Correlation between germline mutations in MMR genes and microsatellite instability in ovarian cancer specimens.
A high proportion of ovarian cancers from women who carry germline mutations in mismatch repair (MMR) genes demonstrate microsatellite instability (MSI). The utility of pre-screening ovarian cancer specimens for MSI to identify potential patients for germline screening for MMR mutations is uncertain. 656 women with malignant ovarian cancer underwent both MSI testing and germline mutation testing for large rearrangements in three MMR genes, MLH1, MSH2 and MSH6. Germline DNA sequencing data for the same genes was available. Among the 656 women, only four (0.6%) carried a clearly pathogenic MMR mutation. All four cancers from patients with mutations had loss of two or more microsatellite markers (MSI-high). Eighty-four of 652 (13.0%) women without a mutation had MSI-high ovarian cancers. Using MSI-high as a prescreening criterion, the sensitivity of MSI testing to identify germline MMR gene mutations was 100% and the positive predictive value was 4.5%. Germline mutations in MLH1, MSH2 and MSH6 are rare among unselected cases of ovarian cancer. Patients with germline mutations often will have MSI-positive cancers and pre-screening of ovarian cancer specimens may be an efficient way of identifying patients with Lynch syndrome.
Women's College Research Institute, Women's College Hospital, University of Toronto, 790 Bay Street, 7th Floor, Toronto, ON, M5G 1N8, Canada.
Mohammad R
MR
Akbari
Women's College Research Institute, Women's College Hospital, University of Toronto, 790 Bay Street, 7th Floor, Toronto, ON, M5G 1N8, Canada.
Shiyu
S
Zhang
Departments of Cancer Epidemiology, Moffitt Cancer Center, Biostatistics, Anatomic Pathology, and Experimental Therapeutics, 12902 Magnolia Drive, Tampa, FL, 33612, USA.
Deborah
D
Cragun
Departments of Cancer Epidemiology, Moffitt Cancer Center, Biostatistics, Anatomic Pathology, and Experimental Therapeutics, 12902 Magnolia Drive, Tampa, FL, 33612, USA.
Ji-Hyun
JH
Lee
Departments of Cancer Epidemiology, Moffitt Cancer Center, Biostatistics, Anatomic Pathology, and Experimental Therapeutics, 12902 Magnolia Drive, Tampa, FL, 33612, USA.
Domenico
D
Coppola
Samuel Lunenfeld Research Institute, and Dalla Lana School of Public Health, University of Toronto, 600 University Avenue, Toronto, ON, M5G 1X5, Canada.
John
J
McLaughlin
Department of Chronic Disease Epidemiology, Yale School of Public Health, 60 College St., New Haven, CT, 06510, USA.
Harvey A
HA
Risch
Department of Gynecology-Oncology, Princess Margaret Hospital, University of Toronto, 610 University Avenue, Toronto, ON, M5T 2M9, Canada.|Department of Obstetrics and Gynecology, Faculty of Medicine, University of Toronto, 610 University Avenue, Toronto, ON, M5T 2M9, Canada.
Barry
B
Rosen
Department of Pathology, Princess Margaret Hospital, 610 University Avenue, Toronto, ON, M5T 2M9, Canada.
Patricia
P
Shaw
Departments of Cancer Epidemiology, Moffitt Cancer Center, Biostatistics, Anatomic Pathology, and Experimental Therapeutics, 12902 Magnolia Drive, Tampa, FL, 33612, USA.
Thomas A
TA
Sellers
Department of Community and Family Medicine, Duke Comprehensive Cancer Center, Duke University Medical Center, Box 2949, Durham, NC, 27710, USA.
Joellen
J
Schildkraut
Women's College Research Institute, Women's College Hospital, University of Toronto, 790 Bay Street, 7th Floor, Toronto, ON, M5G 1N8, Canada. steven.narod@wchospital.ca.
Steven A
SA
Narod
Departments of Cancer Epidemiology, Moffitt Cancer Center, Biostatistics, Anatomic Pathology, and Experimental Therapeutics, 12902 Magnolia Drive, Tampa, FL, 33612, USA.
Tuya
T
Pal
D014408:Biomarkers, Tumor / Q000235:genetics*; D000077216:Carcinoma, Ovarian Epithelial; D053843:DNA Mismatch Repair / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D018095:Germ-Line Mutation; D006801:Humans; D053842:Microsatellite Instability; D008875:Middle Aged; D000070957:MutL Protein Homolog 1 / Q000235:genetics*; D051718:MutS Homolog 2 Protein / Q000235:genetics*; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000235:genetics*; D012680:Sensitivity and Specificity
D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; C501486:MLH1 protein, human; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein
Microsatellite Instability; Ovarian cancer