title: Risk of secondary malignancy (including breast) in patients with mismatch-repair protein deficiency.
abstract: Lynch syndrome (LS) is an autosomal dominant inherited disease that is associated with an increased risk for colorectal and endometrial cancer due to germline mutations in mismatch-repair (MMR) genes. Whereas primary tumors in this syndrome are widely recognized, the relative risk(s) of secondary malignancies, particularly breast cancer, in LS patients are still poorly characterized. To provide an improved assessment of these risks, MMR status was evaluated in secondary tumors from a series of patients with index tumors of known MMR status (both proficient and deficient). A total of 1252 tumors (index tumors) and all secondary malignancies were tested for MMR by immunohistochemistry (MSH2, MSH6, MLH1, PMS2) between 1992 and 2013. Tumors with MLH1/PMS2 deficiency were tested for hypermethylation or BRAF mutation, when appropriate. Of the 1252 index tumors, 162 were MMR deficient (dMMR), and, of that subset, 32 secondary tumors were identified (19.7%). In contrast, 80 secondary tumors were identified in the proficient (intact) group (7.3%). Although secondary malignancies were more common in the dMMR group (P=0.0001), there was no trend in tumor type. Specifically, breast cancer was not overly represented in the dMMR group. When secondary tumors had dMMR, they were more likely to have deficiency in MSH2/MSH6 than in MLH1/PMS2 (P=0.01). Of the patients with tumors exhibiting dMMR, women were more likely to have a dMMR secondary tumor in this series (P=0.0001); however, breast cancer was not overly represented, and our study provides no evidence that it is more frequent in LS. MSH2/MSH6 deficiency is more commonly associated with a secondary tumor compared with MLH1/PMS2 deficiency, when methylation/BRAF status is taken into account.
authors.affiliation: Department of Pathology, Stanford Hospital and Clinics, Stanford, CA.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Clay
authors.forename: Kimberly H
authors.initials: KH
authors.lastname: Allison
authors.forename: Ann K
authors.initials: AK
authors.lastname: Folkins
authors.forename: Teri A
authors.initials: TA
authors.lastname: Longacre
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency; D000251:Adenosine Triphosphatases / Q000172:deficiency; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000172:deficiency* / Q000235:genetics; D001943:Breast Neoplasms / Q000737:chemistry* / Q000235:genetics / Q000473:pathology; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000737:chemistry* / Q000235:genetics / Q000473:pathology; D019175:DNA Methylation; D053843:DNA Mismatch Repair / Q000235:genetics; D004252:DNA Mutational Analysis; D045643:DNA Repair Enzymes / Q000172:deficiency; D004268:DNA-Binding Proteins / Q000172:deficiency; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000172:deficiency; D009154:Mutation; D016609:Neoplasms, Second Primary; D009687:Nuclear Proteins / Q000172:deficiency; D011446:Prospective Studies; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D012189:Retrospective Studies; D012307:Risk Factors; D055815:Young Adult
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; C501486:MLH1 protein, human; D009687:Nuclear Proteins; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D000251:Adenosine Triphosphatases; C094934:PMS2 protein, human; C497172:MSH2 protein, human; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D045643:DNA Repair Enzymes