The role of defective mismatch repair in small bowel adenocarcinoma in celiac disease.
Celiac disease is associated with an increased risk of small bowel adenocarcinoma. The aims of this study were to investigate the molecular basis, assess outcomes, and identify clinicopathologic characteristics of small bowel adenocarcinoma in celiac disease. Retrospective case control cohort study of all celiac disease patients treated at our institution for small bowel adenocarcinoma and matched control patients with sporadic small bowel adenocarcinoma from July 1960 to November 2002. Mismatch repair (MMR) status was accessed by testing tissue for microsatellite instability (MSI) and for hMLH1 and hMSH2 protein expression. Over a 40-year time period, 18 patients with small bowel adenocarcinoma and celiac disease were treated at the Mayo Clinic. One celiac disease patient was excluded. High-frequency MSI (MSI-H) was identified in 8 of 11 (73%) and 2 of 22 (9%) available small bowel adenocarcinoma specimens in the celiac disease and control groups, respectively. In the celiac disease group, MSI-H was associated with loss of hMLH1 and hMSH2 in 6 and 1 specimens, respectively. Loss of hMLH1 occurred in both control tumors. Stage was associated with celiac disease status (P = 0.018), and 78% of controls were stage III or IV compared with 47% of celiac disease patients. Overall, survival was better (P = 0.025) in the celiac disease group compared with stage-matched controls. Celiac disease patients with small bowel adenocarcinoma had a high incidence defective MMR (73%) compared with controls and had better survival compared with stage-matched controls. In addition, celiac disease patients presented more frequently with early-stage small bowel adenocarcinoma. The better survival and earlier presentation of small bowel adenocarcinoma in celiac disease appears to be biologically associated with defective MMR.
Potter
D Dean
DD
Division of Gastroenterologic and General Surgery, Mayo Clinic and Mayo Foundation, Rochester, Minnesota 55905, USA.
Murray
Joseph A
JA
Donohue
John H
JH
Burgart
Lawrence J
LJ
Nagorney
David M
DM
van Heerden
Jon A
JA
Plevak
Matthew F
MF
Zinsmeister
Alan R
AR
Thibodeau
Stephen N
SN
D048868:Adaptor Proteins, Signal Transducing; D000230:Adenocarcinoma / Q000150:complications / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020137:Base Pair Mismatch; D002352:Carrier Proteins; D002446:Celiac Disease / Q000150:complications* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004260:DNA Repair / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D006801:Humans; D007414:Intestinal Neoplasms / Q000150:complications / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics; D015996:Survival Rate
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; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein