MHC Class II alleles in ulcerative colitis-associated colorectal cancer.
OBJECTIVE
Patients with ulcerative colitis are at risk for colorectal cancer (CRC). Although prior studies have shown a link between HLA genotypes and ulcerative colitis (UC) susceptibility, none have investigated HLA genotypes and UC-CRC. We therefore investigated HLA-DR/DQ alleles in UC-CRC cases and UC-controls. Furthermore, since methylation of the Class II transactivator (CIITA) gene may silence HLA expression in tumours, we correlated HLA allele frequencies with CIITA gene methylation and HLA-DR expression.


METHODS
Cases and controls were matched for duration/extent of ulcerative colitis, age, ethnicity and gender, but not for primary sclerosing cholangitis (PSC). DNA was extracted from archived tissue blocks from 114 UC-CRC cases and 114 UC-controls. HLA-DR/DQ genotyping was performed using sequence-specific-oligonucleotide polymerase chain reaction (SSO-PCR). CIITA methylation was determined using methylation-specific PCR. HLA-DR immunohistochemistry was done following standard protocols.


RESULTS
UC-CRC cases were more likely than UC-controls to carry the DR17 or DR13 alleles (p<0.0001 or p = 0.02, respectively). Although CIITA methylation did not vary significantly between cases and controls, DR17 and DQ2 were associated with CIITA methylation (p = 0.04 and 0.02, respectively). UC-controls more frequently carried the DR7, DR1 or DQ5 alleles (p = 0.002, 0.05 or 0.01, respectively). After adjusting for PSC, DR17 remained significantly associated with an increased risk for UC-CRC while DR7 and DQ5 remained protective.


CONCLUSIONS
We report a significant association between specific HLA alleles and either the risk for (DR17) or protection from (DR7, DQ5) UC-CRC. This suggests a possible genetic predisposition for increased UC-CRC risk. In addition, DQ2 and DR17 were associated with CIITA methylation.
Garrity-Park
M M
MM
Division of Experimental Pathology and Medicine, Mayo Clinic College of Medicine, Rochester, MN 55905, USA. garrity.megan@mayo.edu
Loftus
E V
EV
Sandborn
W J
WJ
Bryant
S C
SC
Smyrk
T C
TC
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D003093:Colitis, Ulcerative / Q000150:complications / Q000235:genetics* / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000150:complications / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005787:Gene Frequency; D005802:Genes, MHC Class II; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006683:HLA-DQ Antigens / Q000235:genetics; D006684:HLA-DR Antigens / Q000235:genetics; D015798:HLA-DR1 Antigen / Q000235:genetics; D015809:HLA-DR7 Antigen / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D016015:Logistic Models; D008297:Male; D008745:Methylation; D008875:Middle Aged; D009687:Nuclear Proteins / Q000378:metabolism; D016133:Polymerase Chain Reaction / Q000379:methods; D012306:Risk; D015534:Trans-Activators / Q000378:metabolism
D006683:HLA-DQ Antigens; C410042:HLA-DQ5 antigen; D006684:HLA-DR Antigens; D015798:HLA-DR1 Antigen; D015809:HLA-DR7 Antigen; C083728:MHC class II transactivator protein; D009687:Nuclear Proteins; D015534:Trans-Activators