Hereditary nonpolyposis colon cancer: Revised Bethesda criteria, immunohistochemistry, microsatellite instability, germline analysis, and emerging issues in genetic testing

Abstract

Clinical criteria aid in the decision to pursue genetic testing for suspected cases of hereditary nonpolyposis colon cancer (HNPCC) and continue to be refined. Sequence analysis offers the greatest opportunity for definitive germline mutation testing; however, prescreening through microsatellite instability and/or immunohistochemistry offers a cost effective alternative, and recent studies suggest both are complementary. BRAF mutations and hMLH1 promoter methylation appear to have negative predictive value for identifying individuals with HNPCC, but further studies are needed. We review strategies for the evaluation of suspected HNPCC, as well as emerging issues in testing.

Sebaceous lesions and their associated syndromes: Part II

“…123 However, IHC cannot differentiate between loss of MLH1 expression caused by a germline mutation versus somatic hypermethylation. 78 Also, some germline missense mutations may be erroneously interpreted as normal by IHC, because they may result in an antigenically intact but nonfunctional protein. 78,124,125 The advantage of MSI is that some studies have shown it to be somewhat more sensitive at detecting patients with germline MMR defects than IHC.…”

“…78 Also, some germline missense mutations may be erroneously interpreted as normal by IHC, because they may result in an antigenically intact but nonfunctional protein. 78,124,125 The advantage of MSI is that some studies have shown it to be somewhat more sensitive at detecting patients with germline MMR defects than IHC. 121,122,[126][127][128][129][130][131][132] Vasen et al 123 found in their review of prospective studies looking at the sensitivity of MSI versus IHC that MSI was indeed more sensitive than IHC (98% vs 94%, respectively).…”

“…121,122,[126][127][128][129][130][131][132] Still other authors advocate using both MSI and IHC to screen tumors in patients with a concerning family history. 78 For patients with defects in MLH1 as detected by IHC, analysis of methylation of the promoter region of MLH1 should be considered before germline testing. Hypermethylation of this region can lead to a loss of MLH1 function.…”

“…Mutations in this gene are highly associated with somatic mutations of MLH1. 78,[136][137][138][139] BRAF is a gene from the Raf family of Ras-regulated kinases. BRAF mutations have been reported in a variety of sporadic tumors, such as melanomas, colorectal cancers, ovarian tumors, and Barrett adenocarcinoma.…”

“…BRAF mutations have been reported in a variety of sporadic tumors, such as melanomas, colorectal cancers, ovarian tumors, and Barrett adenocarcinoma. 78,136,140 Some authors suggest that larger studies need to be performed on the use of BRAF clinically despite the fact that it is already commercially available. 78 Both tests are performed on tissue extracted from the patient's tumor.…”