Frequent genomic alterations in epithelium measured by microsatellite instability following allogeneic hematopoietic cell transplantation in humans.
Although typically found in cancers, frameshift mutations in microsatellites have also been detected in chronically inflamed tissues. Allogeneic hematopoietic cell transplantation (HCT) may potentially produce chronic tissue stress through graft-versus-host reactions. We examined non-neoplastic epithelial tissues (colon, buccal) obtained 1 to 5061 days after human allogeneic HCT for the presence of genomic alterations at 3 tetranucleotide and 3 mononucleotide microsatellite loci. Novel bands indicative of microsatellite instability (MSI) at tetranucleotide repeats were detected in laser-microdissected colonic crypts and in buccal smears of 75% and 42% of patients who received an allograft, respectively. In contrast, no MSI was found in similar tissues from control subjects and from patients after intensive chemotherapy or in buccal cells from patients after autologous HCT. The MSI found in colon, which was often affected by graft-versus-host disease, was not due to loss of expression or nitrosylation of DNA repair proteins. MSI in clinically intact oral mucosa was more frequently found at later time points after HCT. MSI was also found in 3 posttransplant squamous cell cancers examined. Our data show that genomic alterations in epithelium regularly occur after allogeneic HCT and may be implicated in the evolution of posttransplantation diseases, including secondary cancer.
Faber
Philipp
P
Department of Hematology/Oncology, Albert Ludwigs University, Freiburg, Germany.
Fisch
Paul
P
Waterhouse
Miguel
M
Schmitt-Gräff
Annette
A
Bertz
Hartmut
H
Finke
Jürgen
J
Spyridonidis
Alexandros
A
D000328:Adult; D000368:Aged; D002610:Cheek / Q000473:pathology; D003106:Colon / Q000473:pathology; D004260:DNA Repair / Q000235:genetics; D004848:Epithelium / Q000473:pathology; D005260:Female; D042822:Genomic Instability / Q000235:genetics*; D006086:Graft vs Host Disease / Q000235:genetics / Q000473:pathology; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000473:pathology / Q000628:therapy; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D011499:Protein Processing, Post-Translational / Q000235:genetics; D014184:Transplantation, Homologous; D018911:Trinucleotide Repeats / Q000235:genetics*