SolidTumors-GI,Pancreatic,Hepatobiliary

Question 1

85% of colorectal carcinomas are associated with what gene/chr mutation.

Answer 1

-APC gene on chr5

Question 2

In APC gene related tumors what is required for progression?

Answer 2

Mutation or LOH of the 2nd APC gene and KRAS mutation

Question 3

Genetics of Familial Adenomatous Polyposis (FAP).

Answer 3

Germline APC mutation

Question 4

FAP manifestations.

Answer 4

• > 100 adenomatous polyps by 35
• Adenoca by 50

Increased incidence of:

• Fundic Gland Polyps
• Ampullary adenoma
• small bowel/ampullary Adenoca
• Thyroid cancer
• Fibromatosis

Question 5

Mutation ass. w/ Attenuated FAP.

Answer 5

5’ or 3’ end of APC

Question 6

Other APC germline mutation syndromes.

Answer 6

• Gardner syndrome

- Turcot syndrome

Question 7

In addition to features of FAP, what other findings are seen in Gardner syndrome?

Answer 7

• Epidermal cysts
• Osteomas (mandibular/maxillary)
• Fibromatoses
• Hypertrophy of retinal pigment epithelium

Question 8

In addition to features of FAP, what other findings are seen in Turcot syndrome?

Answer 8

-CNS tumors

may be caused by APC gene mutations or MMR gene mutations

Question 9

Characteristic Clinicopathologic features of APC associated tumors:

• Polyp type
• colon region
• Histology

Answer 9

• TA
• Left-sided (Descending colon)
• Columnar/psuedostratified with lumens and dirty necrosis w/ infiltrating advancing edge

Question 10

15% of colorectal carcinomas are associated with genetic abnormality?

Answer 10

-Mismatch repair

Question 11

What do MR genes encode for?

Answer 11

Enzymes that correct erros in DNA replication

Question 12

MMR gene enzymes work as Dimers, what are the main ones?

Answer 12

• MSH2/MSH6

- MLH1/PMS2

Question 13

What are the major oncogenic mutations in MMR protein defects?

Answer 13

• BRAF
• KRAS
• p16INK4a

Question 14

Microsatellite Instability (MSI) is….

Answer 14

• Alteration in length of microsatellite repeat sequences

- Surrogate marker for MMR dysfunction

Question 15

What causes sporadic MMR inactivation?

Answer 15

Hypermethylation of the promoter sequence

Question 16

Most germline MMR mutations cause what syndrome?

Answer 16

Lynch Syndrome (HNPCC; Hereditary NonPolyposis Colorectal Cancer)

Question 17

Which mutations account for 90% of Lynch Syndrome (HNPCC) cases?

Answer 17

• MLH1

- MSH2

Question 18

Characteristic Clinicopathologic features of MMR associated tumors:

• Polyp
• Presentation
• Region of Colon
• Cancer subtype
• Dirty Necrosis??
• Key Histo feature

Answer 18

• SSA
• Large exophytic mass
• Right colon (Ascending)
• Mucinous (colloid) differentiation
• NO dirty necrosis
• Tumor Infiltrating Lymphocytes and/or “Crohnlike” nodular lymphoid reaction
• Pushing tumor margin

Question 19

MSI testing:

Answer 19

• panel of 5 microsatellites

- DNA from tumor vs. normal tissue (or blood)

Question 20

MSI high Vs MSI low

Answer 20

MSI high - at least 2 microsatellites

MSI low - 1 unstable locus

(otherwise microsatellite stable)

Question 21

MMR gene assessment by IHC:

- MLH1 mutation

Answer 21

• MLH1 - NEG.
• PMS2 - NEG.
• MSH2 - Pos.
• MSH6 - Pos.

Question 22

MMR gene assessment by IHC:

- PMS2

Answer 22

• MLH1 - Pos.
• PMS2 - NEG.
• MSH2 - Pos.
• MSH6 - Pos.

Question 23

MMR gene assessment by IHC:

- MSH2

Answer 23

• MLH1 - Pos.
• PMS2 - Pos.
• MSH2 - NEG.
• MSH6 - NEG.

Question 24

MMR gene assessment by IHC:

- MSH6

Answer 24

• MLH1 - Pos.
• PMS2 - Pos.
• MSH2 - Pos.
• MSH6 - NEG.

Question 25

Resistance to EGFR monoclonal Ab (cetuximab) is found in tumors with what specific mutations?

Answer 25

- BRAF (V600E) | - KRAS (codons 12/13)

Question 26

20% of Gastric cancers and 30% of GE junction tumors overexpress what?

Answer 26

Her2

Question 27

Juvenile Polyposis syndrome: - Inheritance - Cancer risk - Findings

Answer 27

- Autosomal Dominant - Moderate increase - Juvenile polyps in stomach, sm. intestine, colon

Question 28

Peutz-Jeghers syndrome (PJS): - Inheritance - GI Features - Cancer risk

Answer 28

- Autosomal Dominant - Mucocutaneous pigmentation/Hamartomatous polyps - Significant Increased Risk

Question 29

Peutz-Jeghers syndrome: Non-GI findings

Answer 29

- SCTAT - Adenoma malignum (minimal deviation adenoca) - Calcifying Sertoli cell tumor of the testis - Nasal polyposis

Question 30

Most cases of Peutz-Jeghers syndrome are due to what mutations?

Answer 30

STK11/LKB1 gene on chr19p

Question 31

GISTs that are KIT weak or KIT Neg. (5%) are likely to harbor what mutation?

Answer 31

PDGFRA

Question 32

Most pediatric GISTs (and rare Adult) are negative for KIT and PDGFRA, what mutation may they have?

Answer 32

SDH (Succinate Dehydrogenase)

Question 33

Mutation in what KIT exon is highly associated with Imatinib response?

Answer 33

11 | Exons 9, 13, 17 - 40-50% sensitive *KIT negative GISTs may be Imatinib sensitive in 30%

Question 34

What is the most common PDGFRA mutation in GIST, and is it Imatinib sensitive or resistant?

Answer 34

- D842V | - Completely insensitive

Question 35

GIST may be a feature of what syndromes?

Answer 35

- Carney Triad (SDH mutations) - NF1 - Familial GIST syndrome (germline mutation in KIT)

Question 36

Carney Triad.

Answer 36

- GIST (SDH mutations) - Pulmonary chondromas - Extra-adrenal paragangliomas

Question 37

T/F: Peutz-Jeghers syndrome confers 100X increased risk of Pancreatic Ductal Adenocarcinoma.

Answer 37

True

Question 38

Genetic abnormalities associated with Increased risk of HCC.

Answer 38

- Hereditary Hemochromatosis - Tyrosinemia - Glycogen storage disease (types 1&2) - AAT deficiency - Wilson disease - Porphyria Cutanea Tarda - Galactosemia

Question 39

What mutations/defect are consistent with germline or sporadic loss of MLH1?

Answer 39

- BRAF (V600E) | - MLH1 promoter hypermethylation