MASTER NEOPLASM DECK

Question 1

What type of genetic alterations are found upon sequencing HPV-associated SCC within the oropharynx (and to a lesser degree, the oral cavity)?

What about the classic SCC subset?

Answer 1

Back story:
In the OROPHARYNX, as many as 70% of the SCCs (particularly those involving the tonsils, the base of the tongue, and the pharynx) harbor oncogenic variants, particularly HPV-16.
However, HPV-associated SCC of the ORAL CAVITY is less common.

So…

~Genetic alterations of HPV-associated subset: overexpression of p16; also expression of E6 and E7 that leads to the inactivation of p53 and RB.

~Genetic alterations of the classic SCC subset: associated with p53 and NOTCH1 mutations

Question 2

What is typically overexpressed in HPV-associated SCC’s?

Other common genetic alterations?

Answer 2

• p16 (cyclin dependent kinase inhibitor) = overexpressed
• p53 inactivation –> E6
• RB inactivation –> E7

“In addition, owing to the expression of HPV oncoproteins E6 and E7, there is inactivation of p53 and RB proteins.”

Question 3

Which genetic mutation (i.e., translocation and gene products) is thought to play a key role in Mucoepidermoid carcinoma?

Answer 3

• Balanced (11;19) translocation

- Creates fusion gene = MECT1 and MAML2 genes

Question 4

Exposure to what increases risk for Pleomorphic Adenomas?

Associated with what genetic mutation?

Answer 4

• Radiation

- PLAG1 overexpression –> Increased cell growth

Question 5

Which genetic mutations are commonly associated with the “classic - tobacco/alcohol” SCC subset?

Answer 5

• Frequently involve p53

- p63 and NOTCH1

Question 6

Nevoid basal cell carcinoma (Gorlin syndrome) is associated with mutations in what gene and on what chromosome?

This is associated with OKCs!!!

Answer 6

• PTCH (tumor suppressor gene)

- Cr. 9

Question 7

Progression from Barrett Esophagus to Adenocarcinoma occurs over a period of time in a stepwise acquisition of genetic changes, which are seen early on and later in this progression?

Answer 7

• Early: mutations of TP53 and downregulation of CDKN2A

- Later: amplification of EGFR, ERBB2, MET, cyclin D1 and cyclin E

Question 8

Which genetic disorder predisposes a child to Hirschsprung disease?

Answer 8

Down syndrome

Question 9

Which genetic disorders are associated with an increased risk of Pyloric Stenosis?

Answer 9

• Turner syndrome

- Trisomy 18

Question 10

Which genetic abnormality can account for the majority of familial cases of Hirschsprung disease?

Answer 10

Loss-of-function mutation in RET (receptor tyrosine kinase)

Question 11

Which genetic mutations play a role in the development of squamous cell carcinoma of the esophagus?

Answer 11

• Amplification of SOX2
• Over-expression of cyclin D1
• Loss-of-function mutations in TP53, E-cadherin, and NOTCH1

Question 12

The desmoplastic small round cell tumor of the peritoneum is associated with what genetic abnormality?

Answer 12

Reciprocal translocation t(11;22)(p13;q12) that results in the formation of a fusion gene involving EWS and WNT genes

Question 13

What oncoprotein is overexpressed in 33-67% of gallbladder adenocarcinomas?

Answer 13

ERBB2 (Her-2/neu)

Question 14

Majority of GISTs have oncogenic, gain-of-function mutations in what?

Although not as common, what is another mutation associated with GISTs that is overrepresented in the stomach?

Answer 14

• Receptor tyrosine kinase: KIT = majority

- PDGFRA overrepresented in the stomach

Question 15

Genetic mutations causing a loss of what are associated with an increased risk of GIST and paraganglioma (Carney-Stratakis syndrome)?

Answer 15

SDH function (components of mitochondrial succinate dehydrogenase complex)

Question 16

Sporadic intestinal-type gastric cancers are strongly associated w/ mutations that result in increased signaling of which pathway?

Which loss of function and gain of function mutations seen in this type of cancer can lead to increased signaling via this pathway?

Answer 16

• WNT pathway
• G.O.F in gene encoding β-catenin
• L.O.F. or silencing of APC, TGFβ​, BAX, or CDKN2A

Question 17

Loss of which protein is a key step in the development of diffuse gastric cancer?

Answer 17

E-cadherin

Question 18

Which proteins are increased with the t(14;18) and t(1;14) translocations associated w/ gastric MALToma?

Answer 18

• t(14;18) –> MALT1

- t(1;14) –> BCL-10

Question 19

What does the t(11;18) translocation bring together in the development of gastric MALToma (i.e., fusion product)?

Answer 19

Joins API2 gene on cr. 11 w/ the MLT gene on cr. 18

*API2-MLT fusion

MMMMM APPLE MELT SANDWICHES

Question 20

Individuals with what gene mutation related to breast cancer are at an increased risk for developing diffuse gastric cancer?

Answer 20

BRCA2

Question 21

Familial gastric cancer is strongly associated with what genetic mutation?

This gene encodes what?

Answer 21

• Germline loss-of-function mutations in CDH1

- Encodes E-cadherin

Question 22

Which polymorphisms associated with epithelial barrier defects have been implicated in ulcerative colitis?

Answer 22

• ECM1 protein polymorphism —> typically inhibits MM9

- HNFA transcription factor polymorphisms

Question 23

What are the most common mutated genes/pathways in Juvenile Polyposis?

Answer 23

Which gene mutation is most common?

• SMAD4 = most common mutation!
• BMPR1A
• TGF-β signaling pathway

Question 24

Syndromic Juvenile Polyps have which inheritance pattern?

Answer 24

Autosomal Dominant

Question 25

What are some of the recognized extraintestinal manifestations of juvenile polyps?

Answer 25

• Pulmonary arteriovenois malformations
• Digital clubbing
• Congenital malformation (i.e., polydactyly)

Question 26

Which gene mutation/pathways is most often present in patients w/ Peutz-Jeghers Syndrome?

Answer 26

• Loss-of-function (both alleles) of STK11 (tumor suppressor)
• Causes loss of AMP kinase-related pathways regulating cell polarization and acting as a brake on growth/anabolic metabolism

Question 27

Some FAP patients without APC loss may have bi-allelic mutations of which gene and the what is the function of this gene normally?

When present this disorder is called?

Answer 27

• MYH –> base-excision repair gene

- MYH-associated polyposis