PATH: Mutations

Question 1

EARLY: loss-of-funciton in TP53 and down-regulation of CKDN2A
LATE: amplification of EGFR, ERBB2, MET, cyclin D1, and cyclin E

Answer 1

Esophageal Adenocarcinoma

Question 2

1) Amplified SOX2
2) Overexpression of Cyclin D1
3) Loss of function in TP53, E-cadherin, and NOTCH1

Answer 2

Esophageal Squamous Cell Carcinoma

Question 3

Loss of function: APC
Gain of function: gene for Beta-catenin

(Wnt Pathway Upregulation)

Answer 3

Intestinal Type Gastric Adenocarcinoma

Question 4

Germline Loss of APC

Answer 4

FAP

Question 5

CDH1 mutation–> loss of E-cadherin

Answer 5

Diffuse Type Gastric Adenocarcinoma

Question 6

1) ATI2-MLT fusion gene
2) increase MALT1 proteins
3) increase BCL-10 proteins
Constitutive expression of NF-kB.

Answer 6

MALT-oma

Question 7

EARLY: Gain of Function in CD117 (receptor for tyrosine kinase KIT) OR Activation mutation of PDGFRA
LATE: CDKN2A or other

Answer 7

GIST

Question 8

SDHA, SDHB–> HIF-1alpha dysregulation to increase VEGF/IGF1R transcription

Answer 8

Carney-Stratakis Syndrome (GIST)

Question 9

NOD2 –> can’t encode protein that activate NFkB

Answer 9

Crohn Disease

Question 10

ECM1 mutation –> uncontrolled MMP9

Answer 10

Ulcerative Colitis

Question 11

HNFA polymorphisms

Answer 11

Ulcerative Colitis

Question 12

Mutation/ DNA mismatch repair of MSH2 and MLH1

Answer 12

Hereditary Non-Polyposis Colorectal Cancer

Question 13

loss-of-function STK11

Answer 13

Peutz-Jeghers Syndrome

Question 14

EARLY: APC mutation (inactivated)
LATER: KRAS/BRAF mutation (activated)

Answer 14

adenomatous polyp (tubular or vilous)

Question 15

EARLY: APC inactivated
LATER: KRAS/BRAF upregulated
LAST: p53 inactivated and PIK3CA upregulated

Answer 15

Colorectal cancer

Question 16

MSI then BRAF mutation.

Answer 16

Sessile Serrated Adenoma

Question 17

SERPINA1

Answer 17

alpha-1-antitryspin deficiency

Question 18

C282Y mutation of HFE gene

Answer 18

Hereditary Hemochromatosis

Question 19

ATP7B mutation

Answer 19

Wilson’s Disease

Question 20

ADH2*1 polymorphism

Answer 20

Alcoholic Liver Disease predisposition (in Asians)

Question 21

TNF-alpha 238 polymorphism

Answer 21

Alcoholic Liver Disease predisposition (in Caucasians)

Question 22

EARLY: beta-catenin activation and p53 inactivation

Answer 22

HCC

Question 23

HNF1-alpha inactivation

Answer 23

Hepatocellular Adenoma (very benign)

Question 24

Beta-catenin activation

Answer 24

Hepatocellular Adenoma (very high risk for malignant transformation)

Question 25

gp130 activation

Answer 25

inflammatory subtype hepatocellular adenoma

Question 26

Activation of WNT signaling pathway.

Sporadic cases have activation of beta-catenin

Answer 26

Hepatoblastoma

Question 27

Hemojuvelin and HAMP mutation

Answer 27

Type II (Juvenile) Hemochromotosis

Question 28

PRSS1 gain of function (make trypsin resistant to self-inactivation)
SPINK1 loss of function (trypsin inhibitor)
CFTR loss of function

Answer 28

Hereditary Pancreatitis

Question 29

Delta-F508 mutation of CFTR

Answer 29

Cystic Fibrosis

Question 30

Loss of VHL tumor suppressor

Answer 30

Serous Pancreatic Cysts (low malignant potential)

Question 31

Mutation in KRAS oncogene and TP53 and RNF43 tumor suppressors

Answer 31

Mucinous Pancreatic Cysts (malignant potential)

Question 32

Early: KRAS activated, CDKN2A inactivated
Later: TP53 inactivated, SMAD4 inactivated

Answer 32

Pancreatic Adenocarcinoma

Question 33

ABCG8 gene variant of sterol transporter.

Answer 33

Predisposition to Cholesterol stones

Question 34

ERBB2 (Her2/Neu) overexpression (66%)

PBRM1 and MLL3 mutation (25%)

Answer 34

Gallbladder carcinoma

Question 35

JAGGED1 mutation (ligand for NOTCH1)

Answer 35

Alagille Syndrome

Question 36

MRP2 mutation

Answer 36

Dubin-Johnson Syndrome

Question 37

UGT deficiency

Answer 37

Gilbert Syndrome

Question 38

Fumaryl-aceto-acetase deficiency.

Answer 38

Tyrosinemia Type 1

Question 39

Damaged/missing ornithine transcarbamylase

Answer 39

Ornithine Transcarbamylase Deficiency (urea cycle disorder)

Question 40

Beta-glucocerebrosidase deficiency

Answer 40

Gaucher Disease

Question 41

Glucose-6-phosphatase deficiency

Answer 41

von Gierke Disease

Question 42

PBGD Deficiency

Answer 42

Acute Intermittent Porphyria