title: Microsatellite instability in hereditary and sporadic breast cancers.
abstract: Sporadic cancers and familial breast cancers are characterized by an increase in genetic instability. Little is known about whether mismatch repair defects accompany this genetic instability. We investigated invasive and/or in situ breast cancers from 30 women with deleterious BRCA1/2 mutations and unclassified variant BRCA1/2 alterations. Forty cases of sporadic breast cancers were also investigated, including 7 medullary carcinomas. Malignant and benign lesions were examined from all cases to better understand tumor progression. Automated immunohistochemistry, with antibodies directed against hMLH1 and hMSH2, was used to screen cases for possible mismatch repair defects. When loss of expression was noted, DNA ploidy was performed by cytomorphometry. DNA, after laser microdissection, was extracted from a majority of familial cases and their corresponding controls, and microsatellite instability analysis was performed. None of the familial or sporadic cases had loss of hMSH2 expression. All but one lesion, a DCIS arising in a deleterious BRCA2 mutation carrier, had loss of hMLH1 expression and a tetraploid profile by image cytomorphometry. There was no MSI in any explored lesions (n = 34), as determined by molecular analysis, including the DCIS with loss of hMLH1 expression. We conclude that DNA mismatch repair defects involving hMLH1 and hMSH2 underexpression are extremely rare events in sporadic and familial breast cancer. Mismatch repair gene mutations may be secondary random events in breast cancer progression.
authors.affiliation: 1Division of Laboratory Genetics, Mayo Clinic and Mayo Foundation, Rochester, MN, USA. camilo.adem@psl.ap-hop-paris.fr
authors.forename: Camilo
authors.initials: C
authors.lastname: Adem
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Soderberg
authors.forename: Julie M
authors.initials: JM
authors.lastname: Cunningham
authors.forename: Carol
authors.initials: C
authors.lastname: Reynolds
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Sebo
authors.forename: Stephen N
authors.initials: SN
authors.lastname: Thibodeau
authors.forename: Lynn C
authors.initials: LC
authors.lastname: Hartmann
authors.forename: Robert B
authors.initials: RB
authors.lastname: Jenkins
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D020137:Base Pair Mismatch; D001943:Breast Neoplasms / Q000235:genetics*; D002285:Carcinoma, Intraductal, Noninfiltrating / Q000235:genetics; D002352:Carrier Proteins; D016022:Case-Control Studies; D004247:DNA / Q000235:genetics; D019175:DNA Methylation; D004260:DNA Repair / Q000235:genetics*; D004268:DNA-Binding Proteins; D005260:Female; D024522:Genes, BRCA2 / Q000502:physiology; D006801:Humans; D007124:Immunoenzyme Techniques; D008207:Lymphatic Metastasis / Q000235:genetics; D018895:Microsatellite Repeats; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D009154:Mutation; D009361:Neoplasm Invasiveness / Q000235:genetics; D009363:Neoplasm Proteins / Q000235:genetics; D009687:Nuclear Proteins; D011003:Ploidies; D011518:Proto-Oncogene Proteins / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C501486:MLH1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D004247:DNA; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein