title: Impact of "Killer Immunoglobulin-Like Receptor /Ligand" Genotypes on Outcome following Surgery among Patients with Colorectal Cancer: Activating KIRs Are Associated with Long-Term Disease Free Survival.
abstract: Approximately 30% of patients with stage II/III colorectal cancer develop recurrence following surgery. How individual regulation of host mediated anti-tumor cytotoxicity is modified by the killer-cell immunoglobulin-like receptor (KIRs) genotype is essential for prediction of outcome. We analyzed the frequency of KIR and KIR ligand Human Leukocyte Antigen Class I genotypes, and their effects on recurrence and disease-free survival (DFS). Out of randomly selected 87 colorectal cancer patients who underwent R0 resection operations between 2005 and 2008, 29 patients whose cancers progressed within a median five-year follow-up period were compared with 58 patients with no recurrence within the same time period. Recurrent cases shared similar tumor stages with non-recurrent cases, but had different localizations. We used DNA isolated from pathological archival lymphoid and tumor tissues for KIR and KIR ligand (HLA-C, group C1, group C2, and HLA-A-Bw4) genotyping. Among cases with recurrence, KIR2DL1 (inhibitory KIR) and A-Bw4 (ligand for inhibitory KIR3DL1) were observed more frequently (p=0.017 and p=0.024); and KIR2DS2 and KIR2DS3 (both activating KIRs) were observed less frequently (p=0.005 and p=0.043). Similarly, in the non-recurrent group, inhibitory KIR-ligand combinations 2DL1-C2 and 2DL3-C1 were less frequent, while the activating combination 2DS2-C1 was more frequent. The lack of KIR2DL1, 2DL1-C2, and 2DL3-C1 improved disease-free survival (DFS) (100% vs. 62.3%, p=0.05; 93.8% vs. 60.0%, p=0.035; 73.6% vs. 55.9%, p=0.07). The presence of KIR2DS2, 2DS3, and 2DS2-C1 improved DFS (77.8% vs. 48.5%, p=0.01; 79.4% vs. 58.5%, p=0.003; 76.9% vs. 51.4%, p=0.023). KIR2DS3 reduced the risk of recurrence (HR=0.263, 95% CI = 0.080-0.863, p=0.028). The number of activating KIRs are correlated strongly with DFS, none/ one/ two KIR : 54/77/98 months (p=0.004). In conclusion the inheritance of increasing numbers of activating KIRs and lack of inhibitory KIRs, independent of tumor localization or stage, is associated with long-term DFS.
authors.affiliation: Department of General Surgery, Hacettepe University, Ankara, Turkey.
authors.forename: Kemal
authors.initials: K
authors.lastname: Beksac
authors.affiliation: Department of Hematology, Ankara University, Ankara, Turkey.
authors.forename: Meral
authors.initials: M
authors.lastname: Beksac
authors.affiliation: Department of Hematology, Ankara University, Ankara, Turkey.
authors.forename: Klara
authors.initials: K
authors.lastname: Dalva
authors.affiliation: Department of Biostatistics, Hacettepe University, Ankara, Turkey.
authors.forename: Ergun
authors.initials: E
authors.lastname: Karaagaoglu
authors.affiliation: Department of General Surgery, Hacettepe University, Ankara, Turkey.
authors.forename: M Bulent
authors.initials: MB
authors.lastname: Tirnaksiz
mesh_terms: D000368:Aged; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000601:surgery; D018572:Disease-Free Survival; D005260:Female; D005500:Follow-Up Studies; D015972:Gene Expression Regulation, Neoplastic; D005838:Genotype; D015235:HLA-B Antigens / Q000235:genetics / Q000378:metabolism; D015236:HLA-C Antigens / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000601:surgery; D009367:Neoplasm Staging; D011379:Prognosis; D054340:Receptors, KIR / Q000235:genetics / Q000378:metabolism; D054342:Receptors, KIR2DL1 / Q000235:genetics / Q000378:metabolism; D054341:Receptors, KIR3DL1 / Q000235:genetics / Q000378:metabolism; D012189:Retrospective Studies; D016896:Treatment Outcome
chemical_list: D015235:HLA-B Antigens; C042388:HLA-Bw4 antigen; D015236:HLA-C Antigens; C093100:KIR2DL1 protein, human; C433932:KIR2DS2 protein, human; C541358:KIR2DS3 protein, human; C515083:KIR3DL1 protein, human; D054340:Receptors, KIR; D054342:Receptors, KIR2DL1; D054341:Receptors, KIR3DL1