Colorectal cancer

MHC Class II alleles in ulcerative colitis-associated colorectal cancer

M M Garrity-Park¹, E V Loftus, Jr², W J Sandborn², S C Bryant³, T C Smyrk⁴

¹ Division of Experimental Pathology and Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota, USA
² Miles and Shirley Fiterman Center for Digestive Diseases, Mayo Clinic College of Medicine, Rochester, Minnesota, USA
³ Division of Biostatistics, Mayo Clinic College of Medicine, Rochester, Minnesota, USA
⁴ Division of Anatomic Pathology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA

^{Correspondence to} M M Garrity-Park, 200 First Street SW, Stabile 2-50, Rochester, MN 55905, USA; garrity.megan{at}mayo.edu

Objectives: 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.

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