Genetics and syndromes

Question 1

Main lung cancer genes (3)

Answer 1

EGFR: female, Asian, non smoker, lepidic, respond to TKIs (gefitinib, erlotinib)

ALK (EML4-ALK): young, non smoker, solid and signet ring/mucinous, respond to crizotinib

KRAS: smoker, mucinous, don’t respond to TKIs

Question 2

Main melanoma genes (3)

Answer 2

BRAF (50%): mainly V600E

NRAS

C-KIT (esp acral and mucosal)

Question 3

Main CRC genes

Answer 3

APC (tumour suppressor): 80%, if germline=FAP

BRAF (methylated in non-Lynch MSI-H)

KRAS

germline MMR genes (Lynch)

nb: can have more than one of these

Question 4

Other Lynch syndrome tumours

Answer 4

SUB SCOPES

skin

urothelial

brain

stomach

CRC
ovarian

pancreatobiliary

endometrial

small bowel

Question 5

colorectal polyposis syndromes

Answer 5

FAP

serrated

MutYH

juvenile

Peutz-Jeghers

Question 6

GIST genes

Answer 6

C-KIT in 80%: respond to TKI (imatanib)

PDGFR

BRAF

SDH A, D, C, D

NF1

Question 7

APC in CRC

Answer 7

action: degrades oncogene b-catenin (which becomes IHC+)

if germline APC = FAP (100s-1000s adenomas, 100% lifetime risk CRC, also small bowel adenoma, gastric polyps, thyroid ca)

Gardners = FAP + fibroma, osteoma, epidermoid cyst, pilomatrixoma

Turcots = FAP + brain tumour (or Lynch + brain tumour)

Question 8

main breast cancer genes

Answer 8

HER2 (proto-oncogene): if amplified, poor prognosis but good response to trastuzumab

E-cadeherin (cell adhesion molecule): esp lobular

BRCA 1 (tumour suppressor): triple negative, medullary ca, also ovarian ca

BRCA 2 (tumour suppressor): high grade ca, also ovary/prostate/pancreatic

Question 9

MEN1 (Wermer syndrome)

Answer 9

MEN1 gene

pituitary adenoma

parathyroid hyperplasia

pancreatic endocrine neoplasm

Question 10

MEN2

Answer 10

RET oncogene

2A (Sipple syndrome): medullary thyroid ca (100%), parathyroid hyperplasia, phaeo

2B: medullary thyroid ca, phaeo, ganglioneuromatosis GI tract, Marfanoid

Question 11

NF1

Answer 11

AD or sporadic

JOG the PLANC

JXG

Optic nerve glioma (PA)

GIST

Plexiform neurofibroma

Lisch nodules

Neurofibroma (diffuse)

Cafe au lait spots

Question 12

NF2

Answer 12

AD or sporadic

SCAM:

Spinal cord ependymoma

Cafe au lait spots

Acoustic schwannoma (bilateral)

Meningioma

Question 13

what is Lynch-like syndrome?

Answer 13

MMR-deficient on IHC, but no germline mutation, no BRAF mutation and no promotor methylation

(could be: 1. false+ IHC 2. true Lynch but mut not detected 3. biallelic somatic mut in MMR genes)

Question 14

If there is MMR loss on IHC what could it be? (3)

Answer 14

MLH1 promoter hypermethylation (silences BRAF)

Lynch syndrome

germline epimutation