cancer predisposition syndromes

Question 1

whats cowden syndrome

Answer 1

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

Question 2

whats causes Cowden syndrome

Answer 2

PTEN muts (mainly truncating, rest: missense)

40% of muts are in exon 5

Question 3

what treatment is there for Cowdens

Answer 3

Main focus: management of cancer.

Rapamycin : specific mTOR inhibitor

(use of PI3K/Akt/mTOR inhibitors in oncology)

Question 4

Whats Familial Multiple Endocrine Neoplasia

Answer 4

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

Question 5

What causes Familial Multiple Endocrine Neoplasia type 1 (MEN1)

Answer 5

MEN1 (TSG) Mutations: LoF

Question 6

What causes Familial Multiple Endocrine Neoplasia type 2 (MEN2)

Answer 6

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).

Question 7

what are the clinical features of Neurofibromatosis Type 1

Answer 7

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

Question 8

what causes Neurofibromatosis Type 1

Answer 8

mutation of NF1 (neurofibromin) 17q11.2

Sequence analysis detects ~ 90% muts.
Dels/dups = 4-5% of muts

Question 9

discuss mosaicism and Neurofibromatosis

Answer 9

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

Question 10

Name some Differential Diagnoses of NF1

Answer 10

NF1-noonan syndrome:

McCune-Albright syndrome

multiple endocrine neoplasia type 2B

Question 11

what are the clinical features of Neurofibromatosis Type 2

Answer 11

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

Question 12

what causes Neurofibromatosis Type 2

Answer 12

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

Question 13

Name a Differential Diagnoses of NF2

Answer 13

Schwannomatosis can also be caused by mutations in the SMARCB1 gene

Question 14

what genes are mutated in Lynch Sydrome (Hereditary non-polyposis colorectal cancer)

Answer 14

90%: MLH1, MSH2 /

7-10% MSH6 /

Question 15

whats the testing order for lynch

Answer 15

1)IHC. 2) sequence MSH2,6, MLH1. 3) MS-PCR MLH1 promoter. 4) BRAF V600E

Question 16

What genes mutated in FAP familial adenomatous polyposis

Answer 16

APC 5q21

25% de novo /
75% inherited

> 300 muts: 80% nonsense/frameshift. codons 1284-1580

Question 17

what are the clinical features of tuberous sclerosis

Answer 17

highly variable expressivity of phenotype.

CNS: cortical tubers and SENS. seizures, mild-severe ID, behavioural probs.
facial angifibromas. benign angiomyolipomas. cardiac rhabdomyomas. rentianl lesions

Question 18

whats causes tuberous sclerosis

Answer 18

75-85%: TSC1 (9q34) and TSC2 (16p13.3) muts. TSC2 (69%)

bind together and form GAP protein

Question 19

how test for tuberous sclerosis

Answer 19

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)

Question 20

whats the treatment for tuberous sclerosis

Answer 20

Rapamycin : specific mTOR inhibitor

replaces defective GAP by inhibiting mTORC1