title: DNA mismatch repair deficiency in breast carcinoma: a pilot study of triple-negative and non-triple-negative tumors.
abstract: Recent studies have suggested that breast cancer is part of the tumor spectrum in Lynch syndrome (LS). However, the frequency and significance of DNA mismatch repair (MMR) deficiency in breast carcinoma in general is unclear. Some triple-negative breast carcinomas (TNBCs) have morphologic features similar to those described in LS-associated colorectal carcinomas; therefore, we hypothesized that TNBCs might be more likely to have MMR deficiency. In this study, we tested our hypothesis in a series of 226 TNBCs along with a control series of 90 non-triple-negative tumors, utilizing DNA MMR protein immunohistochemistry followed by PCR microsatellite instability testing and MLH1 promoter methylation testing. By immunohistochemistry, we identified 4 triple-negative carcinomas (4/226, 1.8%) showing loss of MMR proteins (3 lost MLH1 and PMS2, and 1 lost MSH2 and MSH6); whereas none of the 90 non-triple-negative carcinomas showed loss of protein. Further testing of the 3 MLH1/PMS2 protein-deficient carcinomas identified 1 tumor showing high-frequency microsatellite instability and MLH1 promoter hypermethylation. All 4 MMR protein-deficient carcinomas were ductal type with high histologic and nuclear grades. Prominent lymphocytic infiltration was noted in 2 tumors. The clinical characteristics and survival outcome varied widely among the 4 patients. In conclusion, our results suggest that DNA MMR deficiency is rare in breast carcinoma, and as such, testing of breast carcinoma for the detection of LS may best be restricted to high-risk individuals only. Our data also suggest that not all MMR protein-deficient breast tumors show microsatellite instability, and MLH1 promoter methylation is the molecular basis for at least a subset of microsatellite instable breast tumors. Although MMR-deficient breast carcinomas share certain morphologic features with the more typical types of LS-associated tumors, better characterization, and a better understanding of their clinical behavior await further analysis with a larger sample size.
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Yong H
authors.initials: YH
authors.lastname: Wen
authors.forename: Edi
authors.initials: E
authors.lastname: Brogi
authors.forename: Zhaoshi
authors.initials: Z
authors.lastname: Zeng
authors.forename: Muzaffar
authors.initials: M
authors.lastname: Akram
authors.forename: Jeff
authors.initials: J
authors.lastname: Catalano
authors.forename: Philip B
authors.initials: PB
authors.lastname: Paty
authors.forename: Larry
authors.initials: L
authors.lastname: Norton
authors.forename: Jinru
authors.initials: J
authors.lastname: Shia
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism; D000251:Adenosine Triphosphatases / Q000378:metabolism; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D019175:DNA Methylation; D053843:DNA Mismatch Repair / Q000235:genetics*; D045643:DNA Repair Enzymes / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D005260:Female; D006801:Humans; D053842:Microsatellite Instability; D008875:Middle Aged; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010865:Pilot Projects; D011401:Promoter Regions, Genetic; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000378:metabolism*; D011980:Receptors, Progesterone / Q000378:metabolism*; D046888:Tissue Array Analysis
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000251:Adenosine Triphosphatases; D014408:Biomarkers, Tumor; D045643:DNA Repair Enzymes; D004268:DNA-Binding Proteins; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D009687:Nuclear Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; C501486:MLH1 protein, human; C094934:PMS2 protein, human