Clinical consequences of molecular diagnosis in families with mismatch repair gene germline mutations.
Hereditary nonpolyposis colorectal cancer (HNPCC), clinically defined by the Amsterdam criteria, is associated with mismatch repair gene germline mutations. This study was performed to evaluate the efficiency of combined clinical and molecular diagnostics in identifying carriers of a mutated gene in families meeting criteria of the Bethesda guidelines and to examine the influence of molecular diagnosis on clinical decision-making in carriers and noncarriers. Seventy-two patients meeting criteria of the Bethesda guidelines were tested for microsatellite instabilities (MSI). MSI-H tumors were found in 38 (52.8%) index patients. Complete sequencing of hMLH1 and hMSH2 in 38 MSI-H patients and of hMSH6 in one of these patients revealed 15 pathogenic germline mutations, including three novel mutations, and three novel unclassified germline variants. Twelve of the 15 pathogenic mutations were found in patients fulfilling the Amsterdam I/II criteria. Surgical and genetic counseling was offered to the affected families; as a result of molecular diagnosis in the 15 families, 26 index patients and affected carriers and 8 asymptomatic carriers of a mutated mismatch repair gene were included in the surveillance program, and 26 noncarriers were excluded from this program. Although germline mutations are detected in only 20.8% of patients fulfilling criteria of the Bethesda guidelines, family history and MSI-H tumor classification are both strong indicators for germline mutations in hMSH2, hMLH1, and hMSH6 genes, resulting in a 51.9% mutation detection rate. Identification of individual mutation status allows clear-cut decisions on whether or not inclusion in surveillance programs is indicated.
Pistorius
S R
SR
Department of Visceral, Thoracic and Vascular Surgery, Technical University of Dresden, Fetscherstrasse 74, 01307 Dresden, Germany. spisto2522@aol.com
Kruppa
C
C
Haas
S
S
Plaschke
J
J
Kruger
S
S
Bulitta
C J
CJ
Nagel
M
M
Saeger
H D
HD
Schackert
H K
HK
D048868:Adaptor Proteins, Signal Transducing; D000293:Adolescent; D000328:Adult; D002352:Carrier Proteins; D002648:Child; D015179:Colorectal Neoplasms / Q000175:diagnosis / Q000235:genetics / Q000473:pathology; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000175:diagnosis / Q000235:genetics / Q000473:pathology; D004268:DNA-Binding Proteins / Q000235:genetics*; D005091:Exons; D005192:Family Health; D005260:Female; D005820:Genetic Testing; D018095:Germ-Line Mutation; D006579:Heterozygote; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics*; D009687:Nuclear Proteins; D016133:Polymerase Chain Reaction; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D019680:Trinucleotide Repeat Expansion
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; C501486:MLH1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein