is not offered
How is FAP diagnosed?
based on family history and CRC phnotype >100 polyps.
Genetic testing by sequencing and MLPA. Now commonly included in a CC panel
15% of APC -ve cases have a MUTYH mutation so this testing should be considered.
What is the treatment of FAP?
safest preventative strategy is surgical removal of the colon when polyps start to develop
chemotherapy includes NSAIDs, COX-2 inhibitors
What is attenuated FAP?
milder phnotype with fewer polyps (<100), likely to be underdiganosed and associated with specific mutations.
What is MAP?
MUTYH associated polyposis
AR
Similar to FAP (10-100 polyps) family history can help distinguish the likely diagnosis.
FAP and MAP are example of simillar phenotype different mechanism
what is the age of onset of MAP
mean age of onset is 48yrs with 40-100% lifetime risk
there is a small increased risk of adenoma in heterozygotes but screening is not warranted.
What is the role of the MUTYH gene?
Involved in BER- repair of the most common form of oxidative damage 8-oxoguanine which pairs with A instead of C resulting in a G:C to T:A transition. The glycolase excises the 8)G from the sugar phosphate backbone so the base can be repaired.
MAP mutation spectrum
almost all mutations are missense and their affect on the glycolase range from a completer to partial loss of activity
Y179C and G396D account for 90% of mutation in N EU mutations
60% of tumours also have a KRAS mutation
Testing strategy for MAP
testing is offered to patients with 10-100 polyps and no APC mutation (in reality both are likely to be tested together as part of a panel)
- can pre-screen for common N EU mutations
- failure to detect a second mut could indicate the presence of a large del, rearrangement, or another gene is responsible
what screening is offered for MAP?
colonoscopy from 18yrs and upper GI tract investigations from 25-30 therefore PST is not offered to minors
What is the incidence and risk factors of breast cancer?
Most common female cancer in the UK with 1 in 8 lifetime risk. Incidence is increasing in western countries with increased life expectancy and move to a more wetern lifetsyle
risk factors: age, genetics, HRT, smoking, obesity, alcohol. Strongest risk factor is a strong family history of BC- 15-20% of BC has a family but gene found in known familial BC gene in ~10% of cases
what factors support a suspicion of a BRCA1/2 mutation?
- BC < 50yrs
- 2x primary BC
- breast and ovarian cancer in a single individual
- breast and ovarian cancer in close relative from the same side of the family
- male BC
ovarian cancer at any age
BRCA1/2 mutation in a family member
algorithms have been developed to calculate the liklihood that an individual have a BRCA1/2 mutation (BODICEA, Myriad, BRCAPRO)
According to NICE guidelines what prior probability of BRCA1/2 mutation is required for genetic testing
10%$ (reduced from 20% in 2013). in some centers it may be offered to all women with triple negative BC
What is HBOC?
hereditary breast and ovarian cancer syndrome- due to mutations in BRCA1 and 2 (no sequence similarity to each other). results in increased risk of breast and ovarian cancer including Fallopian tube and peritoneal. Also increased risk of pancreatic and prostrate cancer and melanomas.
what is the penetrance of HBOC?
incomplete penetrance 38-87% lifetime risk of BC and 16-63% increased risk of OC
BRCA1
accounts for 64% of HBOC
higher overall lifetime risk of cancer than BRCA2 and cancer at much earlier age than gen pop
common in triple -ve BC
BRCA2
34% of HBOC
Associated with a wider range of cancer and higher cancer risk in males- 20% prostrate cancer and 10% male BC
BRCA1/2 protein function
involved in HR, repair of DSBs and NER
BRCA1 forms a complex with BARD1 and co-localises with BRCA2 and RAD51 at sites of DNA damage
- involved in pathways controlling cell cycle progression, check point control, gene transcription, regulation and ubiquitination
- expressed in most tissue suggesting that the expression pattern is not responsible for the restricted tissue phenotype of BC
BRCA2/RAD51 mediate HR
ss binding protein which prevents degradation of DNA at stalled replication forks. Phosphorylated when not required and dissociates from RAD51
What is the mutation spectrum in HBOC
Mainly frameshift but some missense
ENIGMA consortium focuses on determining the clinical significance of BRCA1/2 and other cancer variants
foudner mutations are present in some populations e.g. askenanzi jew (AKJ) AKJ also have a high carrier freq - BRCA1 c.68_69delAG - BRCA1 c.5266dupC - BRCA2 c.5496delT 1/1000 in UK general pop 1/40-50 in AKJ pop
some genotype phenotype correlations have been reported but are not used in clinical practice. Ovarian cancer variants cluster around exon 11 in BRCA1 and 2
What is the testing strategy for breast cancer?
