DDSEP® 8 Quick Quiz

March 2016 Quiz 2

Publish date: March 1, 2016

A 49-year-old African American man presents to your outpatient gastroenterology clinic with a history of hematochezia for the past 5 months. To evaluate these symptoms you perform a colonoscopy that demonstrates a 5-cm cecal adenocarcinoma and one 5-mm adenoma in the transverse colon that is removed completely with snare polypectomy. He reports that his mother had three 5- to 6-mm colorectal adenomas on her only colonoscopy at age 60 years. He has no other family history of cancer or polyps in his other first- or second-degree relatives. Based on his history, you order tumor immunohistochemistry and microsatellite instability (MSI) testing. The tumor is MSI-high and demonstrates loss of MSH2 and MSH6 and intact expression of MLH1 and PMS2. No germline mutations in MSH2 or MSH6 are detected on genetic testing.

Which of the following statements is the best next step in this patient’s management?

A. Full gene sequencing for MLH1 should be performed.

B. Full gene sequencing for PMS2 should be performed.

C. No further evaluation for Lynch syndrome is indicated as this is likely a sporadic colorectal cancer.

D. Tests for MLH1 hypermethylation and BRAF testing should be performed to confirm that this is a sporadic colorectal cancer.

E. Genetic testing for an EPCAM mutation should be performed.

Q2: ANSWER: E

Critique

These results could be due to Lynch syndrome as a result of an EPCAM mutation. With hereditary nonpolyposis colorectal cancer (HNPCC), also known as Lynch syndrome, patients are at an increased risk for colorectal and several other cancers owing to inactivating germline mutations in mismatch repair genes (MMR), including MLH1, MSH2, MSH6, and PMS2. Germline EPCAM deletions in the 3’ region can cause HNPCC. The EPCAM deletions lead to methylation of the MSH2 promoter and ultimately silencing of MSH2 gene. Silencing of the MSH2 gene results in a pattern of MSH2 and MSH6 loss on immunohistochemistry. Since immunohistochemistry shows no loss of expression of MLH1 or PMS2 proteins, this indicates the absence of a mutation in MLH1 and PMS2 genes. The presence of high microsatellite instability and loss of expression of two mismatch repair proteins indicates the presence of Lynch syndrome and not a sporadic colorectal cancer. Therefore MLH1 hypermethylation and BRAF testing is not indicated.

Reference

1. Umar A., Boland C., Terdiman J.P., et al. Revised Bethesda guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst. 2004;96:261-8.

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