Expression of DNA mismatch repair proteins and MSH2 polymorphisms in nonmelanoma skin cancers of organ transplant recipients.
BACKGROUND
Organ transplant recipients (OTRs) have an increased risk of skin cancer. Treatment with azathioprine, commonly used in post-transplant immunosuppressive regimens, results in incorporation of 6-thioguanine (6-TG) into DNA. Mismatch repair (MMR)-defective cells are resistant to killing by 6-TG. Azathioprine exposure confers a survival advantage on MMR-defective cells, which are hypermutable and may therefore contribute to azathioprine-related nonmelanoma skin cancer, a phenomenon we have previously demonstrated in transplant-associated sebaceous carcinomas. The MSH2 protein is an important component of DNA MMR. The -6 exon 13 T>C MSH2 polymorphism is associated with impaired MMR, drug resistance and certain cancers.


OBJECTIVE
To investigate (i) whether loss of MMR protein expression and microsatellite instability are over-represented in squamous cell carcinomas (SCCs) from OTRs on azathioprine compared with SCCs from immunocompetent patients, and (ii) whether the MSH2 -6 exon 13 polymorphism is over-represented in OTRs with skin cancer on azathioprine.


METHODS
(i) Immunohistochemical staining was used to assess expression of the MMR proteins MSH2 and MLH1 in cutaneous SCCs from OTRs on azathioprine and from immunocompetent patients. (ii) Blood samples from OTRs on azathioprine with and without skin cancer were genotyped for the -6 exon 13 MSH2 polymorphism.


RESULTS
(i) MSH2 and MLH1 protein expression was not altered in SCCs from OTRs on azathioprine and there was no difference in expression between SCCs from OTRs and immunocompetent patients. (ii) There was no association between MSH2 polymorphism genotype frequency and OTR skin cancer status.


CONCLUSIONS
Despite previous findings in transplant-associated sebaceous carcinomas, defective MMR and the -6 exon 13 MSH2 polymorphism are unlikely to play a significant role in the development of SCC in OTRs on azathioprine.
Perrett
C M
CM
Centre for Cutaneous Research and Department of Dermatology, Institute of Cell and Molecular Science, Barts and The London School of Medicine and Dentistry, Queen Mary, University of London, 4 Newark Street, London E1 2AT, U.K. conalperrett@hotmail.com
Harwood
C A
CA
McGregor
J M
JM
Warwick
J
J
Cerio
R
R
Karran
P
P
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D001379:Azathioprine / Q000627:therapeutic use; D020137:Base Pair Mismatch / Q000235:genetics; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000378:metabolism; D053843:DNA Mismatch Repair / Q000235:genetics*; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D016377:Organ Transplantation / Q000009:adverse effects*; D011110:Polymorphism, Genetic / Q000235:genetics; D012878:Skin Neoplasms / Q000235:genetics* / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D014408:Biomarkers, Tumor; D007166:Immunosuppressive Agents; C501486:MLH1 protein, human; D009687:Nuclear Proteins; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D001379:Azathioprine