sequencing and MLPA- usually part of an NGS panel nowadays
- may pre screen for AKJ mutations in appropriate individuals
PST for at risk family members (requires counselling)
NICE guidelines- unaffected family members
- may also test FFPE tumour tissue to ID familial mut if no other sample from the affected is available
Point to consider for variant interpretation in cancer syndromes
- co-segregation with disease may support pathogenicity but this is complicated by reduced penetrance and phenocopies
- tumour can be examined for LOH as support of WT allele may support pathogenicity whereas loss of mutated allele exclude pathogenicity
What are the ethics associated with genetic testing in breast cancer?
PST requires counselling- it is unethical to offer PST to minors as BC does not onset in childhood
- family member may chose not to disclose their result so thei family members can’t be tested. alternatively testing may infer the result of a family member who chose not to be tested
- variable age of onset, need fukll understanding of risk associated with result and treatment options
What treatements are available for breast cancer?
surgery, chemo, hormone therapy
- herceptin can be offered for Her +ve tumours (tested for by IHC)
- prophylactic masectomy decreases BC risk by 90%
- bilateral prophylactic oophrectomy decreases risk by 53% for OC
- 10-24% of BRC1 and 65-99% of BRCA2 are ER+ve- these can be treated by tamoxifen (ER inhibitor) this can result in a 30-50% risk reduction and can result in menopausal symptoms and increased risk of thromboembolism and endometrial cancer so need to know tumour is ER +ve for there to be a risk benefit
knowledge of the germline mutation can influence treatment choice including surgery as risks vary for different cancer types.
Describe synthetic lethality and PARP inhibitors
PARP enzytme repairs ssBs by BER. When PARP is inhibitied these persist in the cell and develop into DSBs on replication.
HR is defective in BRCA1/2 mutated tumours therefore the DSBs can’t be repaired either and the cell accumulates lots of damage- this cant be repaired and targets the cell for apoptosis.
Normal cells are spared as they have functioning HR
Phase 3 trial of olaparib and talazoparib- 3 month progression free survival in BRCA germline carriers and metastatic disease compared to standard chemo- currenlty in use in UK for some OV cancer and in trials for BCV
surveillance techniques: self-examination, MRI and mamography. the method depends on the risk group, age and mutated gene.
Name other syndromes associated with an increased risk of BC?
Li Farumeni (TP53)- associated with increased risk of early onset BC, brain tumours, soft tissue sarcomms, osteosarcomma and adrenocortical carcinoma
Peutz-Jeghers (STK11)- associated with harmatomatous polyps and increased risk of CRC and melanin deposits in the fingers and lips
- cancer risk is also increased fro breast, lung, uterus and ovary
- 93% cumulative cancer risk
Cowden syndrome (PTEN)
Multiple harmatoma syndrome - increased risk of breast cancer and non-medullary thyroid cancer (mostly pre-menopausal)
Also have cutaneous fetures: oral mucosal papillomas, tricholomas and acral kertoses
Hereditary diffuse gastric cancer/ lobular breast cancer (CHD1)
39-52% lifetime risk of lobular BC
What are the moderate penetrance BC susceptibility genes?
pathogenic variants in genes associated with damage repair may also have a moderate penetrance for BC- CHEK2, PALB2, ATM
How are polygenic risk scores used in BC
Low penetrance BC SNPs have been identified by GWAS- risk inferred by each individual loci is low and polygenic risk scores based on a number of associated SNPs has been used to stratify BC risk in different populations.
