Molecular Path of GI Tumors Flashcards Preview

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Flashcards in Molecular Path of GI Tumors Deck (21):
1

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

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

2

Describe the chromosomal instability (CIN) pathway of colorectal cancer

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

3

What syndrome is associated with CIN pathway of colorectal cancer?

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

4

Describe the microsatellite instability pathway

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

5

What is microsatellite instability?

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

6

What is the role of mismatch repair genes in MSI?

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

7

Describe sporadic MSI mutations

Epigenetic silencing: hypermethylation of MLH1
BRAF mutations

8

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

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

9

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

MSH2
MLH1
MSH6
PMS2

10

Epi of Lynch Syndrome: Risk for cancer

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

11

What are challenges to Lynch Syndrome dx? (3)

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

12

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

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

13

Why test for lynch syndrome? (3)

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

14

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

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

15

What is CIMP?

Which mutations are seen?

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

16

What is role of EGFR pathway in CRC?

Important therapeutic target: cetuximab, panitumumab

...but EGFR mutations are rare in CRC

17

What testing should all pts with EGFR mutations undergo?

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

18

Describe GI Stromal Tumors:
Cell of origin, most common location and predominant morphology

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

19

Describe gross appearance of GIST (treated with imatinib)

Submucosal tumor
Areas of hemorrhage and necrosis

20

What are molecular mutations of GIST? (2)

Tyrosine kinase mutations that are mutually exclusive

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

21

Describe markers of response to imatinib

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