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Eight novel MSH6 germline mutations in patients with familial and nonfamilial colorectal cancer selected by loss of protein expression in tumor tissue.
Hum Mutat. 2004 Mar; 23(3):285.HM

Abstract

Germline mutations in mismatch repair (MMR) genes, predominantly in MLH1 and MSH2, are responsible for hereditary nonpolyposis colorectal cancer (HNPCC), a cancer-susceptibility syndrome with high penetrance. In addition, MSH6 mutations have been reported to account for about 10% of all germline mismatch repair (MMR) gene mutations in HNPCC patients, and have been associated with a later age of onset of the disease compared to MLH1 and MSH2 mutations. Here, we report eight novel germline mutations in MSH6. The patients were selected by having developed tumors with loss of MSH6 protein expression. All tumors showed high-level microsatellite instability (MSI-H). Seven mutations resulted in premature stop codons, comprised of two nonsense mutations (c.426G>A [p.W142X], c.2105C>A [p.S702X]), two insertions (c.2611_2614dupATTA [p.I872fsX10], c.3324dupT [p.I1109fsX3]) and three deletions (c.1190_1191delAT [p.Y397fsX3], c.1632_1635delAAAA [p.E544fsX26], c.3513_3514delTA [p.1171fsX5]). In addition, an amino acid substitution of an arginine residue (c.2314C>T [p.R772W]) conserved throughout a wide variety of mutS homologs has been found in a patient not fulfilling the Bethesda criteria for HNPCC. Our results emphasize the suitability of IHC as a pre-selection tool for MSH6 mutation analysis and the high frequency of germline mutation detection in patients with MSH6-deficient tumors. In addition, our findings point towards a broad variability regarding penetrance associated with MSH6 germline mutations.

Authors+Show Affiliations

Department of Surgical Research, Dresden University of Technology, Germany. plaschke@rcs.urz.tu-dresden.deNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Multicenter Study
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

14974087

Citation

Plaschke, Jens, et al. "Eight Novel MSH6 Germline Mutations in Patients With Familial and Nonfamilial Colorectal Cancer Selected By Loss of Protein Expression in Tumor Tissue." Human Mutation, vol. 23, no. 3, 2004, p. 285.
Plaschke J, Krüger S, Dietmaier W, et al. Eight novel MSH6 germline mutations in patients with familial and nonfamilial colorectal cancer selected by loss of protein expression in tumor tissue. Hum Mutat. 2004;23(3):285.
Plaschke, J., Krüger, S., Dietmaier, W., Gebert, J., Sutter, C., Mangold, E., Pagenstecher, C., Holinski-Feder, E., Schulmann, K., Möslein, G., Rüschoff, J., Engel, C., Evans, G., & Schackert, H. K. (2004). Eight novel MSH6 germline mutations in patients with familial and nonfamilial colorectal cancer selected by loss of protein expression in tumor tissue. Human Mutation, 23(3), 285.
Plaschke J, et al. Eight Novel MSH6 Germline Mutations in Patients With Familial and Nonfamilial Colorectal Cancer Selected By Loss of Protein Expression in Tumor Tissue. Hum Mutat. 2004;23(3):285. PubMed PMID: 14974087.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Eight novel MSH6 germline mutations in patients with familial and nonfamilial colorectal cancer selected by loss of protein expression in tumor tissue. AU - Plaschke,Jens, AU - Krüger,Stefan, AU - Dietmaier,Wolfgang, AU - Gebert,Johannes, AU - Sutter,Christian, AU - Mangold,Elisabeth, AU - Pagenstecher,Constanze, AU - Holinski-Feder,Elke, AU - Schulmann,Karsten, AU - Möslein,Gabriela, AU - Rüschoff,Josef, AU - Engel,Christoph, AU - Evans,Gareth, AU - Schackert,Hans K, AU - ,, PY - 2004/2/20/pubmed PY - 2004/3/26/medline PY - 2004/2/20/entrez SP - 285 EP - 285 JF - Human mutation JO - Hum Mutat VL - 23 IS - 3 N2 - Germline mutations in mismatch repair (MMR) genes, predominantly in MLH1 and MSH2, are responsible for hereditary nonpolyposis colorectal cancer (HNPCC), a cancer-susceptibility syndrome with high penetrance. In addition, MSH6 mutations have been reported to account for about 10% of all germline mismatch repair (MMR) gene mutations in HNPCC patients, and have been associated with a later age of onset of the disease compared to MLH1 and MSH2 mutations. Here, we report eight novel germline mutations in MSH6. The patients were selected by having developed tumors with loss of MSH6 protein expression. All tumors showed high-level microsatellite instability (MSI-H). Seven mutations resulted in premature stop codons, comprised of two nonsense mutations (c.426G>A [p.W142X], c.2105C>A [p.S702X]), two insertions (c.2611_2614dupATTA [p.I872fsX10], c.3324dupT [p.I1109fsX3]) and three deletions (c.1190_1191delAT [p.Y397fsX3], c.1632_1635delAAAA [p.E544fsX26], c.3513_3514delTA [p.1171fsX5]). In addition, an amino acid substitution of an arginine residue (c.2314C>T [p.R772W]) conserved throughout a wide variety of mutS homologs has been found in a patient not fulfilling the Bethesda criteria for HNPCC. Our results emphasize the suitability of IHC as a pre-selection tool for MSH6 mutation analysis and the high frequency of germline mutation detection in patients with MSH6-deficient tumors. In addition, our findings point towards a broad variability regarding penetrance associated with MSH6 germline mutations. SN - 1098-1004 UR - https://www.unboundmedicine.com/medline/citation/14974087/Eight_novel_MSH6_germline_mutations_in_patients_with_familial_and_nonfamilial_colorectal_cancer_selected_by_loss_of_protein_expression_in_tumor_tissue_ L2 - https://doi.org/10.1002/humu.9217 DB - PRIME DP - Unbound Medicine ER -