SNPs can also modify the risk of an individual with a pathogenic variant in a cancer predisposition gene and polygenic risk scores have been developed ti modify the estimiated risk in patients with BRCA1/2 and CHEK2 variants
What is the genes have UKCGG consensus for inclusion in a BC NGS panel?
UK cancer genetics group published a consensus list of gene with sufficient evidence of clinical utility in testing BRCA1/2 PALB2 PTEN STK11 CHEK2- truncating mutations only ATM- val242Gly only
including low penetrance genes in the panel can lead to difficulties with interpretation. if the clinical significance is unclear is can’t be used for clinical decision making and is not useful. Detection of a variant in a low penetrance gene in a family with a high incidence of BC may not account for all the risk in the family and there may be a second diagnosis present.
what are the characteristic findings in NF1?
neurofibromas and cafe au lait patches
How is NF1 diagnosed?
Usually unequivocally clinically diagnosed by the age of 8 and symptoms develop with age.
clinical diagnosis is based on: - 5 cafe au lait macules - NF1 in a first degree relative - freckling in the armpit or groin -2+ neurofibromas - 2 + lisch nodules - distinctive bony lesions cognitive impairment (reduced IQ and behavioural problems) is the most common neurological manifestation
what is the life expectancy for NF1?
life expectancy usually reduced by 8 years sue to malignancy and vasculopathy
How is NF1 molecularly diagnosed?
Not usually required and diagnosed clinically.
Very high new mutation rate
50% de novo and somatic mosaic is common, this can result in segmental NF1 where is is only present in one or a few tissues. Therefore diagnosis using peripheral blood may not detect the mutation in sporadic cases.
tumour testing can be useful but interpretation can be complicated by the potential for a high number of acquired mutations. Testign tyumour tissue can be useful for variant interp, LOH of the WY allele suypport pathogenicity of the variant on the mutated allele whereas loss of the variant allele excludes pathogenicity.
Testing PB is appropriate for familial cases as the mutation will be present in all tissues (non mosaic)
Genotype-phenotype correlations in NF1?
whole gene deletions are associated with earlier onset and a increased no. of neurofibromas
NF1 dup can be associated with ID and seizures
There is high clinical variability due to the presence of modifier genes
Treatment for NF1
No cure so treatment is based on treating symptoms
- vit D supplementation for fracture risk
Possible therapies could include:
gene replacement for LOF mutations
exons skipping to treat specific exons
genome editing for small muts
what is the clinical phenotype of NF1?
tumours around the brain and spinal cord can cause
pain, weakness and numbness in arms and legs (usually benign)
5% develop a malignant tumour most commonly of the peripheral nerve sheath.
children also have a 100-fold increased risk of suffering from a myeloid disorder
what is the location and product of the NF1 gene?
Found on 17q11.2 and encodes neurofibromin
NF1 acts as a TSG whihc -vely regulates RAS. When NF1 is mutated there is increased RAS signalling resulting in cell survival and growth through the MAPK and PI3K pathways
What are the differential diagnosis for NF1?
Noonans- share some dysmorphoc features (hypertelorism, down-slanting palepebral fissures, low set ears)
Leopard syndrome
McCune Albright syndrome (irregular cafe au lait patches)
MEN2B- tumours can be confused with neurofibromas
Describe NF2
Less common than NF1 but also AD
Characterised by the presence of vestibular schwannomas- these are benign intrcranial tumours of the myelin forming cells of the vestibular cochlea nerve and result in hearing loss, tinitis and balance problems
onset is between 18 and 24 yrs
How is NF2 diagnosed?
bilateral vestibular schwanomma or
1st degree relative with NF2 and unilateral VS
or 2 of: menigioma, schwannoma, glioma, neurofribroma
NF2 gene
encodes neurofibromin 2 AKA merlin of swchanomin
TSG in the PI2K/ Akt patheway and loss of merlin allows cells (especially schwann cells) to multiply quickly
What is the genetic testing in NF2?
sequencing and MLPA of NF2
- as with NF1 mosaicism can complicate testing
Large dels incl. NF2 which are cytogentically visible result in childhood onset and LD e.g. r(20) or chr 20 translocations.
