cancer predisposition syndromes Flashcards
whats cowden syndrome
autosomal dominant inheritance w variable expression. late 20s.
devept of hamartomas (99%). increased risk of developing cancers (breast, thyroid & endometrial).
Progressive macrocephaly in 1st yrs of life
whats causes Cowden syndrome
PTEN muts (mainly truncating, rest: missense)
40% of muts are in exon 5
what treatment is there for Cowdens
Main focus: management of cancer.
Rapamycin : specific mTOR inhibitor
(use of PI3K/Akt/mTOR inhibitors in oncology)
Whats Familial Multiple Endocrine Neoplasia
encompasses several distinct syndromes featuring tumors of endocrine glands: pancreatic islets, duodenal endocrine cells, and the anterior pituitary
94% penetrance by age 50 most of the tumors are non-metastasising
What causes Familial Multiple Endocrine Neoplasia type 1 (MEN1)
MEN1 (TSG) Mutations: LoF
What causes Familial Multiple Endocrine Neoplasia type 2 (MEN2)
RET( protooncogene): single best example of a germline GoF oncogene cancer predisposition
activating mutations in the intra- and extra-cellular parts of gene cause slightly diff phen in severity and onset (MEN2A vs MEN2B).
what are the clinical features of Neurofibromatosis Type 1
1 in 3-4,000
cafe au lait spots (≥6x).
Freckling in armpit or groin.
neurofibromas (≥2x) , (benign) present in more than 95% of adult pts
Lisch Nodules (Small lumps on the iris)
Cognitive Impairment (low IQ, LD & behavioural problems)
Features typically increase w age
what causes Neurofibromatosis Type 1
mutation of NF1 (neurofibromin) 17q11.2
Sequence analysis detects ~ 90% muts.
Dels/dups = 4-5% of muts
discuss mosaicism and Neurofibromatosis
Somatic mosaicism = common due to high rate of de novo mutation
Due to high levels of mosaicism (especially segmental mosaicism), testing blood isn’t ideal for NF1 or NF2 (unless its germline)
Large dels are difficult to diagnose in low-level mosaics
direct testing of tumour DNA & RNA/cDNA is done
Name some Differential Diagnoses of NF1
NF1-noonan syndrome:
McCune-Albright syndrome
multiple endocrine neoplasia type 2B
what are the clinical features of Neurofibromatosis Type 2
1 in 25,000 .Average onset : 18-24 years
Bilateral vestibular schwannomas (benign intracranial tumour). A 1st-degree relative with NF2 AND
Unilateral vestibular schwannoma.
Gradualhearing loss.
Ringing or buzzing in the ears (tinnitus).
Balance problems, particularly in the dark or walking on uneven ground .
may have cafe-au-lait spots, but usually fewer than people with NF1
what causes Neurofibromatosis Type 2
Inactivating mutations (TSG) NF2 22q12.2
Combined sequencing and MLPA is estimated to detect a mut in ~72% of simplex cases and 92% of familial cases
Name a Differential Diagnoses of NF2
Schwannomatosis can also be caused by mutations in the SMARCB1 gene
what genes are mutated in Lynch Sydrome (Hereditary non-polyposis colorectal cancer)
90%: MLH1, MSH2 /
7-10% MSH6 /
whats the testing order for lynch
1)IHC. 2) sequence MSH2,6, MLH1. 3) MS-PCR MLH1 promoter. 4) BRAF V600E
What genes mutated in FAP familial adenomatous polyposis
APC 5q21
25% de novo /
75% inherited
> 300 muts: 80% nonsense/frameshift. codons 1284-1580
what are the clinical features of tuberous sclerosis
highly variable expressivity of phenotype.
CNS: cortical tubers and SENS. seizures, mild-severe ID, behavioural probs.
facial angifibromas. benign angiomyolipomas. cardiac rhabdomyomas. rentianl lesions
whats causes tuberous sclerosis
75-85%: TSC1 (9q34) and TSC2 (16p13.3) muts. TSC2 (69%)
bind together and form GAP protein
how test for tuberous sclerosis
bidirectional snager seq and MLPA
TSC1: mainly truncating muts (nonsense, frameshift, splice site)
TSC2: maj trauncating, but large abns seen 10% (exon/gene del, dup, chrom rearr)
whats the treatment for tuberous sclerosis
Rapamycin : specific mTOR inhibitor
replaces defective GAP by inhibiting mTORC1
