Tissue identity testing of cancer by short tandem repeat polymorphism: pitfalls of interpretation in the presence of microsatellite instability.
Tissue identity testing by short tandem repeat (STR) polymorphism offers discriminating power in resolving tissue mix-up or contamination. However, one caveat is the presence of microsatellite unstable tumors, in which genetic alterations may drastically change the STR wild-type polymorphism leading to unexpected allelic discordance. We examined how tissue identity testing results can be altered by the presence of microsatellite instability (MSI). Eleven cases of MSI-unstable (9 intestinal and 2 endometrial adenocarcinomas) and 10 cases of MSI-stable tumors (all colorectal adenocarcinomas) were included. All had been previously tested by polymerase chain reaction testing at 5 National Cancer Institute (NCI) recommended MSI loci and/or immunohistochemistry for DNA mismatch repair proteins (MLH1, MSH2, MSH6, and PMS2). Tissue identity testing targeting 15 STR loci was performed using AmpF/STR Identifiler Amplification. Ten of 11 MSI-unstable tumors demonstrated novel alleles at 5 to 12 STR loci per case and frequently with 3 or more allelic peaks. However, all affected loci showed identifiable germline allele(s) in MSI-high tumors. A wild-type allelic profile was seen in 7 of 10 MSI-stable tumors. In the remaining 3 cases, isolated novel alleles were present at a unique single locus in addition to germline alleles. Loss of heterozygosity was observed frequently in both MSI-stable (6/11 cases) and MSI-unstable tumors (8/10 cases). In conclusion, MSI may significantly alter the wild-type allelic polymorphism, leading to potential interpretation errors of STR genotyping. Careful examination of the STR allelic pattern, high index of suspicion, and follow-up MSI testing are crucial to avoid erroneous conclusions and subsequent clinical and legal consequences.
Department of Pathology, Yale University School of Medicine, New Haven, CT 06520-8023, USA.
Melissa
M
Much
Department of Pathology, Yale University School of Medicine, New Haven, CT 06520-8023, USA.
Natalia
N
Buza
Department of Pathology, Yale University School of Medicine, New Haven, CT 06520-8023, USA. Electronic address: pei.hui@yale.edu.
Pei
P
Hui
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D053843:DNA Mismatch Repair; D045643:DNA Repair Enzymes / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D016889:Endometrial Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004938:Esophageal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D056426:Genetic Loci; D005838:Genotype; D006801:Humans; D008297:Male; D053842:Microsatellite Instability; D018895:Microsatellite Repeats; D008875:Middle Aged; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D011110:Polymorphism, Genetic
D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; C501486:MLH1 protein, human; D009687:Nuclear Proteins; 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
Cancer; Microsatellite instability; Tissue genotyping