What are the characteristic features of tuberous sclerosis?
characterised by the development of (benign) harmatomas. Symptpmsa can be mild to severe with multi organ involvement
How is TSC disgnosed?
primarily diagnosed by the presence of skin lesions or secondary to epilepsy
what is the genetic cause of TSC
Due to LOF mutations in TSC1 or TSC2- these act as a TSG in the MTOR pathway. In the active state they inhibit MTOR activation
There are currently no specific drugs available but trials involveing MTOR inhibitors (e.g. rapamycin) are showing promising results
2/3 are de novo. High mutation rate means mosaicism is common and this can complicate diagnosis
TSC1 is found on 9q34 and TSC2 is on 16p13.3 (can be deleted as part of a contigous del including PKD1 resulting in TSC ans early onset PKD
What are the clinical features of TSC?
ASHLEAF
A: Ashelaf spots
S: Shagreens patches
H: Heart rhabdomyomas- can cause arrythmias
L: lung fibrosis and restircitve lung disease
E: epilepsy from cortical tuber (main cause of morbidity and mortality
A: angiomyolipoma in the kidney (benign tuours can cause end d=stage kidney disease)
F: facila angiofribromas
harmatomas in cortex and ventricles may also result in sever ID, behavioral problems and ADHD
CNS symptoms are present in 90-95% and (predominantly epilepsy)
Clinical diagnosis of TSC
can be made prenatally by the observation of cortical tubers on USS from the 2nd trimester.
most have normal life expectancy
main cause of mortality is from brain and kidney tumours
What is the role of the TSC complex as a TSG?
TSC1 (stabilises TSC1 to prevent ubiquitin degradation subunit) and TSC2 (catalytic subunit form a heterodimer with GTPase activity = TSC2 mutations are generally associated with more severe disease
- in the absence of growth signals they inhibit cell growth by converting Rheb GTP (active) to Rheb GDP (inactive). Normallly Rheb GTP activates the MTOR pathway resulting in cell growth so TSC complex inhibits this.
TSC complex is inhibited by cell growth signal
regulated post-transcriptionally by phosphorylation
MTOR is also inhibited by the drug rapamycin
Mosaicism in TSC/ Genetic testing issues
Present in a significant number of patients therefore testing of tissues other than PB may be appropriate e.g. skin, saliva, tumour, hair
detection of mosaicism is technically challenging below 2% (e.g. patients with single organ involvement)
Genetic testing is also complicated by the large size of the gene and the large number of pathogenic mutations. majority of mutations ar truncating mutations, deletions or rearrangements
What is the penetrance of TSC?
AD disorder with incomplete penetrance
variabel expressivity is due to the fact the the TSC complex is regulated by and regulates a variation of different signalling pathways in the cell.
What treatments are available for TSC
No cure so treatment aims to treat symptoms and early identification of potentially aggressive lesions.
MTOR inhibitor (rapamycin and afinitor) can make up for deficient TSC complex by inhibiting downstream MTOR to prevent cell growth. FDA approved in 2010 for patients with enlarging brain tumours & can also be applied topically for facial angiofibromas
MTOR inhibitors are cytostatic not cytotoxic.
MTOR inhibition may be compensated for by PDGFRB (tyr kinase). Inhibition of both in mice using rapamycin and imatinib has been shown to decrease tumour size without toxicity.
What is MEN?
