Microsatellite instability as a predictor of a mutation in a DNA mismatch repair gene in familial colorectal cancer

Abstract

Germline alterations in human DNA mismatch repair genes are associated with hereditary nonpolyposis colorectal cancer (HNPCC). Mutation analysis of the genes reveals carriers with a high risk of colorectal cancer, who will benefit from surveillance. We wanted to find the best predictive parameter of a germline mutation in those genes among patients with familial colorectal cancer. Affected members from a total of 83 unrelated colorectal cancer families previously analyzed for mutations in MSH2 and MLH1 were used to evaluate different parameters' ability to predict a germline mutation. We studied various clinical criteria such as family structure, age of onset, and prevalence of endometrial cancer, as well as microsatellite instability in the tumors from the families. In total, 124 tumors from 59 of the families were tested for microsatellite instability (MSI) using PCR‐based mono‐ and dinucleotide markers to establish whether the families could be scored as MSI‐positive or ‐negative. The finding of MSI‐positive tumors in a family was the best predictor of a germline mutation, and was found in 73% of the MSI‐positive, but in less than 3% of the MSI‐negative families (P < 0.0001). In contrast, MSI in unselected colorectal cancer is not as useful, since most of these MSI‐positive tumors are sporadic. The finding of microsatellite instability in colorectal tumors seems efficient enough even to select those with germline mutations among families fulfilling HNPCC Amsterdam criteria, once used in identification of the DNA mismatch repair genes. Genes Chromosomes Cancer 27:17–25, 2000. © 2000 Wiley‐Liss, Inc.

Somatic BRAF-V600E Mutations in Familial Colorectal Cancer

“…Tumors were meticulously dissected and fresh frozen, and tumor genomic DNA was isolated from tumor tissue using standard protocols. MSI test was done as described (13,14) or by using the MSI Multiplex System kit (Promega Corp., Madison, WI) according to the manufacturer's instruction. Microsatellites were separated on an ABI 310 DNA sequencer, and data were analyzed using the GeneScan 3.1 software program (PE Applied Biosystems, Foster City, CA).…”

Novel strategy for optimal sequential application of clinical criteria, immunohistochemistry and microsatellite analysis in the diagnosis of hereditary nonpolyposis colorectal cancer

“…[7][8][9][10][11] It has been shown that the presence of high-level microsatellite instabilities is a strong and extremely sensitive predictor for germline mutations in cases with early tumor onset or a positive family history. [12][13][14] This genomic instability is characterized by small deletions or insertions within simple repeat sequences in tumor DNA caused by the inability of the defective mismatch repair system to correct DNA replication errors. 15,16 Another predictive but less expensive screening method is the analysis of tumor tissue for reduction or loss of expression of mismatch repair proteins by immunohistochemical staining with monoclonal antibodies.…”

Loss of mismatch repair protein immunostaining in colorectal adenomas from patients with hereditary nonpolyposis colorectal cancer

“…3,[13][14][15][16][17][18][19] Detection of defective mismatch repair through analysis of microsatellite instability and/or loss of mismatch repair protein immunostaining in colorectal carcinomas predicts HNPCC with high sensitivity and specificity. 4,5,20 Clinically, analysis of defective mismatch repair in an HNPCC-associated adenoma is sometimes requested since this may be the only tumor tissue available and to pinpoint the gene that mutation analysis should focus on. We therefore assessed immunohistochemical expression of the mismatch repair proteins MLH1, PMS2, MSH2, and MSH6 in 35 adenomas from 26 HNPCC patients.…”