Molecular Path of GI Tumors

Question 1

Describe basic epidemiology of colorectal cancer: Prevalence of new cases, deaths and lifetime risk

Answer 1

New cases per 100k: 42.4
Deaths: 15.5
Lifetime risk: 4.5%

Question 2

Describe the chromosomal instability (CIN) pathway of colorectal cancer

Answer 2

APC==>ß-catenin==>KRAS (low dysplasia adenoma)==>Loss of heterozygosity, TP53 (high grade dysplasia)==>lots of genes (carcinoma)

Question 3

What syndrome is associated with CIN pathway of colorectal cancer?

Answer 3

FAP– autosomal dominant due to mutation in APC gene leads to 100-2500 polyps throughout GI tract and virtually 100% lifetime risk of colorectal adenocarcinoma

Question 4

Describe the microsatellite instability pathway

Answer 4

Normal mucosa with BRAF mutation, CIMP==>Sessile serrated adenoma/polyp==>MLH1 methylation (mutator phenotype), a sessile serrated adenoma/poly with dysplasia===>Carcinoma

Question 5

What is microsatellite instability?

Answer 5

Simple repetitive DNA sequences (can be repeated up to 100 times) that are liable for errors during DNA replication

Question 6

What is the role of mismatch repair genes in MSI?

Answer 6

Mismatch repair genes typically identify/correct errors of duplication

Failure of mismatch repair apparatus leads to errors and alterations in length of micro satellite sequence

Question 7

Describe sporadic MSI mutations

Answer 7

Epigenetic silencing: hypermethylation of MLH1

BRAF mutations

Question 8

Describe epidemiology of sporadic MSI Colorectal carcinomas:
Prevalence
Age/sex
Mutation
Precursor

Answer 8

MSI in 10-15% of sporadic CRCs
Occur in older patients (W>M)
Loss of mismatch repair function due to silencing of MLH1
Precursor lesion: sessile serrated adenoma

Question 9

What are the germline mismatch repair mutations that occur in Lynch MSI? (4)

Answer 9

MSH2
MLH1
MSH6
PMS2

Question 10

Epi of Lynch Syndrome: Risk for cancer

Answer 10

Earlier onset CRC
Lifetime risk ~80%
Increased frequency of multiple CRC
Increased risk of extracolonic malignancies

Question 11

What are challenges to Lynch Syndrome dx? (3)

Answer 11

Polyps seen at younger age, but not as dramatic as FAP
No increase in number of polyps
Rapid progression to malignancy

Question 12

What are bethesda guidelines for detection/dx of Lynch syndrome? (4)

Answer 12

CRC before 50yo
Multiple HNPCC-related cancers
Family history of CRC before 50yo
CRC with certain histological features (i.e signet ring)

Question 13

Why test for lynch syndrome? (3)

Answer 13

Test close family members
MSI CRCs have favorable stage-adjusted prognosis
5FU chemotherapy is commonly used in CRC treatment, but it does not improve survival in MSI CRC

Question 14

What are testing methods for MSI-H CRC? (2)

Answer 14

PCR

IHC for MLH1, MSH2 (absence of brown staining indicates loss of genes)

Question 15

What is CIMP?

Which mutations are seen?

Answer 15

CpG Island methylator phenotype:
Promoter methylation leads to gene silencing of tumor suppressor genes
Mutation seen: KRAS most common, TP53 or BRAF are uncommon

Question 16

What is role of EGFR pathway in CRC?

Answer 16

Important therapeutic target: cetuximab, panitumumab

…but EGFR mutations are rare in CRC

Question 17

What testing should all pts with EGFR mutations undergo?

Answer 17

Pts with metastatic CRC with EGFR mutations should undergo KRAS testing– if KRAS mutation present then anti-EGFR mutation will not be effective
If KRAS negative then test for BRAF

Question 18

Describe GI Stromal Tumors:

Cell of origin, most common location and predominant morphology

Answer 18

GIST=90% GI mesenchymal tumors
Arise from ICC cells, most commonly in stomach
Most commonly spindle cell morphology but can be epithelioid

Question 19

Describe gross appearance of GIST (treated with imatinib)

Answer 19

Submucosal tumor

Areas of hemorrhage and necrosis

Question 20

What are molecular mutations of GIST? (2)

Answer 20

Tyrosine kinase mutations that are mutually exclusive

KIT (85%): Exon 9, 11, 13
PDGFRA (10%): exon 18

Question 21

Describe markers of response to imatinib

Answer 21

Both KIT and PDGFRA are responsive to imatininb unless there are acquired/secondary mutations that result in resistance

5-10% of GIST tumors are negative for KIT/PDGFRA– they are unresponsive to imatinib