Multiple endocrine neoplasia
4 subtypes
describe MEN1
due to LOF mutation in the TSG MEN1 which encodes menin at 11q13
results in tumours of the parathyroid, duodenum, pancreatic islets, pituitary gland. With the exception of gastric tumours most are not metastatic but cause signification clinical phenotype due to the secretion of endocrine hormones: IGH, insulin, gastrin, adrenocorticotropic hormone
the over production of hormones aids in the diagnosis.
Testing is by sequencing and MLPA (may be included in an NGS panel). Screening by biochemistry and imaging may be offered to family members even if a pathogenic mutation is not found
Describe MEN2 and 3
previously MEN2A and 2B
- associated with medullary thyroid carcinoma (100%), phaeochromocytoma (50%) and parathyroid tumours (50%)
caused by GOF activating mutation in RET oncogene. the location of the mutation determines the phenotype
- 1st tyr kinase domain = familial medullary thyroid carcinoma
- TM domain = MEN2
- 2nd tyr kinase domain = MEN3
any patient with medullary thyroid carcinoma should be offered testing for RET
Describe MEN4
AD LOF mutations in CDKN1B
MEN1 phenotype with no MEN1 mutation
Describe the genetics and symptoms of VHL
Caused by LOF mutations *throughout the coding seq) in the VHL gene Associated with benign and malignant neoplasm -renal cysts -hemangiomas -parangangliomas -phaeochromocytoma (only in type 1) -epidyidymal cysts -pancreatic cysts
80-90% penetrance by 65yrs
Describe Peutz Jeghers
Due to LOF mutations in STK11- test my MLPA and seq
Associated with harmatomatous intestinal polyps and increased risk of CRC
- also results in dark spots on lips, armpits and groin.
surveillance is by colonoscopy, eneteroscopy, and polypectomy to remove polyps
Part of a group of disorders called lentiginomas- mostly due to mutations in the RAS/MAPK pathwya which is a targewt of MTOR signalling (leopard syndrome, PTEN, noonans)
Describe hereditary paragnaglioma/phaeochromocytoma syndromes
Due to mutations in SDHA, SDHB, SDHC, SDHD, SDHAF2 and TMEM127- therefore multigenen testing is required for diagnosis.
paraganglioma- tumour of the parganglia at the base of the skull (rare and usually benign)
phaeochromocytoma- rare usually benign tumour of the chromaffin cells- adrenal cortex
tumours occur at all ages and incidence increases at 40-50 years
The predisposing genes all appear to have different actions but despite this result in the same tumours clinically ans histologically
- highest malignancy with SDHB and PND is available if a pathogenic mutation has been identified
- genetic predisposition is indicated by family history, early onset of tumours (<45yrs) and the presence of multiple tumours
- may also get papilliary, renal and GI tumours
Describe PTEN harmatoma syndrome
AD due to LOF mutation in the PTEN TSG
PTEN acts as a tyr phosphatase - regulates PI3K/Akt/MTOR pathway and MTOR inhibitors have been approved by the FDA for treating PYEN syndromes
1) Cowden syndrome
- increased risk of breast cancer and endometiral tumours
- facial trichelommas, papilommatous papukles
-90% penetrance by 30 yrs
2) Bannayan-Riley- Ruvalcaba syndrome (BRRS)
micorcephlay, lipomatosis, hemangiomatosis, pigmented macules of the glans penis
PTEN-related proteus syndrome- progressive segmental and patchy growth of multiple tissues- most commonly connective tissue, epidermal naevi and skeleton.
Describe cutaneous malignant melanoma
ADF mutations in CDKN2A which encodes 2 unrelated proteins
P14 ARF destabilises the p53-MDM2 interaction releasing p53 to activate cell cycle arrest and apoptosis
P16INK4a- inhibits Cdk4/6 so that RB remains unphosphorylated and bound to E2F- preventing E2F from locating to the nucleus to activate transcriptions g gene required for cell cycle transition.
TSG and mutations associated with skin cancer- penetracne is dependent on age and sun exposure
